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Sample records for prevent cardiac hypertrophy

  1. Targeting the CaMKII/ERK Interaction in the Heart Prevents Cardiac Hypertrophy

    Science.gov (United States)

    Cipolletta, Ersilia; Rusciano, Maria Rosaria; Maione, Angela Serena; Santulli, Gaetano; Sorriento, Daniela; Del Giudice, Carmine; Ciccarelli, Michele; Franco, Antonietta; Crola, Catherine; Campiglia, Pietro; Sala, Marina; Gomez-Monterrey, Isabel; De Luca, Nicola; Trimarco, Bruno; Iaccarino, Guido; Illario, Maddalena

    2015-01-01

    Aims Activation of Ca2+/Calmodulin protein kinase II (CaMKII) is an important step in signaling of cardiac hypertrophy. The molecular mechanisms by which CaMKII integrates with other pathways in the heart are incompletely understood. We hypothesize that CaMKII association with extracellular regulated kinase (ERK), promotes cardiac hypertrophy through ERK nuclear localization. Methods and Results In H9C2 cardiomyoblasts, the selective CaMKII peptide inhibitor AntCaNtide, its penetratin conjugated minimal inhibitory sequence analog tat-CN17β, and the MEK/ERK inhibitor UO126 all reduce phenylephrine (PE)-mediated ERK and CaMKII activation and their interaction. Moreover, AntCaNtide or tat-CN17β pretreatment prevented PE induced CaMKII and ERK nuclear accumulation in H9C2s and reduced the hypertrophy responses. To determine the role of CaMKII in cardiac hypertrophy in vivo, spontaneously hypertensive rats were subjected to intramyocardial injections of AntCaNtide or tat-CN17β. Left ventricular hypertrophy was evaluated weekly for 3 weeks by cardiac ultrasounds. We observed that the treatment with CaMKII inhibitors induced similar but significant reduction of cardiac size, left ventricular mass, and thickness of cardiac wall. The treatment with CaMKII inhibitors caused a significant reduction of CaMKII and ERK phosphorylation levels and their nuclear localization in the heart. Conclusion These results indicate that CaMKII and ERK interact to promote activation in hypertrophy; the inhibition of CaMKII-ERK interaction offers a novel therapeutic approach to limit cardiac hypertrophy. PMID:26110816

  2. Targeting the CaMKII/ERK Interaction in the Heart Prevents Cardiac Hypertrophy.

    Directory of Open Access Journals (Sweden)

    Ersilia Cipolletta

    Full Text Available Activation of Ca2+/Calmodulin protein kinase II (CaMKII is an important step in signaling of cardiac hypertrophy. The molecular mechanisms by which CaMKII integrates with other pathways in the heart are incompletely understood. We hypothesize that CaMKII association with extracellular regulated kinase (ERK, promotes cardiac hypertrophy through ERK nuclear localization.In H9C2 cardiomyoblasts, the selective CaMKII peptide inhibitor AntCaNtide, its penetratin conjugated minimal inhibitory sequence analog tat-CN17β, and the MEK/ERK inhibitor UO126 all reduce phenylephrine (PE-mediated ERK and CaMKII activation and their interaction. Moreover, AntCaNtide or tat-CN17β pretreatment prevented PE induced CaMKII and ERK nuclear accumulation in H9C2s and reduced the hypertrophy responses. To determine the role of CaMKII in cardiac hypertrophy in vivo, spontaneously hypertensive rats were subjected to intramyocardial injections of AntCaNtide or tat-CN17β. Left ventricular hypertrophy was evaluated weekly for 3 weeks by cardiac ultrasounds. We observed that the treatment with CaMKII inhibitors induced similar but significant reduction of cardiac size, left ventricular mass, and thickness of cardiac wall. The treatment with CaMKII inhibitors caused a significant reduction of CaMKII and ERK phosphorylation levels and their nuclear localization in the heart.These results indicate that CaMKII and ERK interact to promote activation in hypertrophy; the inhibition of CaMKII-ERK interaction offers a novel therapeutic approach to limit cardiac hypertrophy.

  3. Epigallocatechin-3 gallate prevents cardiac hypertrophy induced by pressure overload in rats

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    Hao, Jia; Kim, Chan-Hyung; Ha, Tae-Sun; Ahn, Hee-Yul

    2007-01-01

    Pressure overload diseases, such as valvular stenosis and systemic hypertension, manifest morphologically in patients as cardiac concentric hypertrophy. Prevention of cardiac remodeling due to increased pressure overload is important to reduce morbidity and mortality. Epigallocatechin-3 gallate (EGCG) is a major bioactive polyphenol present in green tea which has been found to be a nitric oxide-mediated vasorelaxant and to be cardioprotective in myocardial ischemia-reperfusion injury. Therefo...

  4. Resveratrol prevents the development of pathological cardiac hypertrophy and contractile dysfunction in the SHR without lowering blood pressure.

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    Thandapilly, Sijo J; Wojciechowski, Peter; Behbahani, John; Louis, Xavier L; Yu, Liping; Juric, Danijel; Kopilas, Melanie A; Anderson, Hope D; Netticadan, Thomas

    2010-02-01

    Cardiac hypertrophy is a compensatory enlargement of the heart in response to stress such as hypertension. It is beneficial in reducing stress placed on the heart. However, when the stress is of a chronic nature, it becomes pathological and leads to cardiac dysfunction and heart failure. Current treatments for hypertension and heart failure have proven beneficial but are not highly specific and associated with side effects. Accordingly, there is an important need for alternative strategies to provide safe and effective treatment. Ten-week-old male spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats were treated with resveratrol (2.5 mg/kg/day) for a period of 10 weeks. Systolic blood pressure, and cardiac structure and function were measured in all groups at different time points of resveratrol treatment. Oxidative stress was also determined in all groups after 10 weeks of resveratrol treatment. SHRs were characterized with high blood pressure and concentric hypertrophy from 15 weeks of age. Cardiac functional abnormalities were also evident in SHR from 15 weeks onwards. Resveratrol treatment significantly prevented the development of concentric hypertrophy, and systolic and diastolic dysfunction in SHR without lowering blood pressure. Resveratrol also significantly reduced the oxidative stress levels of cardiac tissue in SHR. Resveratrol treatment was beneficial in preventing the development of concentric hypertrophy and cardiac dysfunction in SHR. The cardioprotective effect of resveratrol in SHR may be partially mediated by a reduction in oxidative stress. Thus, resveratrol may have potential in preventing cardiac impairment in patients with essential hypertension.

  5. Diuretics prevent thiazolidinedione-induced cardiac hypertrophy without compromising insulin-sensitizing effects in mice.

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    Chang, Cherng-Shyang; Tsai, Pei-Jane; Sung, Junne-Ming; Chen, Ju-Yi; Ho, Li-Chun; Pandya, Kumar; Maeda, Nobuyo; Tsai, Yau-Sheng

    2014-02-01

    Much concern has arisen regarding critical adverse effects of thiazolidinediones (TZDs), including rosiglitazone and pioglitazone, on cardiac tissue. Although TZD-induced cardiac hypertrophy (CH) has been attributed to an increase in plasma volume or a change in cardiac nutrient preference, causative roles have not been established. To test the hypothesis that volume expansion directly mediates rosiglitazone-induced CH, mice were fed a high-fat diet with rosiglitazone, and cardiac and metabolic consequences were examined. Rosiglitazone treatment induced volume expansion and CH in wild-type and PPARγ heterozygous knockout (Pparg(+/-)) mice, but not in mice defective for ligand binding (Pparg(P465L/+)). Cotreatment with the diuretic furosemide in wild-type mice attenuated rosiglitazone-induced CH, hypertrophic gene reprogramming, cardiomyocyte apoptosis, hypertrophy-related signal activation, and left ventricular dysfunction. Similar changes were observed in mice treated with pioglitazone. The diuretics spironolactone and trichlormethiazide, but not amiloride, attenuated rosiglitazone effects on volume expansion and CH. Interestingly, expression of glucose and lipid metabolism genes in the heart was altered by rosiglitazone, but these changes were not attenuated by furosemide cotreatment. Importantly, rosiglitazone-mediated whole-body metabolic improvements were not affected by furosemide cotreatment. We conclude that releasing plasma volume reduces adverse effects of TZD-induced volume expansion and cardiac events without compromising TZD actions in metabolic switch in the heart and whole-body insulin sensitivity. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  6. Regulation of Cardiac Hypertrophy: the nuclear option

    NARCIS (Netherlands)

    D.W.D. Kuster (Diederik)

    2011-01-01

    textabstractCardiac hypertrophy is the response of the heart to an increased workload. After myocardial infarction (MI) the surviving muscle tissue has to work harder to maintain cardiac output. This sustained increase in workload leads to cardiac hypertrophy. Despite its apparent appropriateness,

  7. The role of autophagy in cardiac hypertrophy

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    Li, Lanfang; Xu, Jin; He, Lu; Peng, Lijun; Zhong, Qiaoqing; Chen, Linxi; Jiang, Zhisheng

    2016-01-01

    Autophagy is conserved in nature from lower eukaryotes to mammals and is an important self-cannibalizing, degradative process that contributes to the elimination of superfluous materials. Cardiac hypertrophy is primarily characterized by excess protein synthesis, increased cardiomyocyte size, and thickened ventricular walls and is a major risk factor that promotes arrhythmia and heart failure. In recent years, cardiomyocyte autophagy has been considered to play a role in controlling the hypertrophic response. However, the beneficial or aggravating role of cardiomyocyte autophagy in cardiac hypertrophy remains controversial. The exact mechanism of cardiomyocyte autophagy in cardiac hypertrophy requires further study. In this review, we summarize the controversies associated with autophagy in cardiac hypertrophy and provide insights into the role of autophagy in the development of cardiac hypertrophy. We conclude that future studies should emphasize the relationship between autophagy and the different stages of cardiac hypertrophy, as well as the autophagic flux and selective autophagy. Autophagy will be a potential therapeutic target for cardiac hypertrophy. PMID:27084518

  8. Preventive effects of p-coumaric acid on cardiac hypertrophy and alterations in electrocardiogram, lipids, and lipoproteins in experimentally induced myocardial infarcted rats.

    Science.gov (United States)

    Roy, Abhro Jyoti; Stanely Mainzen Prince, P

    2013-10-01

    The present study evaluated the preventive effects of p-coumaric acid on cardiac hypertrophy and alterations in electrocardiogram, lipids, and lipoproteins in experimentally induced myocardial infarcted rats. Rats were pretreated with p-coumaric acid (8 mg/kg body weight) daily for a period of 7 days and then injected with isoproterenol (100mg/kg body weight) on 8th and 9th day to induce myocardial infarction. Myocardial infarction induced by isoproterenol was indicated by increased level of cardiac sensitive marker and elevated ST-segments in the electrocardiogram. Also, the levels/concentrations of serum and heart cholesterol, triglycerides and free fatty acids were increased in myocardial infarcted rats. Isoproterenol also increased the levels of serum low density and very low density lipoprotein cholesterol and decreased the levels of high density lipoprotein cholesterol. It also enhanced the activity of liver 3-hydroxy-3 methyl glutaryl-Coenzyme-A reductase. p-Coumaric acid pretreatment revealed preventive effects on all the biochemical parameters and electrocardiogram studied in myocardial infarcted rats. The in vitro study confirmed the free radical scavenging property of p-coumaric acid. Thus, p-coumaric acid prevented cardiac hypertrophy and alterations in lipids, lipoproteins, and electrocardiogram, by virtue of its antihypertrophic, antilipidemic, and free radical scavenging effects in isoproterenol induced myocardial infarcted rats. Copyright © 2013 Elsevier Ltd. All rights reserved.

  9. G protein-coupled receptor kinase 2 promotes cardiac hypertrophy

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    Tscheschner, Henrike; Gao, Erhe; Schumacher, Sarah M.; Yuan, Ancai; Backs, Johannes; Most, Patrick; Wieland, Thomas; Koch, Walter J.; Katus, Hugo A.; Raake, Philip W.

    2017-01-01

    The increase in protein activity and upregulation of G-protein coupled receptor kinase 2 (GRK2) is a hallmark of cardiac stress and heart failure. Inhibition of GRK2 improved cardiac function and survival and diminished cardiac remodeling in various animal heart failure models. The aim of the present study was to investigate the effects of GRK2 on cardiac hypertrophy and dissect potential molecular mechanisms. In mice we observed increased GRK2 mRNA and protein levels following transverse aortic constriction (TAC). Conditional GRK2 knockout mice showed attenuated hypertrophic response with preserved ventricular geometry 6 weeks after TAC operation compared to wild-type animals. In isolated neonatal rat ventricular cardiac myocytes stimulation with angiotensin II and phenylephrine enhanced GRK2 expression leading to enhanced signaling via protein kinase B (PKB or Akt), consecutively inhibiting glycogen synthase kinase 3 beta (GSK3β), such promoting nuclear accumulation and activation of nuclear factor of activated T-cells (NFAT). Cardiac myocyte hypertrophy induced by in vitro GRK2 overexpression increased the cytosolic interaction of GRK2 and phosphoinositide 3-kinase γ (PI3Kγ). Moreover, inhibition of PI3Kγ as well as GRK2 knock down prevented Akt activation resulting in halted NFAT activity and reduced cardiac myocyte hypertrophy. Our data show that enhanced GRK2 expression triggers cardiac hypertrophy by GRK2-PI3Kγ mediated Akt phosphorylation and subsequent inactivation of GSK3β, resulting in enhanced NFAT activity. PMID:28759639

  10. Loss of microRNA-22 prevents high-fat diet induced dyslipidemia and increases energy expenditure without affecting cardiac hypertrophy.

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    Diniz, Gabriela Placoná; Huang, Zhan-Peng; Liu, Jianming; Chen, Jinghai; Ding, Jian; Fonseca, Renata Inzinna; Barreto-Chaves, Maria Luiza; Donato, Jose; Hu, Xiaoyun; Wang, Da-Zhi

    2017-12-15

    Obesity is associated with development of diverse diseases, including cardiovascular diseases and dyslipidemia. MiRNA-22 (miR-22) is a critical regulator of cardiac function and targets genes involved in metabolic processes. Previously, we generated miR-22 null mice and we showed that loss of miR-22 blunted cardiac hypertrophy induced by mechanohormornal stress. In the present study, we examined the role of miR-22 in the cardiac and metabolic alterations promoted by high-fat (HF) diet. We found that loss of miR-22 attenuated the gain of fat mass and prevented dyslipidemia induced by HF diet, although the body weight gain, or glucose intolerance and insulin resistance did not seem to be affected. Mechanistically, loss of miR-22 attenuated the increased expression of genes involved in lipogenesis and inflammation mediated by HF diet. Similarly, we found that miR-22 mediates metabolic alterations and inflammation induced by obesity in the liver. However, loss of miR-22 did not appear to alter HF diet induced cardiac hypertrophy or fibrosis in the heart. Our study therefore establishes miR-22 as an important regulator of dyslipidemia and suggests it may serve as a potential candidate in the treatment of dyslipidemia associated with obesity. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  11. Exercise training can prevent cardiac hypertrophy induced by sympathetic hyperactivity with modulation of kallikrein-kinin pathway and angiogenesis.

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    José Antônio Silva

    Full Text Available Sympathetic hyperactivity induces adverse effects in myocardial. Recent studies have shown that exercise training induces cardioprotection against sympathetic overload; however, relevant mechanisms of this issue remain unclear. We analyzed whether exercise can prevent pathological hypertrophy induced by sympathetic hyperactivity with modulation of the kallikrein-kinin and angiogenesis pathways. Male Wistar rats were assigned to non-trained group that received vehicle; non-trained isoproterenol treated group (Iso, 0.3 mg kg(-1 day-(1; and trained group (Iso+Exe which was subjected to sympathetic hyperactivity with isoproterenol. The Iso rats showed hypertrophy and myocardial dysfunction with reduced force development and relaxation of muscle. The isoproterenol induced severe fibrosis, apoptosis and reduced myocardial capillary. Interestingly, exercise blunted hypertrophy, myocardial dysfunction, fibrosis, apoptosis and capillary decreases. The sympathetic hyperactivity was associated with high abundance of ANF mRNA and β-MHC mRNA, which was significantly attenuated by exercise. The tissue kallikrein was augmented in the Iso+Exe group, and kinin B1 receptor mRNA was increased in the Iso group. Moreover, exercise induced an increase of kinin B2 receptor mRNA in myocardial. The myocardial content of eNOS, VEGF, VEGF receptor 2, pAkt and Bcl-2 were increased in the Iso+Exe group. Likewise, increased expression of pro-apoptotic Bad in the Iso rats was prevented by prior exercise. Our results represent the first demonstration that exercise can modulate kallikrein-kinin and angiogenesis pathways in the myocardial on sympathetic hyperactivity. These findings suggest that kallikrein-kinin and angiogenesis may have a key role in protecting the heart.

  12. Regression of Pathological Cardiac Hypertrophy: Signaling Pathways and Therapeutic Targets

    OpenAIRE

    Hou, Jianglong; Kang, Y. James

    2012-01-01

    Pathological cardiac hypertrophy is a key risk factor for heart failure. It is associated with increased interstitial fibrosis, cell death and cardiac dysfunction. The progression of pathological cardiac hypertrophy has long been considered as irreversible. However, recent clinical observations and experimental studies have produced evidence showing the reversal of pathological cardiac hypertrophy. Left ventricle assist devices used in heart failure patients for bridging to transplantation no...

  13. Potassium supplementation reduces cardiac and renal hypertrophy independent of blood pressure in DOCA/salt mice.

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    Wang, Qing; Domenighetti, Andrea A; Pedrazzini, Thierry; Burnier, Michel

    2005-09-01

    We have demonstrated previously that deoxycorticosterone acetate (DOCA)/salt induces cardiac hypertrophy and left ventricular dysfunction independent of blood pressure (BP) in 1-renin gene mice. Because these mice also develop hypokalemia and metabolic alkalosis caused by mineralocorticoid excess, we investigated whether correcting hypokalemia by dietary potassium supplementation would prevent the DOCA/salt-induced cardiac hypertrophy, cardiac dysfunction, and electrocardiographic changes in normotensive, 1-renin gene and hypertensive, 2-renin gene mice. All mice were studied after 5 weeks of DOCA and salt administration. Potassium was given by adding 0.4 or 0.6% KCl to the drinking water. Our results show that correction of hypokalemia and metabolic alkalosis prevents cardiac hypertrophy and normalizes cardiac function without affecting BP in normotensive, 1-renin gene mice. In hypertensive, 2-renin gene mice, potassium supplementation induces a significant decrease in BP. The decrease in BP and correction of kalemia are associated with a significant but partial correction of cardiac hypertrophy. In both group of mice, electrocardiographic alterations were measured after administration of DOCA/salt, which could be corrected by potassium supplementation. Thus, these results show that correction of hypokalemia and metabolic alkalosis does prevent the development of cardiac hypertrophy and normalizes cardiac function independent of BP in normotensive, 1-renin gene mice that receive excess mineralocorticoid and salt. In 2-renin gene, hypertensive mice, potassium supplementation also prevents the development of cardiac hypertrophy, but the effect cannot be separated from the decrease in BP.

  14. Apelin/APJ system: A bifunctional target for cardiac hypertrophy.

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    Lu, Liqun; Wu, Di; Li, Lanfang; Chen, Linxi

    2017-03-01

    Apelin acts as the endogenous ligand of G protein coupled receptors APJ. The apelin/APJ system is responsible for the occurrence and development of cardiovascular diseases. In recent years, apelin/APJ has been considered to play an important role in cardiac hypertrophy, but whether that role is beneficial or aggravating remains controversial. Apelin/APJ alleviates cardiac hypertrophy which is triggered by angiotensin II, oxidative stress and exercise. However, central administration of apelin induces cardiac hypertrophy. Peripheral administration of apelin also promotes the development of cardiac hypertrophy under non-pathological conditions. Furthermore, our laboratory discovers that apelin/APJ is able to induce hypertrophy of cardiomyocytes in vitro. The exact mechanism of apelin/APJ's dual effects in cardiac hypertrophy requires further study. In this paper, we review the controversies associated with apelin/APJ in cardiac hypertrophy and we elaborate the role of apelin/APJ in cardiac hypertrophy related-diseases including obesity, diabetes, hypertension, myocarditis and myocardial infarction. We conclude that further studies should emphasize more about the relationship between apelin/APJ and pathological hypertrophy especially in clinical patients. Moreover, apelin/APJ can be a promising therapeutic target for cardiac hypertrophy. Copyright © 2016. Published by Elsevier B.V.

  15. Glucose Transporters in Cardiac Metabolism and Hypertrophy

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    Shao, Dan; Tian, Rong

    2016-01-01

    The heart is adapted to utilize all classes of substrates to meet the high-energy demand, and it tightly regulates its substrate utilization in response to environmental changes. Although fatty acids are known as the predominant fuel for the adult heart at resting stage, the heart switches its substrate preference toward glucose during stress conditions such as ischemia and pathological hypertrophy. Notably, increasing evidence suggests that the loss of metabolic flexibility associated with increased reliance on glucose utilization contribute to the development of cardiac dysfunction. The changes in glucose metabolism in hypertrophied hearts include altered glucose transport and increased glycolysis. Despite the role of glucose as an energy source, changes in other nonenergy producing pathways related to glucose metabolism, such as hexosamine biosynthetic pathway and pentose phosphate pathway, are also observed in the diseased hearts. This article summarizes the current knowledge regarding the regulation of glucose transporter expression and translocation in the heart during physiological and pathological conditions. It also discusses the signaling mechanisms governing glucose uptake in cardiomyocytes, as well as the changes of cardiac glucose metabolism under disease conditions. PMID:26756635

  16. Modeling Human Cardiac Hypertrophy in Stem Cell-Derived Cardiomyocytes

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    Ekaterina Ovchinnikova

    2018-03-01

    Full Text Available Summary: Cardiac hypertrophy accompanies many forms of cardiovascular diseases. The mechanisms behind the development and regulation of cardiac hypertrophy in the human setting are poorly understood, which can be partially attributed to the lack of a human cardiomyocyte-based preclinical test system recapitulating features of diseased myocardium. The objective of our study is to determine whether human embryonic stem cell-derived cardiomyocytes (hESC-CMs subjected to mechanical stretch can be used as an adequate in vitro model for studying molecular mechanisms of cardiac hypertrophy. We show that hESC-CMs subjected to cyclic stretch, which mimics mechanical overload, exhibit essential features of a hypertrophic state on structural, functional, and gene expression levels. The presented hESC-CM stretch approach provides insight into molecular mechanisms behind mechanotransduction and cardiac hypertrophy and lays groundwork for the development of pharmacological approaches as well as for discovering potential circulating biomarkers of cardiac dysfunction. : In this article, Berezikov, van der Meer, and colleagues used stem cell-derived cardiomyocytes to model human cardiac hypertrophy. Their approach provides novel insights into molecular mechanisms behind mechanotransduction and cardiac hypertrophy and lays groundwork for the development of new pharmacological approaches as well as for discovering new potential circulating biomarkers of cardiac dysfunction. Keywords: stem cells, human cardiomyocytes, hypertrophy, in vitro disease modeling, cardiomyocytes stretch response, mechanotransduction

  17. Regression of Pathological Cardiac Hypertrophy: Signaling Pathways and Therapeutic Targets

    Science.gov (United States)

    Hou, Jianglong; Kang, Y. James

    2012-01-01

    Pathological cardiac hypertrophy is a key risk factor for heart failure. It is associated with increased interstitial fibrosis, cell death and cardiac dysfunction. The progression of pathological cardiac hypertrophy has long been considered as irreversible. However, recent clinical observations and experimental studies have produced evidence showing the reversal of pathological cardiac hypertrophy. Left ventricle assist devices used in heart failure patients for bridging to transplantation not only improve peripheral circulation but also often cause reverse remodeling of the geometry and recovery of the function of the heart. Dietary supplementation with physiologically relevant levels of copper can reverse pathological cardiac hypertrophy in mice. Angiogenesis is essential and vascular endothelial growth factor (VEGF) is a constitutive factor for the regression. The action of VEGF is mediated by VEGF receptor-1, whose activation is linked to cyclic GMP-dependent protein kinase-1 (PKG-1) signaling pathways, and inhibition of cyclic GMP degradation leads to regression of pathological cardiac hypertrophy. Most of these pathways are regulated by hypoxia-inducible factor. Potential therapeutic targets for promoting the regression include: promotion of angiogenesis, selective enhancement of VEGF receptor-1 signaling pathways, stimulation of PKG-1 pathways, and sustention of hypoxia-inducible factor transcriptional activity. More exciting insights into the regression of pathological cardiac hypertrophy are emerging. The time of translating the concept of regression of pathological cardiac hypertrophy to clinical practice is coming. PMID:22750195

  18. Regression of pathological cardiac hypertrophy: signaling pathways and therapeutic targets.

    Science.gov (United States)

    Hou, Jianglong; Kang, Y James

    2012-09-01

    Pathological cardiac hypertrophy is a key risk factor for heart failure. It is associated with increased interstitial fibrosis, cell death and cardiac dysfunction. The progression of pathological cardiac hypertrophy has long been considered as irreversible. However, recent clinical observations and experimental studies have produced evidence showing the reversal of pathological cardiac hypertrophy. Left ventricle assist devices used in heart failure patients for bridging to transplantation not only improve peripheral circulation but also often cause reverse remodeling of the geometry and recovery of the function of the heart. Dietary supplementation with physiologically relevant levels of copper can reverse pathological cardiac hypertrophy in mice. Angiogenesis is essential and vascular endothelial growth factor (VEGF) is a constitutive factor for the regression. The action of VEGF is mediated by VEGF receptor-1, whose activation is linked to cyclic GMP-dependent protein kinase-1 (PKG-1) signaling pathways, and inhibition of cyclic GMP degradation leads to regression of pathological cardiac hypertrophy. Most of these pathways are regulated by hypoxia-inducible factor. Potential therapeutic targets for promoting the regression include: promotion of angiogenesis, selective enhancement of VEGF receptor-1 signaling pathways, stimulation of PKG-1 pathways, and sustention of hypoxia-inducible factor transcriptional activity. More exciting insights into the regression of pathological cardiac hypertrophy are emerging. The time of translating the concept of regression of pathological cardiac hypertrophy to clinical practice is coming. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. Macrophage microRNA-155 promotes cardiac hypertrophy and failure

    NARCIS (Netherlands)

    Heymans, Stephane; Corsten, Maarten F.; Verhesen, Wouter; Carai, Paolo; van Leeuwen, Rick E. W.; Custers, Kevin; Peters, Tim; Hazebroek, Mark; Stöger, Lauran; Wijnands, Erwin; Janssen, Ben J.; Creemers, Esther E.; Pinto, Yigal M.; Grimm, Dirk; Schürmann, Nina; Vigorito, Elena; Thum, Thomas; Stassen, Frank; Yin, Xiaoke; Mayr, Manuel; de Windt, Leon J.; Lutgens, Esther; Wouters, Kristiaan; de Winther, Menno P. J.; Zacchigna, Serena; Giacca, Mauro; van Bilsen, Marc; Papageorgiou, Anna-Pia; Schroen, Blanche

    2013-01-01

    Cardiac hypertrophy and subsequent heart failure triggered by chronic hypertension represent major challenges for cardiovascular research. Beyond neurohormonal and myocyte signaling pathways, growing evidence suggests inflammatory signaling pathways as therapeutically targetable contributors to this

  20. Bezafibrate Attenuates Pressure Overload-Induced Cardiac Hypertrophy and Fibrosis

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    Si-Chi Xu

    2017-01-01

    Full Text Available Background. Peroxisome proliferator-activated receptor-α (PPAR-α is closely associated with the development of cardiac hypertrophy. Previous studies have indicated that bezafibrate (BZA, a PPAR-α agonist, could attenuate insulin resistance and obesity. This study was designed to determine whether BZA could protect against pressure overload-induced cardiac hypertrophy. Methods. Mice were orally given BZA (100 mg/kg for 7 weeks beginning 1 week after aortic banding (AB surgery. Cardiac hypertrophy was assessed based on echocardiographic, histological, and molecular aspects. Moreover, neonatal rat ventricular cardiomyocytes (NRVMs were used to investigate the effects of BZA on the cardiomyocyte hypertrophic response in vitro. Results. Our study demonstrated that BZA could alleviate cardiac hypertrophy and fibrosis in mice subjected to AB surgery. BZA treatment also reduced the phosphorylation of protein kinase B (AKT/glycogen synthase kinase-3β (GSK3β and mitogen-activated protein kinases (MAPKs. BZA suppressed phenylephrine- (PE- induced hypertrophy of cardiomyocyte in vitro. The protective effects of BZA were abolished by the treatment of the PPAR-α antagonist in vitro. Conclusions. BZA could attenuate pressure overload-induced cardiac hypertrophy and fibrosis.

  1. Cardiac-specific ablation of glutaredoxin 3 leads to cardiac hypertrophy and heart failure

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    Experimental and clinical investigations have demonstrated that reactive oxygen species (ROS) production is increased during cardiac hypertrophy and heart failure. Excess ROS can directly impair cardiac contraction through modification of Ca2+ handling proteins or activate multiple effectors and sig...

  2. Swimming training increases cardiac vagal activity and induces cardiac hypertrophy in rats

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    A. Medeiros

    2004-12-01

    Full Text Available The effect of swimming training (ST on vagal and sympathetic cardiac effects was investigated in sedentary (S, N = 12 and trained (T, N = 12 male Wistar rats (200-220 g. ST consisted of 60-min swimming sessions 5 days/week for 8 weeks, with a 5% body weight load attached to the tail. The effect of the autonomic nervous system in generating training-induced resting bradycardia (RB was examined indirectly after cardiac muscarinic and adrenergic receptor blockade. Cardiac hypertrophy was evaluated by cardiac weight and myocyte morphometry. Plasma catecholamine concentrations and citrate synthase activity in soleus muscle were also determined in both groups. Resting heart rate was significantly reduced in T rats (355 ± 16 vs 330 ± 20 bpm. RB was associated with a significantly increased cardiac vagal effect in T rats (103 ± 25 vs 158 ± 40 bpm, since the sympathetic cardiac effect and intrinsic heart rate were similar for the two groups. Likewise, no significant difference was observed for plasma catecholamine concentrations between S and T rats. In T rats, left ventricle weight (13% and myocyte dimension (21% were significantly increased, suggesting cardiac hypertrophy. Skeletal muscle citrate synthase activity was significantly increased by 52% in T rats, indicating endurance conditioning. These data suggest that RB induced by ST is mainly mediated parasympathetically and differs from other training modes, like running, that seems to mainly decrease intrinsic heart rate in rats. The increased cardiac vagal activity associated with ST is of clinical relevance, since both are related to increased life expectancy and prevention of cardiac events.

  3. Taxifolin protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload

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    Guo, Haipeng; Zhang, Xin; Cui, Yuqian; Zhou, Heng; Xu, Dachun; Shan, Tichao; Zhang, Fan; Guo, Yuan; Chen, Yuguo; Wu, Dawei

    2015-01-01

    Cardiac hypertrophy is a key pathophysiological component to biomechanical stress, which has been considered to be an independent and predictive risk factor for adverse cardiovascular events. Taxifolin (TAX) is a typical plant flavonoid, which has long been used clinically for treatment of cardiovascular and cerebrovascular diseases. However, very little is known about whether TAX can influence the development of cardiac hypertrophy. In vitro studies, we found that TAX concentration-dependently inhibited angiotensin II (Ang II) induced hypertrophy and protein synthesis in cardiac myocytes. Then we established a mouse model by transverse aortic constriction (TAC) to further confirm our findings. It was demonstrated that TAX prevented pressure overload induced cardiac hypertrophy in mice, as assessed by ventricular mass/body weight, echocardiographic parameters, myocyte cross-sectional area, and the expression of ANP, BNP and β-MHC. The excess production of reactive oxygen species (ROS) played critical role in the development of cardiac hypertrophy. TAX arrested oxidative stress and decreased the expression of 4-HNE induced by pressure overload. Moreover, TAX negatively modulated TAC-induced phosphorylation of ERK1/2 and JNK1/2. Further studies showed that TAX significantly attenuated left ventricular fibrosis and collagen synthesis through abrogating the phosphorylation of Smad2 and Smad2/3 nuclear translocation. These results demonstrated that TAX could inhibit cardiac hypertrophy and attenuate ventricular fibrosis after pressure overload. These beneficial effects were at least through the inhibition of the excess production of ROS, ERK1/2, JNK1/2 and Smad signaling pathways. Therefore, TAX might be a potential candidate for the treatment of cardiac hypertrophy and fibrosis. - Highlights: • We focus on the protective effect of taxifolin on cardiac remodeling. • Taxifolin inhibited cardiac hypertrophy and attenuated ventricular fibrosis. • Taxifolin

  4. Taxifolin protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload

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    Guo, Haipeng; Zhang, Xin [Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan (China); Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan (China); Cui, Yuqian [Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan (China); Zhou, Heng [Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan (China); Xu, Dachun [Department of Cardiology, Shanghai Tenth People' s Hospital of Tongji University, Shanghai (China); Shan, Tichao; Zhang, Fan [Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan (China); Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan (China); Guo, Yuan [Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan (China); Chen, Yuguo, E-mail: chen919085@163.com [Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan (China); Department of Emergency, Qilu Hospital of Shandong University, Jinan (China); Wu, Dawei, E-mail: wdwu55@163.com [Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan (China); Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan (China)

    2015-09-01

    Cardiac hypertrophy is a key pathophysiological component to biomechanical stress, which has been considered to be an independent and predictive risk factor for adverse cardiovascular events. Taxifolin (TAX) is a typical plant flavonoid, which has long been used clinically for treatment of cardiovascular and cerebrovascular diseases. However, very little is known about whether TAX can influence the development of cardiac hypertrophy. In vitro studies, we found that TAX concentration-dependently inhibited angiotensin II (Ang II) induced hypertrophy and protein synthesis in cardiac myocytes. Then we established a mouse model by transverse aortic constriction (TAC) to further confirm our findings. It was demonstrated that TAX prevented pressure overload induced cardiac hypertrophy in mice, as assessed by ventricular mass/body weight, echocardiographic parameters, myocyte cross-sectional area, and the expression of ANP, BNP and β-MHC. The excess production of reactive oxygen species (ROS) played critical role in the development of cardiac hypertrophy. TAX arrested oxidative stress and decreased the expression of 4-HNE induced by pressure overload. Moreover, TAX negatively modulated TAC-induced phosphorylation of ERK1/2 and JNK1/2. Further studies showed that TAX significantly attenuated left ventricular fibrosis and collagen synthesis through abrogating the phosphorylation of Smad2 and Smad2/3 nuclear translocation. These results demonstrated that TAX could inhibit cardiac hypertrophy and attenuate ventricular fibrosis after pressure overload. These beneficial effects were at least through the inhibition of the excess production of ROS, ERK1/2, JNK1/2 and Smad signaling pathways. Therefore, TAX might be a potential candidate for the treatment of cardiac hypertrophy and fibrosis. - Highlights: • We focus on the protective effect of taxifolin on cardiac remodeling. • Taxifolin inhibited cardiac hypertrophy and attenuated ventricular fibrosis. • Taxifolin

  5. Antiandrogenic therapy with finasteride attenuates cardiac hypertrophy and left ventricular dysfunction.

    Science.gov (United States)

    Zwadlo, Carolin; Schmidtmann, Elisa; Szaroszyk, Malgorzata; Kattih, Badder; Froese, Natali; Hinz, Hebke; Schmitto, Jan Dieter; Widder, Julian; Batkai, Sandor; Bähre, Heike; Kaever, Volkhard; Thum, Thomas; Bauersachs, Johann; Heineke, Joerg

    2015-03-24

    In comparison with men, women have a better prognosis when experiencing aortic valve stenosis, hypertrophic cardiomyopathy, or heart failure. Recent data suggest that androgens like testosterone or the more potent dihydrotestosterone contribute to the development of cardiac hypertrophy and failure. Therefore, we analyzed whether antiandrogenic therapy with finasteride, which inhibits the generation of dihydrotestosterone by the enzyme 5-α-reductase, improves pathological ventricular remodeling and heart failure. We found a strongly induced expression of all 3 isoforms of the 5-α-reductase (Srd5a1 to Srd5a3) in human and mouse hearts with pathological hypertrophy, which was associated with increased myocardial accumulation of dihydrotestosterone. Starting 1 week after the induction of pressure overload by transaortic constriction, mice were treated with finasteride for 2 weeks. Cardiac function, hypertrophy, dilation, and fibrosis were markedly improved in response to finasteride treatment in not only male, but also in female mice. In addition, finasteride also very effectively improved cardiac function and mortality after long-term pressure overload and prevented disease progression in cardiomyopathic mice with myocardial Gαq overexpression. Mechanistically, finasteride, by decreasing dihydrotestosterone, potently inhibited hypertrophy and Akt-dependent prohypertrophic signaling in isolated cardiac myocytes, whereas the introduction of constitutively active Akt blunted these effects of finasteride. Finasteride, which is currently used in patients to treat prostate disease, potently reverses pathological cardiac hypertrophy and dysfunction in mice and might be a therapeutic option for heart failure. © 2015 American Heart Association, Inc.

  6. Effect of angiotensin II blockade on cardiac hypertrophy and remodelling: a review.

    Science.gov (United States)

    Dahlöf, B

    1995-11-01

    hypertension is a serious prognostic indicator and selective angiotensin II blockade is a new anti-hypertensive treatment modality with promising properties, especially for prevention and reversal of cardiac hypertrophy including pathological fibrosis and cardiac remodelling after myocardial infarction. Thus, taking into account the shortcomings of today's anti-hypertensive treatment to achieve normalisation of excessive cardiovascular morbidity and mortality, as well as the seemingly great importance of the renin-angiotensin system for hypertension-induced functional and structural abnormalities, a therapy based on a specific All antagonist could offer obvious advantages in a high risk hypertensive patient with cardiovascular hypertrophy. This hypothesis will be investigated in a large prospective trial (Losartan Intervention For End-point reduction in hypertension: The LIFE Study).

  7. Mitochondrial adaptations to physiological vs. pathological cardiac hypertrophy

    Science.gov (United States)

    Abel, E. Dale; Doenst, Torsten

    2011-01-01

    Cardiac hypertrophy is a stereotypic response of the heart to increased workload. The nature of the workload increase may vary depending on the stimulus (repetitive, chronic, pressure, or volume overload). If the heart fully adapts to the new loading condition, the hypertrophic response is considered physiological. If the hypertrophic response is associated with the ultimate development of contractile dysfunction and heart failure, the response is considered pathological. Although divergent signalling mechanisms may lead to these distinct patterns of hypertrophy, there is some overlap. Given the close relationship between workload and energy demand, any form of cardiac hypertrophy will impact the energy generation by mitochondria, which are the key organelles for cellular ATP production. Significant changes in the expression of nuclear and mitochondrially encoded transcripts that impact mitochondrial function as well as altered mitochondrial proteome composition and mitochondrial energetics have been described in various forms of cardiac hypertrophy. Here, we review mitochondrial alterations in pathological and physiological hypertrophy. We suggest that mitochondrial adaptations to pathological and physiological hypertrophy are distinct, and we shall review potential mechanisms that might account for these differences. PMID:21257612

  8. Nuclear Factor of Activated T cells (NFAT): key regulator of cardiac hypertrophy and skeletal muscle adaptation

    NARCIS (Netherlands)

    Bourajjaj, M.

    2008-01-01

    Despite significant progress in the prevention and treatment of cardiovascular diseases, heart failure is still a leading cause of morbidity and mortality in industrial countries. Sustained cardiac hypertrophy, which is defined as an increase in heart size resulting from an increase in cardiomyocyte

  9. AVE 0991 attenuates cardiac hypertrophy through reducing oxidative stress.

    Science.gov (United States)

    Ma, Yuedong; Huang, Huiling; Jiang, Jingzhou; Wu, Lingling; Lin, Chunxi; Tang, Anli; Dai, Gang; He, Jiangui; Chen, Yili

    2016-06-10

    AVE 0991, the nonpeptide angiotensin-(1-7) (Ang-(1-7)) analog, is recognized as having beneficial cardiovascular effects. However, the mechanisms have not been fully elucidated. This study was designed to investigate the effects of AVE 0991 on cardiac hypertrophy and the mechanisms involved. Mice were underwent aortic banding to induce cardiac hypertrophy followed by the administration of AVE 0991 (20 mg kg·day (-1)) for 4 weeks. It was shown that AVE 0991 reduced left ventricular hypertrophy and improved heart function, characterized by decreases in left ventricular weight and left ventricular end-diastolic diameter, and increases in ejection fraction. Moreover, AVE 0991 significantly down-regulated mean myocyte diameter and attenuate the gene expression of the hypertrophic markers. Furthermore, AVE 0991 inhibited the expression of NOX 2 and NOX 4, meaning that AVE 0991 reduced oxidative stress of cardiac hypertrophy mice. Our data showed that AVE 0991 treatment could attenuate cardiac hypertrophy and improve heart function, which may be due to reduce oxidative stress. Copyright © 2016. Published by Elsevier Inc.

  10. Through thick and thin: A circulating growth factor inhibits age-related cardiac hypertrophy

    OpenAIRE

    McPherron, Alexandra C.

    2013-01-01

    In an intriguing new study, Loffredo et al., report that joining the circulation of old mice with that of young mice reduces age-related cardiac hypertrophy. They also found that the growth factor GDF11 is a circulating negative regulator of cardiac hypertrophy which suggests that raising GDF11 levels may be useful to treat cardiac hypertrophy associated with aging.

  11. How does pressure overload cause cardiac hypertrophy and dysfunction? High-ouabain affinity cardiac Na+ pumps are crucial.

    Science.gov (United States)

    Blaustein, Mordecai P

    2017-11-01

    Left ventricular hypertrophy is frequently observed in hypertensive patients and is believed to be due to the pressure overload and cardiomyocyte stretch. Three recent reports on mice with genetically engineered Na + pumps, however, have demonstrated that cardiac ouabain-sensitive α 2 -Na + pumps play a key role in the pathogenesis of transaortic constriction-induced hypertrophy. Hypertrophy was delayed/attenuated in mice with mutant, ouabain-resistant α 2 -Na + pumps and in mice with cardiac-selective knockout or transgenic overexpression of α 2 -Na + pumps. The latter, seemingly paradoxical, findings can be explained by comparing the numbers of available (ouabain-free) high-affinity (α 2 ) ouabain-binding sites in wild-type, knockout, and transgenic hearts. Conversely, hypertrophy was accelerated in α 2 -ouabain-resistant (R) mice in which the normally ouabain-resistant α 1 -Na + pumps were mutated to an ouabain-sensitive (S) form (α 1 S/S α 2 R/R or "SWAP" vs. wild-type or α 1 R/R α 2 S/S mice). Furthermore, transaortic constriction-induced hypertrophy in SWAP mice was prevented/reversed by immunoneutralizing circulating endogenous ouabain (EO). These findings show that EO and its receptor, ouabain-sensitive α 2 , are critical factors in pressure overload-induced cardiac hypertrophy. This complements reports linking elevated plasma EO to hypertension, cardiac hypertrophy, and failure in humans and elucidates the underappreciated role of the EO-Na + pump pathway in cardiovascular disease. Copyright © 2017 the American Physiological Society.

  12. Angiotensin II Facilitates Matrix Metalloproteinase-9-Mediated Myosin Light Chain Kinase Degradation in Pressure Overload-Induced Cardiac Hypertrophy

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    Shun Wang

    2017-12-01

    Full Text Available Background/Aims: Angiotensin II (Ang II has been shown to promote cardiac remodeling during the process of hypertrophy. Myosin light chain kinase (MLCK, a specific kinase for the phosphorylation of myosin light chain 2 (MLC2, plays an important role in regulating cardiac muscle contraction and hypertrophy. However, whether Ang II could facilitate cardiac hypertrophy by altering the expression of MLCK remains unclear. This study aimed to investigate this effect and the underlying mechanisms. Methods: Cardiac hypertrophy was induced via pressure overload in rats, which were then evaluated via histological and biochemical measurements and echocardiography. Angiotensin-converting enzyme inhibitor (ACEI was used to inhibit Ang II. Neonatal rat cardiomyocytes were stimulated with Ang II to induce hypertrophy and were treated with a matrix metalloproteinase 9 (MMP9 inhibitor. Myocyte hypertrophy was evaluated using immunofluorescence and qRT-PCR. Degradation of recombinant human MLCK by recombinant human MMP9 was tested using a cleavage assay. The expression levels of MLCK, MLC2, phospho-myosin light chain 2 (p-MLC2, myosin phosphatase 2 (MYPT2, and calmodulin (CaM were measured using western blotting. Results: ACEI improved cardiac function and remodeling and increased the levels of MLCK and p-MLC2 as well as reduced the expression of MMP9 in pressure overload-induced cardiac hypertrophy. Moreover, the MMP9 inhibitor alleviated myocyte hypertrophy and upregulated the levels of MLCK and p-MLC2 in Ang II-induced cardiomyocyte hypertrophy. Recombinant human MLCK was concentration- and time-dependently degraded by recombinant human MMP9 in vitro, and this process was prevented by the MMP9 inhibitor. Conclusion: Our results suggest that Ang II is involved in the degradation of MLCK in pressure overload-induced cardiac hypertrophy and that this process was mediated by MMP9.

  13. Rapamycin Attenuated Cardiac Hypertrophy Induced by Isoproterenol and Maintained Energy Homeostasis via Inhibiting NF-κB Activation

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    Xi Chen

    2014-01-01

    Full Text Available Rapamycin, also known as sirolimus, is an immunosuppressant drug used to prevent rejection organ (especially kidney transplantation. However, little is known about the role of Rapa in cardiac hypertrophy induced by isoproterenol and its underlying mechanism. In this study, Rapa was administrated intraperitoneally for one week after the rat model of cardiac hypertrophy induced by isoproterenol established. Rapa was demonstrated to attenuate isoproterenol-induced cardiac hypertrophy, maintain the structure integrity and functional performance of mitochondria, and upregulate genes related to fatty acid metabolism in hypertrophied hearts. To further study the implication of NF-κB in the protective role of Rapa, cardiomyocytes were pretreated with TNF-α or transfected with siRNA against NF-κB/p65 subunit. It was revealed that the upregulation of extracellular circulating proinflammatory cytokines induced by isoproterenol was able to be reversed by Rapa, which was dependent on NF-κB pathway. Furthermore, the regression of cardiac hypertrophy and maintaining energy homeostasis by Rapa in cardiomyocytes may be attributed to the inactivation of NF-κB. Our results shed new light on mechanisms underlying the protective role of Rapa against cardiac hypertrophy induced by isoproterenol, suggesting that blocking proinflammatory response by Rapa might contribute to the maintenance of energy homeostasis during the progression of cardiac hypertrophy.

  14. Pharmacological targeting of CDK9 in cardiac hypertrophy

    Czech Academy of Sciences Publication Activity Database

    Kryštof, Vladimír; Chamrád, Ivo; Jorda, Radek; Kohoutek, J.

    2010-01-01

    Roč. 30, č. 4 (2010), s. 646-666 ISSN 0198-6325 R&D Projects: GA ČR GA204/08/0511; GA ČR GA301/09/1832; GA ČR GA301/08/1649 Institutional research plan: CEZ:AV0Z50380511 Keywords : P-TEFb * cardiac myocyte * cardiac hypertrophy Subject RIV: CE - Biochemistry Impact factor: 10.228, year: 2010

  15. Early dystrophin loss is coincident with the transition of compensated cardiac hypertrophy to heart failure.

    Science.gov (United States)

    Prado, Fernanda P; Dos Santos, Daniele O; Blefari, Valdecir; Silva, Carlos A; Machado, Juliano; Kettelhut, Isis do Carmo; Ramos, Simone G; Baruffi, Marcelo Dias; Salgado, Helio C; Prado, Cibele M

    2017-01-01

    Hypertension causes cardiac hypertrophy, one of the most important risk factors for heart failure (HF). Despite the importance of cardiac hypertrophy as a risk factor for the development of HF, not all hypertrophied hearts will ultimately fail. Alterations of cytoskeletal and sarcolemma-associated proteins are considered markers cardiac remodeling during HF. Dystrophin provides mechanical stability to the plasma membrane through its interactions with the actin cytoskeleton and, indirectly, to extracellular matrix proteins. This study was undertaken to evaluate dystrophin and calpain-1 in the transition from compensated cardiac hypertrophy to HF. Wistar rats were subjected to abdominal aorta constriction and killed at 30, 60 and 90 days post surgery (dps). Cardiac function and blood pressure were evaluated. The hearts were collected and Western blotting and immunofluorescence performed for dystrophin, calpain-1, alpha-fodrin and calpastatin. Statistical analyses were performed and considered significant when pDystrophin expression was lightly increased at 30 and 60 dps and HH group. HD group showed decreased expression of dystrophin and calpastatin and increased expression of calpain-1 and alpha-fodrin fragments. The first signals of dystrophin reduction were observed as early as 60 dps. In conclusion, some hearts present a distinct molecular pattern at an early stage of the disease; this pattern could provide an opportunity to identify these failure-prone hearts during the development of the cardiac disease. We showed that decreased expression of dystrophin and increased expression of calpains are coincident and could work as possible therapeutic targets to prevent heart failure as a consequence of cardiac hypertrophy.

  16. Secretoneurin suppresses cardiac hypertrophy through suppression of oxidant stress.

    Science.gov (United States)

    Chen, Hua-Li; Liu, Yan; Jiang, Wei; Wang, Xiao-Xiao; Yuan, Guo-Lin; Zhao, Yi-Lin; Yu, Chao

    2018-03-05

    The neuropeptide secretoneurin (SN) plays protective roles in myocardial ischemia. In the present study, the effect of SN in cardiac hypertrophy was investigated. We observed that, in isoproterenol (ISO) treatment induced cardiac or cardiomyocytes hypertrophy, a marked increase in the expression of endogenous SN in mouse plasma, myocardium and primary-cultured cardiomyocytes occurs. In hypertrophic mice, the heart size, heart weight/body weight (HW/BW) ratio, cardiomyocyte size, and atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) expression were significantly higher than those in controls but were effectively suppressed by SN gene therapy. Similarly, the protective effects of SN were also observed in cultured cardiomyocytes following ISO treatment. SN significantly increased the activity of catalase and superoxide dismutase (SOD) in parallel with the decrease in reactive oxygen species levels in cardiomyocytes. We observed that SN evoked the activation of all of the AMPK, P38/MAPK and ERK/MAPK pathways in cardiomyocytes, but pretreatment with only AMPK inhibitor (compound C) and ERK1/2/MAPK inhibitor (PD98059) counteracted the protective effects of SN against cardiomyocyte hypertrophy and the suppressive effects of SN on oxidant stress in cardiomyocytes. These results indicated that endogenous SN is induced in hypertrophic cardiomyocytes, and may play a protective role in the pathogenesis of cardiac hypertrophy. These results suggest that exogenous SN supplementation protects the cardiac hypertrophy induced by ISO treatment through the activation of AMPK and ERK/MAPK pathways, thus upregulating antioxidants and suppressing oxidative stress. Copyright © 2018 Elsevier B.V. All rights reserved.

  17. The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy

    Science.gov (United States)

    Aronsen, Jan Magnus; Ferrini, Arianna; Brien, Patrick; Alkass, Kanar; Tomasso, Antonio; Agrawal, Asmita; Bergmann, Olaf; Reik, Wolf; Roderick, Hywel Llewelyn

    2016-01-01

    Cardiac hypertrophic growth in response to pathological cues is associated with reexpression of fetal genes and decreased cardiac function and is often a precursor to heart failure. In contrast, physiologically induced hypertrophy is adaptive, resulting in improved cardiac function. The processes that selectively induce these hypertrophic states are poorly understood. Here, we have profiled 2 repressive epigenetic marks, H3K9me2 and H3K27me3, which are involved in stable cellular differentiation, specifically in cardiomyocytes from physiologically and pathologically hypertrophied rat hearts, and correlated these marks with their associated transcriptomes. This analysis revealed the pervasive loss of euchromatic H3K9me2 as a conserved feature of pathological hypertrophy that was associated with reexpression of fetal genes. In hypertrophy, H3K9me2 was reduced following a miR-217–mediated decrease in expression of the H3K9 dimethyltransferases EHMT1 and EHMT2 (EHMT1/2). miR-217–mediated, genetic, or pharmacological inactivation of EHMT1/2 was sufficient to promote pathological hypertrophy and fetal gene reexpression, while suppression of this pathway protected against pathological hypertrophy both in vitro and in mice. Thus, we have established a conserved mechanism involving a departure of the cardiomyocyte epigenome from its adult cellular identity to a reprogrammed state that is accompanied by reexpression of fetal genes and pathological hypertrophy. These results suggest that targeting miR-217 and EHMT1/2 to prevent H3K9 methylation loss is a viable therapeutic approach for the treatment of heart disease. PMID:27893464

  18. The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy.

    Science.gov (United States)

    Thienpont, Bernard; Aronsen, Jan Magnus; Robinson, Emma Louise; Okkenhaug, Hanneke; Loche, Elena; Ferrini, Arianna; Brien, Patrick; Alkass, Kanar; Tomasso, Antonio; Agrawal, Asmita; Bergmann, Olaf; Sjaastad, Ivar; Reik, Wolf; Roderick, Hywel Llewelyn

    2017-01-03

    Cardiac hypertrophic growth in response to pathological cues is associated with reexpression of fetal genes and decreased cardiac function and is often a precursor to heart failure. In contrast, physiologically induced hypertrophy is adaptive, resulting in improved cardiac function. The processes that selectively induce these hypertrophic states are poorly understood. Here, we have profiled 2 repressive epigenetic marks, H3K9me2 and H3K27me3, which are involved in stable cellular differentiation, specifically in cardiomyocytes from physiologically and pathologically hypertrophied rat hearts, and correlated these marks with their associated transcriptomes. This analysis revealed the pervasive loss of euchromatic H3K9me2 as a conserved feature of pathological hypertrophy that was associated with reexpression of fetal genes. In hypertrophy, H3K9me2 was reduced following a miR-217-mediated decrease in expression of the H3K9 dimethyltransferases EHMT1 and EHMT2 (EHMT1/2). miR-217-mediated, genetic, or pharmacological inactivation of EHMT1/2 was sufficient to promote pathological hypertrophy and fetal gene reexpression, while suppression of this pathway protected against pathological hypertrophy both in vitro and in mice. Thus, we have established a conserved mechanism involving a departure of the cardiomyocyte epigenome from its adult cellular identity to a reprogrammed state that is accompanied by reexpression of fetal genes and pathological hypertrophy. These results suggest that targeting miR-217 and EHMT1/2 to prevent H3K9 methylation loss is a viable therapeutic approach for the treatment of heart disease.

  19. Resistance training and cardiac hypertrophy: unravelling the training effect.

    Science.gov (United States)

    Haykowsky, Mark J; Dressendorfer, Rudolph; Taylor, Dylan; Mandic, Sandra; Humen, Dennis

    2002-01-01

    Resistance training (RT) is a popular method of conditioning to enhance sport performance as well as an effective form of exercise to attenuate the age-mediated decline in muscle strength and mass. Although the benefits of RT on skeletal muscle morphology and function are well established, its effect on left ventricular (LV) morphology remains equivocal. Some investigations have found that RT is associated with an obligatory increase in LV wall thickness and mass with minimal alteration in LV internal cavity dimension, an effect called concentric hypertrophy. However, others report that short- (18 years) RT does not alter LV morphology, arguing that concentric hypertrophy is not an obligatory adaptation secondary to this form of exertion. This disparity between studies on whether RT consistently results in cardiac hypertrophy could be caused by: (i) acute cardiopulmonary mechanisms that minimise the increase in transmural pressure (i.e. ventricular pressure minus intrathoracic pressure) and LV wall stress during exercise; (ii) the underlying use of anabolic steroids by the athletes; or (iii) the specific type of RT performed. We propose that when LV geometry is altered after RT, the pattern is usually concentric hypertrophy in Olympic weightlifters. However, the pattern of eccentric hypertrophy (increased LV mass secondary to an increase in diastolic internal cavity dimension and wall thickness) is not uncommon in bodybuilders. Of particular interest, nearly 40% of all RT athletes have normal LV geometry, and these athletes are typically powerlifters. RT athletes who use anabolic steroids have been shown to have significantly higher LV mass compared with drug-free sport-matched athletes. This brief review will sort out some of the factors that may affect the acute and chronic outcome of RT on LV morphology. In addition, a conceptual framework is offered to help explain why cardiac hypertrophy is not always found in RT athletes.

  20. Differential and Conditional Activation of PKC-Isoforms Dictates Cardiac Adaptation during Physiological to Pathological Hypertrophy

    Science.gov (United States)

    Naskar, Shaon; Datta, Kaberi; Mitra, Arkadeep; Pathak, Kanchan; Datta, Ritwik; Bansal, Trisha; Sarkar, Sagartirtha

    2014-01-01

    A cardiac hypertrophy is defined as an increase in heart mass which may either be beneficial (physiological hypertrophy) or detrimental (pathological hypertrophy). This study was undertaken to establish the role of different protein kinase-C (PKC) isoforms in the regulation of cardiac adaptation during two types of cardiac hypertrophy. Phosphorylation of specific PKC-isoforms and expression of their downstream proteins were studied during physiological and pathological hypertrophy in 24 week male Balb/c mice (Mus musculus) models, by reverse transcriptase-PCR, western blot analysis and M-mode echocardiography for cardiac function analysis. PKC-δ was significantly induced during pathological hypertrophy while PKC-α was exclusively activated during physiological hypertrophy in our study. PKC-δ activation during pathological hypertrophy resulted in cardiomyocyte apoptosis leading to compromised cardiac function and on the other hand, activation of PKC-α during physiological hypertrophy promoted cardiomyocyte growth but down regulated cellular apoptotic load resulting in improved cardiac function. Reversal in PKC-isoform with induced activation of PKC-δ and simultaneous inhibition of phospho-PKC-α resulted in an efficient myocardium to deteriorate considerably resulting in compromised cardiac function during physiological hypertrophy via augmentation of apoptotic and fibrotic load. This is the first report where PKC-α and -δ have been shown to play crucial role in cardiac adaptation during physiological and pathological hypertrophy respectively thereby rendering compromised cardiac function to an otherwise efficient heart by conditional reversal of their activation. PMID:25116170

  1. GSK-3β/NFAT Signaling Is Involved in Testosterone-Induced Cardiac Myocyte Hypertrophy.

    Directory of Open Access Journals (Sweden)

    Javier Duran

    Full Text Available Testosterone induces cardiac hypertrophy through a mechanism that involves a concerted crosstalk between cytosolic and nuclear signaling pathways. Nuclear factor of activated T-cells (NFAT is associated with the promotion of cardiac hypertrophy, glycogen synthase kinase-3β (GSK-3β is considered to function as a negative regulator, mainly by modulating NFAT activity. However, the role played by calcineurin-NFAT and GSK-3β signaling in testosterone-induced cardiac hypertrophy has remained unknown. Here, we determined that testosterone stimulates cardiac myocyte hypertrophy through NFAT activation and GSK-3β inhibition. Testosterone increased the activity of NFAT-luciferase (NFAT-Luc in a time- and dose-dependent manner, with the activity peaking after 24 h of stimulation with 100 nM testosterone. NFAT-Luc activity induced by testosterone was blocked by the calcineurin inhibitors FK506 and cyclosporine A and by 11R-VIVIT, a specific peptide inhibitor of NFAT. Conversely, testosterone inhibited GSK-3β activity as determined by increased GSK-3β phosphorylation at Ser9 and β-catenin protein accumulation, and also by reduction in β-catenin phosphorylation at residues Ser33, Ser37, and Thr41. GSK-3β inhibition with 1-azakenpaullone or a GSK-3β-targeting siRNA increased NFAT-Luc activity, whereas overexpression of a constitutively active GSK-3β mutant (GSK-3βS9A inhibited NFAT-Luc activation mediated by testosterone. Testosterone-induced cardiac myocyte hypertrophy was established by increased cardiac myocyte size and [3H]-leucine incorporation (as a measurement of cellular protein synthesis. Calcineurin-NFAT inhibition abolished and GSK-3β inhibition promoted the hypertrophy stimulated by testosterone. GSK-3β activation by GSK-3βS9A blocked the increase of hypertrophic markers induced by testosterone. Moreover, inhibition of intracellular androgen receptor prevented testosterone-induced NFAT-Luc activation. Collectively, these results

  2. Long Non-Coding RNA-ROR Mediates the Reprogramming in Cardiac Hypertrophy.

    Directory of Open Access Journals (Sweden)

    Feng Jiang

    Full Text Available Cardiac hypertrophy associated with various cardiovascular diseases results in heart failure and sudden death. A clear understanding of the mechanisms of hypertrophy will benefit the development of novel therapies. Long non-coding RNAs (lncRNAs have been shown to play essential roles in many biological process, however, whether lncRNA-ROR plays functional roles in the reprogramming of cardiomyocyte remains unclear.Here we show that lncRNA-ROR plays important roles in the pathogenesis of cardiac hypertrophy. In hypertrophic heart and cardiomyocytes, the expression of lncRNA-ROR is dramatically increased, downregulation of which attenuates the hypertrophic responses. Furthermore, the expression of lncRNA-ROR negatively correlates with miR-133, whose expression is increased when lncRNA-ROR is knocked down. In line with this, overexpression of miR-133 prevents the elevation of lncRNA-ROR and re-expression of ANP and BNP in cardiomyocytes subject to phenylephrine treatment.Taken together, our study demonstrates that lncRNA-ROR promotes cardiac hypertrophy via interacting with miR-133, indicating that lncRNA-ROR could be targeted for developing novel antihypertrophic therapeutics.

  3. Long Non-Coding RNA-ROR Mediates the Reprogramming in Cardiac Hypertrophy.

    Science.gov (United States)

    Jiang, Feng; Zhou, Xiangyu; Huang, Jing

    2016-01-01

    Cardiac hypertrophy associated with various cardiovascular diseases results in heart failure and sudden death. A clear understanding of the mechanisms of hypertrophy will benefit the development of novel therapies. Long non-coding RNAs (lncRNAs) have been shown to play essential roles in many biological process, however, whether lncRNA-ROR plays functional roles in the reprogramming of cardiomyocyte remains unclear. Here we show that lncRNA-ROR plays important roles in the pathogenesis of cardiac hypertrophy. In hypertrophic heart and cardiomyocytes, the expression of lncRNA-ROR is dramatically increased, downregulation of which attenuates the hypertrophic responses. Furthermore, the expression of lncRNA-ROR negatively correlates with miR-133, whose expression is increased when lncRNA-ROR is knocked down. In line with this, overexpression of miR-133 prevents the elevation of lncRNA-ROR and re-expression of ANP and BNP in cardiomyocytes subject to phenylephrine treatment. Taken together, our study demonstrates that lncRNA-ROR promotes cardiac hypertrophy via interacting with miR-133, indicating that lncRNA-ROR could be targeted for developing novel antihypertrophic therapeutics.

  4. Role of copper in regression of cardiac hypertrophy.

    Science.gov (United States)

    Zheng, Lily; Han, Pengfei; Liu, Jiaming; Li, Rui; Yin, Wen; Wang, Tao; Zhang, Wenjing; Kang, Y James

    2015-04-01

    Pressure overload causes an accumulation of homocysteine in the heart, which is accompanied by copper depletion through the formation of copper-homocysteine complexes and the excretion of the complexes. Copper supplementation recovers cytochrome c oxidase (CCO) activity and promotes myocardial angiogenesis, along with the regression of cardiac hypertrophy and the recovery of cardiac contractile function. Increased copper availability is responsible for the recovery of CCO activity. Copper promoted expression of angiogenesis factors including vascular endothelial growth factor (VEGF) in endothelial cells is responsible for angiogenesis. VEGF receptor-2 (VEGFR-2) is critical for hypertrophic growth of cardiomyocytes and VEGFR-1 is essential for the regression of cardiomyocyte hypertrophy. Copper, through promoting VEGF production and suppressing VEGFR-2, switches the VEGF signaling pathway from VEGFR-2-dependent to VEGFR-1-dependent, leading to the regression of cardiomyocyte hypertrophy. Copper is also required for hypoxia-inducible factor-1 (HIF-1) transcriptional activity, acting on the interaction between HIF-1 and the hypoxia responsible element and the formation of HIF-1 transcriptional complex by inhibiting the factor inhibiting HIF-1. Therefore, therapeutic targets for copper supplementation-induced regression of cardiac hypertrophy include: (1) the recovery of copper availability for CCO and other critical cellular events; (2) the activation of HIF-1 transcriptional complex leading to the promotion of angiogenesis in the endothelial cells by VEGF and other factors; (3) the activation of VEGFR-1-dependent regression signaling pathway in the cardiomyocytes; and (4) the inhibition of VEGFR-2 through post-translational regulation in the hypertrophic cardiomyocytes. Future studies should focus on target-specific delivery of copper for the development of clinical application. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. North American ginseng (Panax quinquefolius) suppresses β-adrenergic-dependent signalling, hypertrophy, and cardiac dysfunction.

    Science.gov (United States)

    Tang, Xilan; Gan, Xiaohong Tracey; Rajapurohitam, Venkatesh; Huang, Cathy Xiaoling; Xue, Jenny; Lui, Edmund M K; Karmazyn, Morris

    2016-12-01

    There is increasing evidence for a beneficial effect of ginseng on cardiac pathology. Here, we determined whether North American ginseng can modulate the deleterious effects of the β-adrenoceptor agonist isoproterenol on cardiac hypertrophy and function using in vitro and in vivo approaches. Isoproterenol was administered for 2 weeks at either 25 mg/kg per day or 50 mg/kg per day (ISO25 or ISO50) via a subcutaneously implanted osmotic mini-pump to either control rats or those receiving ginseng (0.9 g/L in the drinking water ad libitum). Isoproterenol produced time- and dose-dependent left ventricular dysfunction, although these effects were attenuated by ginseng. Improved cardiac functions were associated with reduced heart masses, as well as prevention in the upregulation of the hypertrophy-related fetal gene expression. Lung masses were similarly attenuated, suggesting reduced pulmonary congestion. In in vitro studies, ginseng (10 μg/mL) completely suppressed the hypertrophic response to 1 μmol/L isoproterenol in terms of myocyte surface area, as well as reduction in the upregulation of fetal gene expression. These effects were associated with attenuation in both protein kinase A and cAMP response element-binding protein phosphorylation. Ginseng attenuates adverse cardiac adrenergic responses and, therefore, may be an effective therapy to reduce hypertrophy and heart failure associated with excessive catecholamine production.

  6. Mouse models for the study of postnatal cardiac hypertrophy

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    A. Del Olmo-Turrubiarte

    2015-06-01

    Full Text Available The main objective of this study was to create a postnatal model for cardiac hypertrophy (CH, in order to explain the mechanisms that are present in childhood cardiac hypertrophy. Five days after implantation, intraperitoneal (IP isoproterenol (ISO was injected for 7 days to pregnant female mice. The fetuses were obtained at 15, 17 and 19 dpc from both groups, also newborns (NB, neonates (7–15 days and young adults (6 weeks of age. Histopathological exams were done on the hearts. Immunohistochemistry and western blot demonstrated GATA4 and PCNA protein expression, qPCR real time the mRNA of adrenergic receptors (α-AR and β-AR, alpha and beta myosins (α-MHC, β-MHC and GATA4. After the administration of ISO, there was no change in the number of offsprings. We observed significant structural changes in the size of the offspring hearts. Morphometric analysis revealed an increase in the size of the left ventricular wall and interventricular septum (IVS. Histopathological analysis demonstrated loss of cellular compaction and presence of left ventricular small fibrous foci after birth. Adrenergic receptors might be responsible for changing a physiological into a pathological hypertrophy. However GATA4 seemed to be the determining factor in the pathology. A new animal model was established for the study of pathologic CH in early postnatal stages.

  7. Suppression of cardiac myocyte hypertrophy by conjugated linoleic acid: role of peroxisome proliferator-activated receptors alpha and gamma.

    Science.gov (United States)

    Alibin, Caroline P; Kopilas, Melanie A; Anderson, Hope D I

    2008-04-18

    Conjugated linoleic acid (CLA) refers to a naturally occurring mixture of positional and geometric isomers of linoleic acid. Evidence suggests that CLA is a dietary constituent and nutraceutical with anti-cancer, insulin-sensitizing, immunomodulatory, weight-partitioning, and cardioprotective properties. The aim of this study was to evaluate the effects of intervention with CLA on cardiac hypertrophy. In vitro, CLA prevented indicators of cardiomyocyte hypertrophy elicited by endothelin-1, including cell size augmentation, protein synthesis, and fetal gene activation. Similar anti-hypertrophic effects of CLA were observed in hypertrophy induced by angiotensin II, fibroblast growth factor, and mechanical strain. CLA may inhibit hypertrophy through activation of peroxisome proliferator-activated receptors (PPARs). CLA stimulated PPAR activity in cardiomyocytes, and the anti-hypertrophic effects of CLA were blocked by genetic and pharmacological inhibitors of PPAR isoforms alpha and gamma. CLA may disrupt hypertrophic signaling by stimulating diacylglycerol kinase zeta, which decreases availability of diacylglycerol and thereby inhibits the protein kinase Cepsilon pathway. In vivo, dietary CLA supplementation significantly reduced blood pressure and cardiac hypertrophy in spontaneously hypertensive heart failure rats. These data suggest that dietary supplementation with CLA may be a viable strategy to prevent pathological cardiac hypertrophy, a major risk factor for heart failure.

  8. Identification of a core set of genes that signifies pathways underlying cardiac hypertrophy

    DEFF Research Database (Denmark)

    Strom, C.C.; Kruhoffer, M.; Knudsen, S.

    2004-01-01

    Although the molecular signals underlying cardiac hypertrophy have been the subject of intense investigation, the extent of common and distinct gene regulation between different forms of cardiac hypertrophy remains unclear. We hypothesized that a general and comparative analysis of hypertrophic...... gene expression, using microarray technology in multiple models of cardiac hypertrophy, including aortic banding, myocardial infarction, an arteriovenous shunt and pharmacologically induced hypertrophy, would uncover networks of conserved hypertrophy-specific genes and identify novel genes involved...... in hypertrophic signalling. From gene expression analyses (8740 probe sets, n = 46) of rat ventricular RNA, we identified a core set of 139 genes with consistent differential expression in all hypertrophy models as compared to their controls, including 78 genes not previously associated with hypertrophy and 61...

  9. Intermedin suppresses pressure overload cardiac hypertrophy through activation of autophagy.

    Science.gov (United States)

    Chen, Huali; Wang, Xue; Tong, Mingming; Wu, Dan; Wu, Sisi; Chen, Jiaxiang; Wang, Xiaoxiao; Wang, Xulei; Kang, Yu; Tang, Hong; Tang, Chaoshu; Jiang, Wei

    2013-01-01

    Left ventricular hypertrophy is a maladaptive response to pressure overload and an important risk factor for heart failure. Intermedin (IMD), a multi-functional peptide, plays important roles in cardiovascular protection. In this study, we revealed an autophagy-dependent mechanism involved in IMD's protection against cardiac remodeling and cardiomyocyte death in heart hypertrophy. We observed that transverse aortic contraction (TAC) induction, Ang II or ISO exposure induced remarkable increase in the expression of endogenous IMD and its receptor components, CRLR, RAMP1 and RAMP3, in mouse hearts and H9c2 cell cultures, respectively. Furthermore, the heart size, heart weight/body weight ratios, cardiomyocyte size and apoptosis, interstitial collagen, hypertrophic markers including ANP and BNP expression were also significantly increased, which were effectively suppressed by IMD supplementation. In addition, IMD induced capillary angiogenesis and improved functions in hypertrophic hearts. We further observed that IMD induced strong autophagy in hypertrophic hearts and cultured cells, which was paralleling with the decrease in cardiomyocyte size and apoptosis. Furthermore, an autophagy inhibitor, 3-MA, was used to block the IMD-augmented autophagy level, and then the protection of IMD on cardiomyocyte hypertrophy and apoptosis was almost abrogated. We also observed that IMD supplementation stirred intracellular cAMP production, and augmented the ERK1/2 phosphorylation induced by Ang II/ISO exposure in H9c2 cells. In addition, we inhibited PI3K, PKA and MAPK/ERK1/2 signaling pathways by using wortamannin, H89 and PD98059, respectively, in H9c2 cells co-incubating with both IMD and Ang II or ISO, and observed that these inhibitors effectively reduced IMD-augmented autophagy level, but only H89 and PD98059 pre-incubation abrogated the anti-apoptotic action of IMD. These results indicate that the endogenous IMD and its receptor complexes are induced in hypertrophic

  10. Intermedin suppresses pressure overload cardiac hypertrophy through activation of autophagy.

    Directory of Open Access Journals (Sweden)

    Huali Chen

    Full Text Available Left ventricular hypertrophy is a maladaptive response to pressure overload and an important risk factor for heart failure. Intermedin (IMD, a multi-functional peptide, plays important roles in cardiovascular protection. In this study, we revealed an autophagy-dependent mechanism involved in IMD's protection against cardiac remodeling and cardiomyocyte death in heart hypertrophy. We observed that transverse aortic contraction (TAC induction, Ang II or ISO exposure induced remarkable increase in the expression of endogenous IMD and its receptor components, CRLR, RAMP1 and RAMP3, in mouse hearts and H9c2 cell cultures, respectively. Furthermore, the heart size, heart weight/body weight ratios, cardiomyocyte size and apoptosis, interstitial collagen, hypertrophic markers including ANP and BNP expression were also significantly increased, which were effectively suppressed by IMD supplementation. In addition, IMD induced capillary angiogenesis and improved functions in hypertrophic hearts. We further observed that IMD induced strong autophagy in hypertrophic hearts and cultured cells, which was paralleling with the decrease in cardiomyocyte size and apoptosis. Furthermore, an autophagy inhibitor, 3-MA, was used to block the IMD-augmented autophagy level, and then the protection of IMD on cardiomyocyte hypertrophy and apoptosis was almost abrogated. We also observed that IMD supplementation stirred intracellular cAMP production, and augmented the ERK1/2 phosphorylation induced by Ang II/ISO exposure in H9c2 cells. In addition, we inhibited PI3K, PKA and MAPK/ERK1/2 signaling pathways by using wortamannin, H89 and PD98059, respectively, in H9c2 cells co-incubating with both IMD and Ang II or ISO, and observed that these inhibitors effectively reduced IMD-augmented autophagy level, but only H89 and PD98059 pre-incubation abrogated the anti-apoptotic action of IMD. These results indicate that the endogenous IMD and its receptor complexes are induced in

  11. Expression profiling reveals differences in metabolic gene expression between exercise-induced cardiac effects and maladaptive cardiac hypertrophy

    DEFF Research Database (Denmark)

    Strøm, Claes C; Aplin, Mark; Ploug, Thorkil

    2005-01-01

    While cardiac hypertrophy elicited by pathological stimuli eventually leads to cardiac dysfunction, exercise-induced hypertrophy does not. This suggests that a beneficial hypertrophic phenotype exists. In search of an underlying molecular substrate we used microarray technology to identify cardiac...... by quantitative PCR. The exercise program resulted in cardiac hypertrophy without impaired cardiac function. Principal component analysis identified an exercise-induced change in gene expression that was distinct from the program observed in maladaptive hypertrophy. Statistical analysis identified 267 upregulated...... genes and 62 downregulated genes in response to exercise. Expression changes in genes encoding extracellular matrix proteins, cytoskeletal elements, signalling factors and ribosomal proteins mimicked changes previously described in maladaptive hypertrophy. Our most striking observation...

  12. Characterization of endonuclease G and mitochondria-sarcoplasmic reticulum-related proteins during cardiac hypertrophy.

    Science.gov (United States)

    Liang, Xingguang; Ma, Kuifen; Rao, Yuefeng; Hong, Dongsheng; Huo, Zhaoxia; Ye, Ziqi; Huang, Mingzhu; Zhang, Xingguo; Zhao, Qingwei

    2015-09-01

    Endonuclease G (Endo G) is a novel determinant of cardiac hypertrophy. Here, we report the characterization of Endo G and mitochondria-sarcoplasmic reticulum-related proteins during cardiac hypertrophy, and hypothesize that Endo G regulate mitochondrial function partly through Mfn2 and Jp2 during cardiac hypertrophy. Our results show that Endo G levels gradually increased at the beginning of phenylephrine-induced cardiac hypertrophy, accompanied by an abnormal mitochondrial membrane potential. The up-regulation of Mfn2, Jp2, and Endo G appeared at an early stage of cardiac hypertrophy, whereas PGC1α was not up-regulated until a later stage. Abolishing Endo G with siRNA led to the uncoupling of the mitochondrial electron transport chain from ATP production and decreased PGC1α expression, likely by affecting the juxtaposition of the mitochondria and the sarcoplasmic reticulum via Mfn2 and Jp2. Furthermore, abolishing Jp2 altered the expression of Endo G expression and induced mitochondrial dysfunction, suggesting that mitochondrial abnormalities in cardiac hypertrophy are most likely caused by Endo G. Taken together, our study established a link between Endo G and mitochondrial function during cardiac hypertrophy, partly through the effects of Endo G on Mfn2 and Jp2, and revealed a role for Endo G in the crosstalk between the processes controlled by Mfn2 and Jp2 in maladaptive cardiac hypertrophy.

  13. A Systems Biology Approach to Investigating Sex Differences in Cardiac Hypertrophy.

    Science.gov (United States)

    Harrington, Josephine; Fillmore, Natasha; Gao, Shouguo; Yang, Yanqin; Zhang, Xue; Liu, Poching; Stoehr, Andrea; Chen, Ye; Springer, Danielle; Zhu, Jun; Wang, Xujing; Murphy, Elizabeth

    2017-08-19

    Heart failure preceded by hypertrophy is a leading cause of death, and sex differences in hypertrophy are well known, although the basis for these sex differences is poorly understood. This study used a systems biology approach to investigate mechanisms underlying sex differences in cardiac hypertrophy. Male and female mice were treated for 2 and 3 weeks with angiotensin II to induce hypertrophy. Sex differences in cardiac hypertrophy were apparent after 3 weeks of treatment. RNA sequencing was performed on hearts, and sex differences in mRNA expression at baseline and following hypertrophy were observed, as well as within-sex differences between baseline and hypertrophy. Sex differences in mRNA were substantial at baseline and reduced somewhat with hypertrophy, as the mRNA differences induced by hypertrophy tended to overwhelm the sex differences. We performed an integrative analysis to identify mRNA networks that were differentially regulated in the 2 sexes by hypertrophy and obtained a network centered on PPARα (peroxisome proliferator-activated receptor α). Mouse experiments further showed that acute inhibition of PPARα blocked sex differences in the development of hypertrophy. The data in this study suggest that PPARα is involved in the sex-dimorphic regulation of cardiac hypertrophy. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  14. Deletion of soluble epoxide hydrolase attenuates cardiac hypertrophy via down-regulation of cardiac fibroblasts-derived fibroblast growth factor-2.

    Science.gov (United States)

    Zhang, Huanji; Wang, Tong; Zhang, Kun; Liu, Yu; Huang, Feifei; Zhu, Xinhong; Liu, Yang; Wang, Mong-Heng; Tang, Wanchun; Wang, Jingfeng; Huang, Hui

    2014-05-01

    Inhibition of soluble epoxide hydrolase (Ephx2) has been shown to play a protective role in cardiac hypertrophy, but the mechanism is not fully understood. We tested the hypothesis that deletion of soluble epoxide hydrolase attenuates cardiac hypertrophy via down-regulation of cardiac fibroblasts-derived fibroblast growth factor-2. Prospective, controlled, and randomized animal study. University laboratory. Male wild-type C57BL/6 mice and Ephx2 (-/-) mice. Male wild-type or Ephx2 (-/-) mice were subjected to transverse aorta constriction surgery. Four weeks after transverse aorta constriction, Ephx2 (-/-) mice did not develop significant cardiac hypertrophy as that of wild-type mice, indicated by no changes in the ratio of heart weight/body weight and ventricular wall thickness after transverse aorta constriction. Cardiac fibroblast growth factor-2 increased in wild-type-transverse aorta constriction group but this did not change in Ephx2 (-/-)-transverse aorta constriction group, and the serum level of fibroblast growth factor-2 did not change in both groups. In vitro, cardiac fibroblasts were stimulated by angiotensin II to analyze the expression of fibroblast growth factor-2. The effect of increased fibroblast growth factor-2 from cardiac fibroblasts induced by angiotensin II was attenuated by soluble epoxide hydrolase deletion. ERK1/2, p38, and AKT kinase were involved in fibroblast growth factor-2 expression regulated by angiotensin II, and soluble epoxide hydrolase deletion lowered the phosphorylation of ERK1/2 not p38 or AKT to mediate fibroblast growth factor-2 expression. In addition, soluble epoxide hydrolase deletion did not attenuate cardiomyocytes hypertrophy induced by exogenous fibroblast growth factor-2. Our present data demonstrated that deletion of soluble epoxide hydrolase prevented cardiac hypertrophy not only directly to cardiomyocytes but also to cardiac fibroblasts by reducing expression of fibroblast growth factor-2.

  15. Herbal Supplement Ameliorates Cardiac Hypertrophy in Rats with CCl4-Induced Liver Cirrhosis

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    Ping-Chun Li

    2012-01-01

    Full Text Available We used the carbon tetrachloride (CCl4 induced liver cirrhosis model to test the molecular mechanism of action involved in cirrhosis-associated cardiac hypertrophy and the effectiveness of Ocimum gratissimum extract (OGE and silymarin against cardiac hypertrophy. We treated male wistar rats with CCl4 and either OGE (0.02 g/kg B.W. or 0.04 g/kg B.W. or silymarin (0.2 g/kg B.W.. Cardiac eccentric hypertrophy was induced by CCl4 along with cirrhosis and increased expression of cardiac hypertrophy related genes NFAT, TAGA4, and NBP, and the interleukin-6 (IL-6 signaling pathway related genes MEK5, ERK5, JAK, and STAT3. OGE or silymarin co-treatment attenuated CCl4-induced cardiac abnormalities, and lowered expression of genes which were elevated by this hepatotoxin. Our results suggest that the IL-6 signaling pathway may be related to CCl4-induced cardiac hypertrophy. OGE and silymarin were able to lower liver fibrosis, which reduces the chance of cardiac hypertrophy perhaps by lowering the expressions of IL-6 signaling pathway related genes. We conclude that treatment of cirrhosis using herbal supplements is a viable option for protecting cardiac tissues against cirrhosis-related cardiac hypertrophy.

  16. Dual specific phosphatase 12 ameliorates cardiac hypertrophy in response to pressure overload.

    Science.gov (United States)

    Li, Wei-Ming; Zhao, Yi-Fan; Zhu, Guo-Fu; Peng, Wen-Hui; Zhu, Meng-Yun; Yu, Xue-Jing; Chen, Wei; Xu, Da-Chun; Xu, Ya-Wei

    2017-01-01

    Pathological cardiac hypertrophy is an independent risk factor of heart failure. However, we still lack effective methods to reverse cardiac hypertrophy. DUSP12 is a member of the dual specific phosphatase (DUSP) family, which is characterized by its DUSP activity to dephosphorylate both tyrosine and serine/threonine residues on one substrate. Some DUSPs have been identified as being involved in the regulation of cardiac hypertrophy. However, the role of DUSP12 during pathological cardiac hypertrophy is still unclear. In the present study, we observed a significant decrease in DUSP12 expression in hypertrophic hearts and cardiomyocytes. Using a genetic loss-of-function murine model, we demonstrated that DUSP12 deficiency apparently aggravated pressure overload-induced cardiac hypertrophy and fibrosis as well as impaired cardiac function, whereas cardiac-specific overexpression of DUPS12 was capable of reversing this hypertrophic and fibrotic phenotype and improving contractile function. Furthermore, we demonstrated that JNK1/2 activity but neither ERK1/2 nor p38 activity was increased in the DUSP12 deficient group and decreased in the DUSP12 overexpression group both in vitro and in vivo under hypertrophic stress conditions. Pharmacological inhibition of JNK1/2 activity (SP600125) is capable of reversing the hypertrophic phenotype in DUSP12 knockout (KO) mice. DUSP12 protects against pathological cardiac hypertrophy and related pathologies. This regulatory role of DUSP12 is primarily through c-Jun N-terminal kinase (JNK) inhibition. DUSP12 could be a promising therapeutic target of pathological cardiac hypertrophy. DUSP12 is down-regulated in hypertrophic hearts. An absence of DUSP12 aggravated cardiac hypertrophy, whereas cardiomyocyte-specific DUSP12 overexpression can alleviate this hypertrophic phenotype with improved cardiac function. Further study demonstrated that DUSP12 inhibited JNK activity to attenuate pathological cardiac hypertrophy. © 2016 The

  17. Electrocardiographic Characterization of Cardiac Hypertrophy in Mice that Overexpress the ErbB2 Receptor Tyrosine Kinase

    DEFF Research Database (Denmark)

    Sysa-Shah, Polina; Sørensen, Lars L; Abraham, M Roselle

    2015-01-01

    Electrocardiography is an important method for evaluation and risk stratification of patients with cardiac hypertrophy. We hypothesized that the recently developed transgenic mouse model of cardiac hypertrophy (ErbB2(tg)) will display distinct ECG features, enabling WT (wild type) mice...... in other rodent models of cardiac hypertrophy. Furthermore, with appropriate modifications, this method might be translated for use in other species....

  18. Eccentric and concentric cardiac hypertrophy induced by exercise training: microRNAs and molecular determinants.

    Science.gov (United States)

    Fernandes, T; Soci, U P R; Oliveira, E M

    2011-09-01

    Among the molecular, biochemical and cellular processes that orchestrate the development of the different phenotypes of cardiac hypertrophy in response to physiological stimuli or pathological insults, the specific contribution of exercise training has recently become appreciated. Physiological cardiac hypertrophy involves complex cardiac remodeling that occurs as an adaptive response to static or dynamic chronic exercise, but the stimuli and molecular mechanisms underlying transduction of the hemodynamic overload into myocardial growth are poorly understood. This review summarizes the physiological stimuli that induce concentric and eccentric physiological hypertrophy, and discusses the molecular mechanisms, sarcomeric organization, and signaling pathway involved, also showing that the cardiac markers of pathological hypertrophy (atrial natriuretic factor, β-myosin heavy chain and α-skeletal actin) are not increased. There is no fibrosis and no cardiac dysfunction in eccentric or concentric hypertrophy induced by exercise training. Therefore, the renin-angiotensin system has been implicated as one of the regulatory mechanisms for the control of cardiac function and structure. Here, we show that the angiotensin II type 1 (AT1) receptor is locally activated in pathological and physiological cardiac hypertrophy, although with exercise training it can be stimulated independently of the involvement of angiotensin II. Recently, microRNAs (miRs) have been investigated as a possible therapeutic approach since they regulate the translation of the target mRNAs involved in cardiac hypertrophy; however, miRs in relation to physiological hypertrophy have not been extensively investigated. We summarize here profiling studies that have examined miRs in pathological and physiological cardiac hypertrophy. An understanding of physiological cardiac remodeling may provide a strategy to improve ventricular function in cardiac dysfunction.

  19. Tom70 serves as a molecular switch to determine pathological cardiac hypertrophy

    Science.gov (United States)

    Li, Jun; Qi, Man; Li, Changming; Shi, Dan; Zhang, Dasheng; Xie, Duanyang; Yuan, Tianyou; Feng, Jing; Liu, Yi; Liang, Dandan; Xu, Xinran; Chen, Jinjin; Xu, Liang; Zhang, Hong; Ye, Jiangchuan; Lv, Fei; Huang, Jian; Peng, Luying; Chen, Yi-Han

    2014-01-01

    Pathological cardiac hypertrophy is an inevitable forerunner of heart failure. Regardless of the etiology of cardiac hypertrophy, cardiomyocyte mitochondrial alterations are always observed in this context. The translocases of mitochondrial outer membrane (Tom) complex governs the import of mitochondrial precursor proteins to maintain mitochondrial function under pathophysiological conditions; however, its role in the development of pathological cardiac hypertrophy remains unclear. Here, we showed that Tom70 was downregulated in pathological hypertrophic hearts from humans and experimental animals. The reduction in Tom70 expression produced distinct pathological cardiomyocyte hypertrophy both in vivo and in vitro. The defective mitochondrial import of Tom70-targeted optic atrophy-1 triggered intracellular oxidative stress, which led to a pathological cellular response. Importantly, increased Tom70 levels provided cardiomyocytes with full resistance to diverse pro-hypertrophic insults. Together, these results reveal that Tom70 acts as a molecular switch that orchestrates hypertrophic stresses and mitochondrial responses to determine pathological cardiac hypertrophy. PMID:25022898

  20. A Cardiac-enriched MicroRNA, miR-378, Blocks Cardiac Hypertrophy by Targeting Ras Signaling*

    Science.gov (United States)

    Nagalingam, Raghu S.; Sundaresan, Nagalingam R.; Gupta, Mahesh P.; Geenen, David L.; Solaro, R. John; Gupta, Madhu

    2013-01-01

    Understanding the regulation of cardiomyocyte growth is crucial for the management of adverse ventricular remodeling and heart failure. MicroRNA-378 (miR-378) is a newly described member of the cardiac-enriched miRNAs, which is expressed only in cardiac myocytes and not in cardiac fibroblasts. We have previously shown that miR-378 regulates cardiac growth during the postnatal period by direct targeting of IGF1R (Knezevic, I., Patel, A., Sundaresan, N. R., Gupta, M. P., Solaro, R. J., Nagalingam, R. S., and Gupta, M. (2012) J. Biol. Chem. 287, 12913–12926). Here, we report that miR-378 is an endogenous negative regulator of cardiac hypertrophy, and its levels are down-regulated during hypertrophic growth of the heart and during heart failure. In primary cultures of cardiomyocytes, overexpression of miR-378 blocked phenylephrine (PE)-stimulated Ras activity and also prevented activation of two major growth-promoting signaling pathways, PI3K-AKT and Raf1-MEK1-ERK1/2, acting downstream of Ras signaling. Overexpression of miR-378 suppressed PE-induced phosphorylation of S6 ribosomal kinase, pERK1/2, pAKT, pGSK-3β, and nuclear accumulation of NFAT. There was also suppression of the fetal gene program that was induced by PE. Experiments carried out to delineate the mechanism behind the suppression of Ras, led us to identify Grb2, an upstream component of Ras signaling, as a bona fide direct target of miR-378-mediated regulation. Deficiency of miR-378 alone was sufficient to induce fetal gene expression, which was prevented by knocking down Grb2 expression and blocking Ras activation, thus suggesting that miR-378 interferes with Ras activation by targeting Grb2. Our study demonstrates that miR-378 is an endogenous negative regulator of Ras signaling and cardiac hypertrophy and its deficiency contributes to the development of cardiac hypertrophy. PMID:23447532

  1. CSI cardiac prevent 2015

    Directory of Open Access Journals (Sweden)

    S Ramakrishnan

    2015-01-01

    Full Text Available The CSI Cardiac Prevent 2015 was held at Hotel Taj Palace, New Delhi, on September 25-27, 2015. The major challenge was to create interest among cardiologists and physicians on preventive cardiology, a neglected area. The theme of the conference was "Innovations in Heart Disease Prevention.′′ This conference included "CSI at WHF Roadmap Workshop, Inauguration Ceremony, scientific program, plenary sessions, Nursing/Dietician track, Industry Exhibition, Social Events," Great India blood pressure Survey, and CSI Smart Heart App. A total of 848 delegates/faculties attended this conference against a total of 1140 people registered for the meeting.

  2. Transcriptional profile of isoproterenol-induced cardiomyopathy and comparison to exercise-induced cardiac hypertrophy and human cardiac failure

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    McIver Lauren J

    2009-12-01

    Full Text Available Abstract Background Isoproterenol-induced cardiac hypertrophy in mice has been used in a number of studies to model human cardiac disease. In this study, we compared the transcriptional response of the heart in this model to other animal models of heart failure, as well as to the transcriptional response of human hearts suffering heart failure. Results We performed microarray analyses on RNA from mice with isoproterenol-induced cardiac hypertrophy and mice with exercise-induced physiological hypertrophy and identified 865 and 2,534 genes that were significantly altered in pathological and physiological cardiac hypertrophy models, respectively. We compared our results to 18 different microarray data sets (318 individual arrays representing various other animal models and four human cardiac diseases and identified a canonical set of 64 genes that are generally altered in failing hearts. We also produced a pairwise similarity matrix to illustrate relatedness of animal models with human heart disease and identified ischemia as the human condition that most resembles isoproterenol treatment. Conclusion The overall patterns of gene expression are consistent with observed structural and molecular differences between normal and maladaptive cardiac hypertrophy and support a role for the immune system (or immune cell infiltration in the pathology of stress-induced hypertrophy. Cross-study comparisons such as the results presented here provide targets for further research of cardiac disease that might generally apply to maladaptive cardiac stresses and are also a means of identifying which animal models best recapitulate human disease at the transcriptional level.

  3. Endurance exercise effects on cardiac hypertrophy in mice.

    Science.gov (United States)

    Han, Gun-Soo

    2013-12-01

    [Purpose] The purpose of this study was to investigate the effects of eight weeks of an endurance exercise training program on cardiac hypertrophy in mice. [Subjects] Male 129 SvJ/C57BL6 mice (n=12) were used. The exercised mice ran on a motor-driven treadmill five days per week for 40 minutes at a speed of 24 m/min for eight weeks. All mice were weighed once a week to monitor excessive increases or decreases in weight. Peak weight was determined as the highest weekly recorded weight. Post-training weight was also taken on the day of final data collection. Following body weight measurement, the heart was excised from the body and weighed. The ratio of heart weight to body weight was calculated as an indicator of cardiac hypertrophy in the current study. Using an independent t test, the ratio of heart weight to body weight was compared between the exercised mice and the sedentary mice. [Results] The results show that the untrained mice had a significantly greater heart weight to body weight ratio compared with the wild-type mice. There was also a significant difference in body weight between the exercised and sedentary groups. The ratio of heart weight to body weight was lower in the untrained mice, but no significance was observed. [Conclusion] Running on the motor- driven treadmill five days per week for 40 minutes at a speed of 24 m/min for eight weeks did not increase in the ratio of heart weight to body weight in mice compared with the sedentary.

  4. Senescence as a novel mechanism involved in β-adrenergic receptor mediated cardiac hypertrophy

    Science.gov (United States)

    Sun, Rongrong; Zhu, Baoling; Sun, Yan; Shi, Dandan; Chen, Li; Zhang, Youyi; Li, Zijian; Xue, Lixiang

    2017-01-01

    Pathological cardiac hypertrophy used to be elucidated by biomechanical, stretch-sensitive or neurohumoral mechanisms. However, a series of hints have indicated that hypertrophy process simulates senescence program. However, further evidence need to be pursued. To verify this hypothesis and examine whether cardiac senescence is a novel mechanism of hypertrophy induced by isoproterenol, 2-month-old male Sprague Dawley rats were subjected to isoproterenol infusion (0.25mg/kg/day) for 7 days by subcutaneous injection). Key characteristics of senescence (senescence-associated β-galactosidase activity, lipofuscin, expression of cyclin-dependent kinase inhibitors) were examined in cardiac hypertrophy model. Senescence-like phenotype, such as increased senescence-associated β-galactosidase activity, accumulation of lipofuscin and high levels of cyclin-dependent kinase inhibitors (e.g. p16, p19, p21 and p53) was found along the process of cardiac hypertrophy. Cardiac-specific transcription factor GATA4 increased in isoproterenol-treated cardiomyocytes as well. We further found that myocardial hypertrophy could be inhibited by resveratrol, an anti-aging compound, in a dose-dependent manner. Our results showed for the first time that cardiac senescence is involved in the process of pathological cardiac hypertrophy induced by isoproterenol. PMID:28783759

  5. Gastrodin Inhibits Store-Operated Ca2+ Entry and Alleviates Cardiac Hypertrophy

    Directory of Open Access Journals (Sweden)

    Xiaoqiang Yao

    2017-04-01

    Full Text Available Cardiac hypertrophy is a major risk factor for heart failure, which are among the leading causes of human death. Gastrodin is a small molecule that has been used clinically to treat neurological and vascular diseases for many years without safety issues. In the present study, we examined protective effect of gastrodin against cardiac hypertrophy and explored the underlying mechanism. Phenylephrine and angiotensin II were used to induce cardiac hypertrophy in a mouse model and a cultured cardiomyocyte model. Gastrodin was found to alleviate the cardiac hypertrophy in both models. Mechanistically, gastrodin attenuated the store-operated Ca2+ entry (SOCE by reducing the expression of STIM1 and Orai1, two key proteins in SOCE, in animal models as well as in cultured cardiomyocyte model. Furthermore, suppressing SOCE by RO2959, Orai1-siRNAs or STIM1-siRNAs markedly attenuated the phenylephrine-induced hypertrophy in cultured cardiomyocyte model. Together, these results showed that gastrodin inhibited cardiac hypertrophy and it also reduced the SOCE via its action on the expression of STIM1 and Orai1. Furthermore, suppression of SOCE could reduce the phenylephrine-induced cardiomyocyte hypertrophy, suggesting that SOCE-STIM1-Orai1 is located upstream of hypertrophy.

  6. BMP type I receptor ALK2 is required for angiotensin II-induced cardiac hypertrophy

    Science.gov (United States)

    Spagnolli, Ester; Ernande, Laura; Thoonen, Robrecht; Kolodziej, Starsha A.; Leyton, Patricio A.; Cheng, Juan; Tainsh, Robert E. T.; Mayeur, Claire; Rhee, David K.; Wu, Mei. X.; Scherrer-Crosbie, Marielle; Buys, Emmanuel S.; Zapol, Warren M.; Bloch, Kenneth D.; Bloch, Donald B.

    2016-01-01

    Bone morphogenetic protein (BMP) signaling contributes to the development of cardiac hypertrophy. However, the identity of the BMP type I receptor involved in cardiac hypertrophy and the underlying molecular mechanisms are poorly understood. By using quantitative PCR and immunoblotting, we demonstrated that BMP signaling increased during phenylephrine-induced hypertrophy in cultured neonatal rat cardiomyocytes (NRCs), as evidenced by increased phosphorylation of Smads 1 and 5 and induction of Id1 gene expression. Inhibition of BMP signaling with LDN193189 or noggin, and silencing of Smad 1 or 4 using small interfering RNA diminished the ability of phenylephrine to induce hypertrophy in NRCs. Conversely, activation of BMP signaling with BMP2 or BMP4 induced hypertrophy in NRCs. Luciferase reporter assay further showed that BMP2 or BMP4 treatment of NRCs repressed atrogin-1 gene expression concomitant with an increase in calcineurin protein levels and enhanced activity of nuclear factor of activated T cells, providing a mechanism by which BMP signaling contributes to cardiac hypertrophy. In a model of cardiac hypertrophy, C57BL/6 mice treated with angiotensin II (A2) had increased BMP signaling in the left ventricle. Treatment with LDN193189 attenuated A2-induced cardiac hypertrophy and collagen deposition in left ventricles. Cardiomyocyte-specific deletion of BMP type I receptor ALK2 (activin-like kinase 2), but not ALK1 or ALK3, inhibited BMP signaling and mitigated A2-induced cardiac hypertrophy and left ventricular fibrosis in mice. The results suggest that BMP signaling upregulates the calcineurin/nuclear factor of activated T cell pathway via BMP type I receptor ALK2, contributing to cardiac hypertrophy and fibrosis. PMID:26873969

  7. Obesity-associated cardiac pathogenesis in broiler breeder hens: Pathological adaption of cardiac hypertrophy.

    Science.gov (United States)

    Chen, C Y; Lin, H Y; Chen, Y W; Ko, Y J; Liu, Y J; Chen, Y H; Walzem, R L; Chen, S E

    2017-07-01

    Broiler hens consuming feed to appetite (ad libitum; AL) show increased mortality. Feed restriction (R) typically improves reproductive performance and livability of hens. Rapidly growing broilers can exhibit increased mortality due to cardiac insufficiency but it is unknown whether the increased mortality of non-R broiler hens is also due to cardiac compromise. To assess cardiac growth and physiology in fully mature birds, 45-week-old hens were either continued on R rations or assigned to AL feeding for 7 or 21 days. AL hens exhibited increased bodyweight, adiposity, absolute and relative heart weight, ventricular hypertrophy, and cardiac protein/DNA ratio by d 21 (P hens (P Hens allowed AL feeding for 70 d exhibited a higher incidence of mortality (40% vs. 10%) in association with ascites, pericardial effusion, and ventricle dilation. A higher incidence of irregular ECG patterns and rhythmicity consistent with persistently elevated systolic blood pressure and ventricle fibrosis were observed in AL hens (P feeding in broiler hens results in maladaptive cardiac hypertrophy that progresses to overt pathogenesis in contractility and thereby increases mortality. Feed restriction provides clear physiological benefit to heart function of adult broiler hens. © 2017 Poultry Science Association Inc.

  8. Improved bioavailability of targeted Curcumin delivery efficiently regressed cardiac hypertrophy by modulating apoptotic load within cardiac microenvironment

    International Nuclear Information System (INIS)

    Ray, Aramita; Rana, Santanu; Banerjee, Durba; Mitra, Arkadeep; Datta, Ritwik; Naskar, Shaon; Sarkar, Sagartirtha

    2016-01-01

    Cardiomyocyte apoptosis acts as a prime modulator of cardiac hypertrophy leading to heart failure, a major cause of human mortality worldwide. Recent therapeutic interventions have focussed on translational applications of diverse pharmaceutical regimes among which, Curcumin (from Curcuma longa) is known to have an anti-hypertrophic potential but with limited pharmacological efficacies due to low aqueous solubility and poor bioavailability. In this study, Curcumin encapsulated by carboxymethyl chitosan (CMC) nanoparticle conjugated to a myocyte specific homing peptide was successfully delivered in bioactive form to pathological myocardium for effective regression of cardiac hypertrophy in a rat (Rattus norvegicus) model. Targeted nanotization showed higher cardiac bioavailability of Curcumin at a low dose of 5 mg/kg body weight compared to free Curcumin at 35 mg/kg body weight. Moreover, Curcumin/CMC-peptide treatment during hypertrophy significantly improved cardiac function by downregulating expression of hypertrophy marker genes (ANF, β-MHC), apoptotic mediators (Bax, Cytochrome-c) and activity of apoptotic markers (Caspase 3 and PARP); whereas free Curcumin in much higher dose showed minimal improvement during compromised cardiac function. Targeted Curcumin treatment significantly lowered p53 expression and activation in diseased myocardium via inhibited interaction of p53 with p300-HAT. Thus attenuated acetylation of p53 facilitated p53 ubiquitination and reduced the apoptotic load in hypertrophied cardiomyocytes; thereby limiting cardiomyocytes' need to enter the regeneration cycle during hypertrophy. This study elucidates for the first time an efficient targeted delivery regimen for Curcumin and also attributes towards probable mechanistic insight into its therapeutic potential as a cardio-protective agent for regression of cardiac hypertrophy. - Highlights: • Cardiomyocyte targeted Curcumin/CMC-peptide increases bioavailability of the drug. • Curcumin

  9. Over-expression of angiotensin converting enzyme-1 augments cardiac hypertrophy in transgenic rats

    NARCIS (Netherlands)

    Tian, Xiao-Li; Pinto, Yigal Martin; Costerousse, Olivier; Franz, Wolfgang M.; Lippoldt, Andrea; Hoffmann, Sigrid; Unger, Thomas; Paul, Martin

    2004-01-01

    Increased cardiac angiotensin converting enzyme-1 (ACE1) is found in individuals who carry a deletion in intron 16 of ACE1 gene or in individuals who suffer from cardiac disorders, such as hypertrophy. However, whether a single increase in ACE1 expression leads to spontaneous cardiac defects remains

  10. PTRF/Cavin-1 Deficiency Causes Cardiac Dysfunction Accompanied by Cardiomyocyte Hypertrophy and Cardiac Fibrosis.

    Directory of Open Access Journals (Sweden)

    Takuya Taniguchi

    Full Text Available Mutations in the PTRF/Cavin-1 gene cause congenital generalized lipodystrophy type 4 (CGL4 associated with myopathy. Additionally, long-QT syndrome and fatal cardiac arrhythmia are observed in patients with CGL4 who have homozygous PTRF/Cavin-1 mutations. PTRF/Cavin-1 deficiency shows reductions of caveolae and caveolin-3 (Cav3 protein expression in skeletal muscle, and Cav3 deficiency in the heart causes cardiac hypertrophy with loss of caveolae. However, it remains unknown how loss of PTRF/Cavin-1 affects cardiac morphology and function. Here, we present a characterization of the hearts of PTRF/Cavin-1-null (PTRF-/- mice. Electron microscopy revealed the reduction of caveolae in cardiomyocytes of PTRF-/- mice. PTRF-/- mice at 16 weeks of age developed a progressive cardiomyopathic phenotype with wall thickening of left ventricles and reduced fractional shortening evaluated by echocardiography. Electrocardiography revealed that PTRF-/- mice at 24 weeks of age had low voltages and wide QRS complexes in limb leads. Histological analysis showed cardiomyocyte hypertrophy accompanied by progressive interstitial/perivascular fibrosis. Hypertrophy-related fetal gene expression was also induced in PTRF-/- hearts. Western blotting analysis and quantitative RT-PCR revealed that Cav3 expression was suppressed in PTRF-/- hearts compared with that in wild-type (WT ones. ERK1/2 was activated in PTRF-/- hearts compared with that in WT ones. These results suggest that loss of PTRF/Cavin-1 protein expression is sufficient to induce a molecular program leading to cardiomyocyte hypertrophy and cardiomyopathy, which is partly attributable to Cav3 reduction in the heart.

  11. Changes in cardiac phenotype in hypertrophy and failure: From receptor to gene

    NARCIS (Netherlands)

    H.A. van Heugten (Han); J.M.J. Lamers (Jos)

    1997-01-01

    textabstractThe terminally differentiated adult cardiac myocyte cannot undergo cellular division. Growth of the heart in response to chronic hemodynamic overload therefore occurs through hypertrophy of the myocytes. The adaptation of the myocyte during hypertrophy not only involves an increase in

  12. Solving the cardiac hypertrophy riddle: The angiotensin II-mechanical stress connection.

    Science.gov (United States)

    Zablocki, Daniela; Sadoshima, Junichi

    2013-11-08

    A series of studies conducted 20 years ago, documenting the cardiac hypertrophy phenotype and its underlying signaling mechanism induced by angiotensin II (Ang II) and mechanical stress, showed a remarkable similarity between the effect of the Gαq agonist and that of mechanical forces on cardiac hypertrophy. Subsequent studies confirmed the involvement of autocrine/paracrine mechanisms, including stretch-induced release of Ang II in load-induced cardiac hypertrophy. Recent studies showed that the Ang II type 1 (AT1) receptor is also directly activated by mechanical forces, suggesting that AT1 receptors play an important role in mediating load-induced cardiac hypertrophy through both ligand- and mechanical stress-dependent mechanisms.

  13. Kallikrein-related peptidase 8 is expressed in myocardium and induces cardiac hypertrophy

    Science.gov (United States)

    Cao, Buqing; Yu, Qing; Zhao, Wei; Tang, Zhiping; Cong, Binghai; Du, Jiankui; Lu, Jianqiang; Zhu, Xiaoyan; Ni, Xin

    2016-01-01

    The tissue kallikrein-related peptidase family (KLK) is a group of trypsin- and chymotrypsin-like serine proteases that share a similar homology to parent tissue kallikrein (KLK1). KLK1 is identified in heart and has anti-hypertrophic effects. However, whether other KLK family members play a role in regulating cardiac function remains unknown. In the present study, we demonstrated for the first time that KLK8 was expressed in myocardium. KLK8 expression was upregulated in left ventricle of cardiac hypertrophy models. Both intra-cardiac adenovirus-mediated and transgenic-mediated KLK8 overexpression led to cardiac hypertrophy in vivo. In primary neonatal rat cardiomyocytes, KLK8 knockdown inhibited phenylephrine (PE)-induced cardiomyocyte hypertrophy, whereas KLK8 overexpression promoted cardiomyocyte hypertrophy via a serine protease activity-dependent but kinin receptor-independent pathway. KLK8 overexpression increased epidermal growth factor (EGF) production, which was blocked by the inhibitors of serine protease. EGF receptor (EGFR) antagonist and EGFR knockdown reversed the hypertrophy induced by KLK8 overexpression. KLK8-induced cardiomyocyte hypertrophy was also significantly decreased by blocking the protease-activated receptor 1 (PAR1) or PAR2 pathway. Our data suggest that KLK8 may promote cardiomyocyte hypertrophy through EGF signaling- and PARs-dependent but a kinin receptor-independent pathway. It is implied that different KLK family members can subtly regulate cardiac function and remodeling. PMID:26823023

  14. Role of endothelin in the induction of cardiac hypertrophy in vitro.

    Directory of Open Access Journals (Sweden)

    Tepmanas Bupha-Intr

    Full Text Available Endothelin (ET-1 is a peptide hormone mediating a wide variety of biological processes and is associated with development of cardiac dysfunction. Generally, ET-1 is regarded as a molecular marker released only in correlation with the observation of a hypertrophic response or in conjunction with other hypertrophic stress. Although the cardiac hypertrophic effect of ET-1 is demonstrated, inotropic properties of cardiac muscle during chronic ET-1-induced hypertrophy remain largely unclear. Through the use of a novel in vitro multicellular culture system, changes in contractile force and kinetics of rabbit cardiac trabeculae in response to 1 nM ET-1 for 24 hours can be observed. Compared to the initial force at t = 0 hours, ET-1 treated muscles showed a ~2.5 fold increase in developed force after 24 hours without any effect on time to peak contraction or time to 90% relaxation. ET-1 increased muscle diameter by 12.5 ± 3.2% from the initial size, due to increased cell width compared to non-ET-1 treated muscles. Using specific signaling antagonists, inhibition of NCX, CaMKII, MAPKK, and IP3 could attenuate the effect of ET-1 on increased developed force. However, among these inhibitions only IP3 receptor blocker could not prevent the increase muscle size by ET-1. Interestingly, though calcineurin-NFAT inhibition could not suppress the effect of ET-1 on force development, it did prevent muscle hypertrophy. These findings suggest that ET-1 provokes both inotropic and hypertrophic activations on myocardium in which both activations share the same signaling pathway through MAPK and CaMKII in associated with NCX activity.

  15. Aberrant Glycosylation in the Left Ventricle and Plasma of Rats with Cardiac Hypertrophy and Heart Failure.

    Directory of Open Access Journals (Sweden)

    Chiaki Nagai-Okatani

    Full Text Available Targeted proteomics focusing on post-translational modifications, including glycosylation, is a useful strategy for discovering novel biomarkers. To apply this strategy effectively to cardiac hypertrophy and resultant heart failure, we aimed to characterize glycosylation profiles in the left ventricle and plasma of rats with cardiac hypertrophy. Dahl salt-sensitive hypertensive rats, a model of hypertension-induced cardiac hypertrophy, were fed a high-salt (8% NaCl diet starting at 6 weeks. As a result, they exhibited cardiac hypertrophy at 12 weeks and partially impaired cardiac function at 16 weeks compared with control rats fed a low-salt (0.3% NaCl diet. Gene expression analysis revealed significant changes in the expression of genes encoding glycosyltransferases and glycosidases. Glycoproteome profiling using lectin microarrays indicated upregulation of mucin-type O-glycosylation, especially disialyl-T, and downregulation of core fucosylation on N-glycans, detected by specific interactions with Amaranthus caudatus and Aspergillus oryzae lectins, respectively. Upregulation of plasma α-l-fucosidase activity was identified as a biomarker candidate for cardiac hypertrophy, which is expected to support the existing marker, atrial natriuretic peptide and its related peptides. Proteomic analysis identified cysteine and glycine-rich protein 3, a master regulator of cardiac muscle function, as an O-glycosylated protein with altered glycosylation in the rats with cardiac hypertrophy, suggesting that alternations in O-glycosylation affect its oligomerization and function. In conclusion, our data provide evidence of significant changes in glycosylation pattern, specifically mucin-type O-glycosylation and core defucosylation, in the pathogenesis of cardiac hypertrophy and heart failure, suggesting that they are potential biomarkers for these diseases.

  16. Role of serotonin 5-HT2A receptors in the development of cardiac hypertrophy in response to aortic constriction in mice.

    Science.gov (United States)

    Lairez, O; Cognet, T; Schaak, S; Calise, D; Guilbeau-Frugier, C; Parini, A; Mialet-Perez, J

    2013-06-01

    Serotonin, in addition to its fundamental role as a neurotransmitter, plays a critical role in the cardiovascular system, where it is thought to be involved in the development of cardiac hypertrophy and failure. Indeed, we recently found that mice with deletion of monoamine oxidase A had enhanced levels of blood and cardiac 5-HT, which contributed to exacerbation of hypertrophy in a model of experimental pressure overload. 5-HT2A receptors are expressed in the heart and mediate a hypertrophic response to 5-HT in cardiac cells. However, their role in cardiac remodeling in vivo and the signaling pathways associated are not well understood. In the present study, we evaluated the effect of a selective 5-HT2A receptor antagonist, M100907, on the development of cardiac hypertrophy induced by transverse aortic constriction (TAC). Cardiac 5-HT2A receptor expression was transiently increased after TAC, and was recapitulated in cardiomyocytes, as observed with 5-HT2A in situ labeling by immunohistochemistry. Selective blockade of 5-HT2A receptors prevented the development of cardiac hypertrophy, as measured by echocardiography, cardiomyocyte area and heart weight-to-body weight ratio. Interestingly, activation of calmodulin kinase (CamKII), which is a core mechanism in cardiac hypertrophy, was reduced in cardiac samples from M100907-treated TAC mice compared to vehicle-treated mice. In addition, phosphorylation of histone deacetylase 4 (HDAC4), a downstream partner of CamKII was significantly diminished in M100907-treated TAC mice. Thus, our results show that selective blockade of 5-HT2A receptors has beneficial effect in the development of cardiac hypertrophy through inhibition of the CamKII/HDAC4 pathway.

  17. Reduction of blood oxygen levels enhances postprandial cardiac hypertrophy in Burmese python (Python bivittatus).

    Science.gov (United States)

    Slay, Christopher E; Enok, Sanne; Hicks, James W; Wang, Tobias

    2014-05-15

    Physiological cardiac hypertrophy is characterized by reversible enlargement of cardiomyocytes and changes in chamber architecture, which increase stroke volume and via augmented convective oxygen transport. Cardiac hypertrophy is known to occur in response to repeated elevations of O2 demand and/or reduced O2 supply in several species of vertebrate ectotherms, including postprandial Burmese pythons (Python bivittatus). Recent data suggest postprandial cardiac hypertrophy in P. bivittatus is a facultative rather than obligatory response to digestion, though the triggers of this response are unknown. Here, we hypothesized that an O2 supply-demand mismatch stimulates postprandial cardiac enlargement in Burmese pythons. To test this hypothesis, we rendered animals anemic prior to feeding, essentially halving blood oxygen content during the postprandial period. Fed anemic animals had heart rates 126% higher than those of fasted controls, which, coupled with a 71% increase in mean arterial pressure, suggests fed anemic animals were experiencing significantly elevated cardiac work. We found significant cardiac hypertrophy in fed anemic animals, which exhibited ventricles 39% larger than those of fasted controls and 28% larger than in fed controls. These findings support our hypothesis that those animals with a greater magnitude of O2 supply-demand mismatch exhibit the largest hearts. The 'low O2 signal' stimulating postprandial cardiac hypertrophy is likely mediated by elevated ventricular wall stress associated with postprandial hemodynamics. © 2014. Published by The Company of Biologists Ltd.

  18. Experimental and clinical study of cardiac hypertrophy by thallium-201 myocardial scintigraphy

    Energy Technology Data Exchange (ETDEWEB)

    Torii, Yukio (Kyoto Prefectural Univ. of Medicine (Japan))

    1983-09-01

    I studied experimentally the myocardial uptake of /sup 201/Tl in cardiac hypertrophy in rat, and clinically evaluated cardiac shape and dimension in the patients with various types of cardiac hypertrophy. Experimentally, both myocardial blood flow (MBF) and Tl uptake were increased with cardiac weight. There were negative correlations between the extraction fraction and MBF. Tl uptake in Hypertrophy is not always dependent on MBF and affected by the altered metabolism of hypertrophied myocardium. Clinical study was performed in 29 normal subjects and in 90 patients with heart disease. The measurements of left ventricular (LV) size by Tl scintigraphy were well correlated with them by echocardiography. Aortic stenosis and hypertensive heart disease showed thick wall and spherical shape. Both mitral (MR) and aortic (AR) regurgitation showed ventricular dilatation, spherical shape (in chronic MR) and ellipsoid shape (in acute MR and in AR). Decreased ventricular size but normal shape was observed in mitral stenosis and cor pulmonale. Hypertrophic cardiomyopathy showed thick wall with asymmetric septal hypertrophy, while congestive cardiomyopathy showed thin wall with marked ventricular dilatation and spherical shape. I conclude that heart disease has characteristic figures in dimension and shape which may be reflecting cardiac performance or compensating for the load to the heart, and that /sup 201/Tl scintigraphy is useful evaluating cardiac morphology as well as in diagnosing myocardial ischemia.

  19. Caveolin-3 Overexpression Attenuates Cardiac Hypertrophy via Inhibition of T-type Ca2+ Current Modulated by Protein Kinase Cα in Cardiomyocytes*

    Science.gov (United States)

    Markandeya, Yogananda S.; Phelan, Laura J.; Woon, Marites T.; Keefe, Alexis M.; Reynolds, Courtney R.; August, Benjamin K.; Hacker, Timothy A.; Roth, David M.; Patel, Hemal H.; Balijepalli, Ravi C.

    2015-01-01

    Pathological cardiac hypertrophy is characterized by subcellular remodeling of the ventricular myocyte with a reduction in the scaffolding protein caveolin-3 (Cav-3), altered Ca2+ cycling, increased protein kinase C expression, and hyperactivation of calcineurin/nuclear factor of activated T cell (NFAT) signaling. However, the precise role of Cav-3 in the regulation of local Ca2+ signaling in pathological cardiac hypertrophy is unclear. We used cardiac-specific Cav-3-overexpressing mice and in vivo and in vitro cardiac hypertrophy models to determine the essential requirement for Cav-3 expression in protection against pharmacologically and pressure overload-induced cardiac hypertrophy. Transverse aortic constriction and angiotensin-II (Ang-II) infusion in wild type (WT) mice resulted in cardiac hypertrophy characterized by significant reduction in fractional shortening, ejection fraction, and a reduced expression of Cav-3. In addition, association of PKCα and angiotensin-II receptor, type 1, with Cav-3 was disrupted in the hypertrophic ventricular myocytes. Whole cell patch clamp analysis demonstrated increased expression of T-type Ca2+ current (ICa, T) in hypertrophic ventricular myocytes. In contrast, the Cav-3-overexpressing mice demonstrated protection from transverse aortic constriction or Ang-II-induced pathological hypertrophy with inhibition of ICa, T and intact Cav-3-associated macromolecular signaling complexes. siRNA-mediated knockdown of Cav-3 in the neonatal cardiomyocytes resulted in enhanced Ang-II stimulation of ICa, T mediated by PKCα, which caused nuclear translocation of NFAT. Overexpression of Cav-3 in neonatal myocytes prevented a PKCα-mediated increase in ICa, T and nuclear translocation of NFAT. In conclusion, we show that stable Cav-3 expression is essential for protecting the signaling mechanisms in pharmacologically and pressure overload-induced cardiac hypertrophy. PMID:26170457

  20. MYBPH acts as modifier of cardiac hypertrophy in hypertrophic cardiomyopathy (HCM) patients.

    Science.gov (United States)

    Mouton, J M; van der Merwe, L; Goosen, A; Revera, M; Brink, P A; Moolman-Smook, J C; Kinnear, C

    2016-05-01

    Left ventricular hypertrophy is a risk factor for cardiovascular morbidity and mortality. Hypertrophic cardiomyopathy (HCM) is considered a model disease to study causal molecular factors underlying isolated cardiac hypertrophy. However, HCM manifests with various clinical symptoms, even in families bearing the same genetic defects, suggesting that additional factors contribute to hypertrophy. The gene encoding the cardiac myosin binding protein C (cMYBPC) is one of the most frequently implicated genes in HCM. Recently another myosin binding protein, myosin binding protein H (MYBPH) was shown to function in concert with cMYBPC in regulating cardiomyocyte contraction. Given the similarity in sequence, structure and the critical role MYBPH plays in sarcomere contraction, we proposed that MYBPH may be involved in HCM pathogenesis. Family-based genetic association analysis was employed to investigate the contribution of MYBPH in modifying hypertrophy. Seven single nucleotide polymorphisms and haplotypes in MYBPH were investigated for hypertrophy modifying effects in 388 individuals (27 families), in which three unique South African HCM-causing founder mutations (p.R403W and pA797T in β-myosin heavy chain gene (MYH7) and p.R92W in the cardiac troponin T gene (TNNT2)) segregate. We observed a significant association between rs2250509 and hypertrophy traits in the p.A797T MYH7 mutation group. Additionally, haplotype GGTACTT significantly affected hypertrophy within the same mutation group. MYBPH was for the first time assessed as a candidate hypertrophy modifying gene. We identified a novel association between MYBPH and hypertrophy traits in HCM patients carrying the p.A797T MYH7 mutation, suggesting that variation in MYBPH can modulate the severity of hypertrophy in HCM.

  1. Global microRNA profiles and signaling pathways in the development of cardiac hypertrophy

    Energy Technology Data Exchange (ETDEWEB)

    Feng, H.J.; Ouyang, W.; Liu, J.H.; Sun, Y.G.; Hu, R.; Huang, L.H.; Xian, J.L. [Southern Medical University, Department of Nuclear Medicine, Zhujiang Hospital, Guangzhou, China, Department of Nuclear Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou (China); Jing, C.F.; Zhou, M.J. [Sun Yat-Sen University, South China Sea Marine Biotechnology, National Engineering Research Center, Guangzhou, China, National Engineering Research Center, South China Sea Marine Biotechnology, Sun Yat-Sen University, Guangzhou (China)

    2014-04-11

    Hypertrophy is a major predictor of progressive heart disease and has an adverse prognosis. MicroRNAs (miRNAs) that accumulate during the course of cardiac hypertrophy may participate in the process. However, the nature of any interaction between a hypertrophy-specific signaling pathway and aberrant expression of miRNAs remains unclear. In this study, Spague Dawley male rats were treated with transverse aortic constriction (TAC) surgery to mimic pathological hypertrophy. Hearts were isolated from TAC and sham operated rats (n=5 for each group at 5, 10, 15, and 20 days after surgery) for miRNA microarray assay. The miRNAs dysexpressed during hypertrophy were further analyzed using a combination of bioinformatics algorithms in order to predict possible targets. Increased expression of the target genes identified in diverse signaling pathways was also analyzed. Two sets of miRNAs were identified, showing different expression patterns during hypertrophy. Bioinformatics analysis suggested the miRNAs may regulate multiple hypertrophy-specific signaling pathways by targeting the member genes and the interaction of miRNA and mRNA might form a network that leads to cardiac hypertrophy. In addition, the multifold changes in several miRNAs suggested that upregulation of rno-miR-331*, rno-miR-3596b, rno-miR-3557-5p and downregulation of rno-miR-10a, miR-221, miR-190, miR-451 could be seen as biomarkers of prognosis in clinical therapy of heart failure. This study described, for the first time, a potential mechanism of cardiac hypertrophy involving multiple signaling pathways that control up- and downregulation of miRNAs. It represents a first step in the systematic discovery of miRNA function in cardiovascular hypertrophy.

  2. The plasma membrane calcium ATPase 4 signalling in cardiac fibroblasts mediates cardiomyocyte hypertrophy

    Science.gov (United States)

    Mohamed, Tamer M. A.; Abou-Leisa, Riham; Stafford, Nicholas; Maqsood, Arfa; Zi, Min; Prehar, Sukhpal; Baudoin-Stanley, Florence; Wang, Xin; Neyses, Ludwig; Cartwright, Elizabeth J.; Oceandy, Delvac

    2016-01-01

    The heart responds to pathological overload through myocyte hypertrophy. Here we show that this response is regulated by cardiac fibroblasts via a paracrine mechanism involving plasma membrane calcium ATPase 4 (PMCA4). Pmca4 deletion in mice, both systemically and specifically in fibroblasts, reduces the hypertrophic response to pressure overload; however, knocking out Pmca4 specifically in cardiomyocytes does not produce this effect. Mechanistically, cardiac fibroblasts lacking PMCA4 produce higher levels of secreted frizzled related protein 2 (sFRP2), which inhibits the hypertrophic response in neighbouring cardiomyocytes. Furthermore, we show that treatment with the PMCA4 inhibitor aurintricarboxylic acid (ATA) inhibits and reverses cardiac hypertrophy induced by pressure overload in mice. Our results reveal that PMCA4 regulates the development of cardiac hypertrophy and provide proof of principle for a therapeutic approach to treat this condition. PMID:27020607

  3. Interferon Regulatory Factor 7 Functions as a Novel Negative Regulator of Pathological Cardiac Hypertrophy

    Science.gov (United States)

    Jiang, Ding-Sheng; Liu, Yu; Zhou, Heng; Zhang, Yan; Zhang, Xiao-Dong; Zhang, Xiao-Fei; Chen, Ke; Gao, Lu; Peng, Juan; Gong, Hui; Chen, Yingjie; Yang, Qinglin; Liu, Peter P.; Fan, Guo-Chang; Zou, Yunzeng; Li, Hongliang

    2017-01-01

    Cardiac hypertrophy is a complex pathological process that involves multiple factors including inflammation and apoptosis. Interferon regulatory factor 7 (IRF7) is a multifunctional regulator that participates in immune regulation, cell differentiation, apoptosis, and oncogenesis. However, the role of IRF7 in cardiac hypertrophy remains unclear. We performed aortic banding in cardiac-specific IRF7 transgenic mice, IRF7 knockout mice, and the wild-type littermates of these mice. Our results demonstrated that IRF7 was downregulated in aortic banding–induced animal hearts and cardiomyocytes that had been treated with angiotensin II or phenylephrine for 48 hours. Accordingly, heart-specific overexpression of IRF7 significantly attenuated pressure overload–induced cardiac hypertrophy, fibrosis, and dysfunction, whereas loss of IRF7 led to opposite effects. Moreover, IRF7 protected against angiotensin II–induced cardiomyocyte hypertrophy in vitro. Mechanistically, we identified that IRF7-dependent cardioprotection was mediated through IRF7 binding to inhibitor of κB kinase-β, and subsequent nuclear factor-κB inactivation. In fact, blocking nuclear factor-κB signaling with cardiac-specific inhibitors of κBαS32A/S36A super-repressor transgene counteracted the adverse effect of IRF7 deficiency. Conversely, activation of nuclear factor-κB signaling via a cardiac-specific conditional inhibitor of κB kinase-βS177E/S181E (constitutively active) transgene negated the antihypertrophic effect of IRF7 overexpression. Our data demonstrate that IRF7 acts as a novel negative regulator of pathological cardiac hypertrophy by inhibiting nuclear factor-κB signaling and may constitute a potential therapeutic target for pathological cardiac hypertrophy. PMID:24396025

  4. Muscle-specific RING finger 1 negatively regulates pathological cardiac hypertrophy through downregulation of calcineurin A.

    Science.gov (United States)

    Maejima, Yasuhiro; Usui, Soichiro; Zhai, Peiyong; Takamura, Masayuki; Kaneko, Shuichi; Zablocki, Daniela; Yokota, Mitsuhiro; Isobe, Mitsuaki; Sadoshima, Junichi

    2014-05-01

    Muscle-specific RING finger protein-1 (MuRF1) is an E3 ligase that inhibits cardiac hypertrophy. However, how MuRF1 regulates cardiac hypertrophy and function during pressure overload (PO) remains poorly understood. We investigated the role of endogenous MuRF1 in regulating cardiac hypertrophy in response to PO in vivo. Transverse aortic constriction (TAC) for 4 weeks significantly reduced expression of MuRF1 in the mouse heart. After 2 and 4 weeks of TAC, MuRF1 knockout (Murf1(-/-)) mice exhibited enhanced cardiac hypertrophy and left ventricular (LV) dysfunction compared with that of nontransgenic (NTg) mice. Histological analyses showed that Murf1(-/-) mice exhibited more severe fibrosis and apoptosis than NTg mice after TAC. TAC-induced increases in the activity of a nuclear factor of activated T cells (NFAT) luciferase reporter were significantly greater in Murf1(-/-) than in NTg mice. TAC-induced increases in calcineurin A (CnA) expression were also significantly enhanced in Murf1(-/-) compared with that in NTg mice. Coimmunoprecipitation assays showed that endogenous MuRF1 and CnA interact with one another. Polyubiquitination of CnA was attenuated in Murf1(-/-) mouse hearts at baseline and in response to TAC, and the protein stability of CnA was enhanced in cardiomyocytes, in which MuRF1 was downregulated in vitro. Furthermore, MuRF1 directly ubiquitinated CnA in vitro. Cardiac-specific overexpression of ZAKI-4β, an endogenous inhibitor of CnA, significantly suppressed the enhancement of TAC-induced cardiac hypertrophy and dysfunction, as well as increases in cardiac fibrosis and apoptosis, in Murf1(-/-) mice. Endogenous MuRF1 negatively regulates cardiac hypertrophy and dysfunction in response to PO through inhibition of the calcineurin-NFAT pathway. © 2014 American Heart Association, Inc.

  5. Effect of Nigella sativa supplementation to exercise training in a novel model of physiological cardiac hypertrophy.

    Science.gov (United States)

    Al-Asoom, L I; Al-Shaikh, B A; Bamosa, A O; El-Bahai, M N

    2014-09-01

    Exercise training is employed as supplementary therapy to patients with heart failure due to its multiple beneficial cardiac effects including physiological remodeling of the heart. However, precautions might be taken for the concomitant high oxidant release. Nigella sativa (NS) has been found to induce cardiac hypertrophy and enhance cardiac function. Combination of NS supplementation and exercise training might induce a safer model of cardiac hypertrophy. Our aim was to study biomarkers associated with cardiac hypertrophy induced by NS supplementation of exercise-trained rats. Forty-five adult male Wistar rats (body weight 150-220 g) were divided equally into three groups: control, exercise-trained (ET) and NS-treated-exercise-trained (NSET) groups. Daily 800 mg/kg NS was administered orally to NSET group for 8 weeks. Rats of the ET and NSET groups were subjected to treadmill running sessions for 2 h/day for 8 weeks. By the end of the experiment, the following were recorded: body, heart and left ventricular weights (BW, HW, LVW), cardiomyocyte diameter, serum growth hormone, insulin growth factor-I (IGF-I), thyroid hormones, catecholamines, total nitrate, ICAM and antioxidant capacity. A homogenous cardiac hypertrophy was evidenced by increased HW/BW, LVW/BW ratios and cardiomyocyte diameter in the two groups of exercise-trained compared with control rats. Rats of ET group had higher growth hormone. Those of NSET group developed higher IGF-I and total antioxidant capacity, as well as lower serum thyroxin level. Simultaneous NS supplementation to an exercise training program preserves and augments exercise-induced physiological cardiac hypertrophy with step-forward adaptive signs of increased IGF-I and reduced thyroxin level, and with an added advantage of elevation of total serum antioxidant capacity. Thus, the novel model of NSET-induced cardiac hypertrophy might be introduced as a new therapeutic strategy for the treatment of heart failure with superior

  6. Phlorizin Prevents Glomerular Hyperfiltration but not Hypertrophy in Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Slava Malatiali

    2008-01-01

    Full Text Available The relationships of renal and glomerular hypertrophies to development of hyperfiltration and proteinuria early in streptozotocin-induced diabetes were explored. Control, diabetic, phlorizin-treated controls, and diabetic male Fischer rats were used. Phlorizin (an Na+-glucose cotransport inhibitor was given at a dose sufficient to normalize blood glucose. Inulin clearance (Cinulin and protein excretion rate (PER were measured. For morphometry, kidney sections were stained with periodic acid Schiff. At one week, diabetes PER increased 2.8-folds (P<.001, Cinulin increased 80% (P<.01. Kidney wet and dry weights increased 10%–12% (P<.05, and glomerular tuft area increased 9.3% (P<.001. Phlorizin prevented proteinuria, hyperfiltration, and kidney hypertrophy, but not glomerular hypertrophy. Thus, hyperfiltration, proteinuria, and whole kidney hypertrophy were related to hyperglycemia but not to glomerular growth. Diabetic glomerular hypertrophy constitutes an early event in the progression of glomerular pathology which occurs in the absence of mesangial expansion and persists even after changes in protein excretion and GFR are reversed through glycemic control.

  7. Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets.

    Science.gov (United States)

    Tham, Yow Keat; Bernardo, Bianca C; Ooi, Jenny Y Y; Weeks, Kate L; McMullen, Julie R

    2015-09-01

    The onset of heart failure is typically preceded by cardiac hypertrophy, a response of the heart to increased workload, a cardiac insult such as a heart attack or genetic mutation. Cardiac hypertrophy is usually characterized by an increase in cardiomyocyte size and thickening of ventricular walls. Initially, such growth is an adaptive response to maintain cardiac function; however, in settings of sustained stress and as time progresses, these changes become maladaptive and the heart ultimately fails. In this review, we discuss the key features of pathological cardiac hypertrophy and the numerous mediators that have been found to be involved in the pathogenesis of cardiac hypertrophy affecting gene transcription, calcium handling, protein synthesis, metabolism, autophagy, oxidative stress and inflammation. We also discuss new mediators including signaling proteins, microRNAs, long noncoding RNAs and new findings related to the role of calcineurin and calcium-/calmodulin-dependent protein kinases. We also highlight mediators and processes which contribute to the transition from adaptive cardiac remodeling to maladaptive remodeling and heart failure. Treatment strategies for heart failure commonly include diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers and β-blockers; however, mortality rates remain high. Here, we discuss new therapeutic approaches (e.g., RNA-based therapies, dietary supplementation, small molecules) either entering clinical trials or in preclinical development. Finally, we address the challenges that remain in translating these discoveries to new and approved therapies for heart failure.

  8. Interleukin-6 deficiency attenuates angiotensin II-induced cardiac pathogenesis with increased myocyte hypertrophy.

    Science.gov (United States)

    Chen, Fan; Chen, Dandan; Zhang, Yubin; Jin, Liang; Zhang, Han; Wan, Miyang; Pan, Tianshu; Wang, Xiaochuan; Su, Yuheng; Xu, Yitao; Ye, Junmei

    2017-12-16

    Interleukin-6 (IL-6) signaling is critical for cardiomyocyte hypertrophy, while the role of IL-6 in the pathogenesis of myocardium hypertrophy remains controversial. To determine the essential role of IL-6 signaling for the cardiac development during AngII-induced hypertension, and to elucidate the mechanisms, wild-type (WT) and IL-6 knockout (IL-6 KO) mice were infused subcutaneously with either vehicle or AngII (1.5 μg/h/mouse) for 1 week. Immunohistological and serum studies revealed that the extents of cardiac fibrosis, inflammation and apoptosis were reduced in IL-6 KO heart during AngII-stimulation, while cardiac hypertrophy was obviously induced. To investigate the underlying mechanisms, by using myocardial tissue and neonatal cardiomyocytes, we observed that IL-6/STAT3 signaling was activated under the stimulation of AngII both in vivo and in vitro. Further investigation suggested that STAT3 activation enhances the inhibitory effect of EndoG on MEF2A and hampers cardiomyocyte hypertrophy. Our study is the first to show the important role of IL-6 in regulating cardiac pathogenesis via inflammation and apoptosis during AngII-induced hypertension. We also provide a novel link between IL-6/STAT3 and EndoG/MEF2A pathway that affects cardiac hypertrophy during AngII stimulation. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Renal ischemia/reperfusion-induced cardiac hypertrophy in mice: Cardiac morphological and morphometric characterization

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    Cirino-Silva, Rogério; Kmit, Fernanda V; Trentin-Sonoda, Mayra; Nakama, Karina K; Panico, Karine; Alvim, Juliana M; Dreyer, Thiago R; Martinho-Silva, Herculano

    2017-01-01

    Background Tissue remodeling is usually dependent on the deposition of extracellular matrix that may result in tissue stiffness and impaired myocardium contraction. Objectives We had previously demonstrated that renal ischemia/reperfusion (I/R) is able to induce development of cardiac hypertrophy in mice. Therefore, we aimed to characterize renal I/R-induced cardiac hypertrophy. Design C57BL/6 J mice were subjected to 60 minutes’ unilateral renal pedicle occlusion, followed by reperfusion (I/R) for 5, 8, 12 or 15 days. Gene expression, protein abundance and morphometric analyses were performed in all time points. Results Left ventricle wall thickening was increased after eight days of reperfusion (p < 0.05). An increase in the number of heart ventricle capillaries and diameter after 12 days of reperfusion (p < 0.05) was observed; an increase in the density of capillaries starting at 5 days of reperfusion (p < 0.05) was also observed. Analyses of MMP2 protein levels showed an increase at 15 days compared to sham (p < 0.05). Moreover, TGF-β gene expression was downregulated at 12 days as well TIMP 1 and 2 (p < 0.05). The Fourier-transform infrared spectroscopy analysis showed that collagen content was altered only in the internal section of the heart (p < 0.05); such data were supported by collagen mRNA levels. Conclusions Renal I/R leads to impactful changes in heart morphology, accompanied by an increase in microvasculature. Although it is clear that I/R is able to induce cardiac remodeling, such morphological changes is present in only a section of the heart tissue. PMID:28228941

  10. Renal ischemia/reperfusion-induced cardiac hypertrophy in mice: Cardiac morphological and morphometric characterization

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    Rogério Cirino-Silva

    2017-01-01

    Full Text Available Background Tissue remodeling is usually dependent on the deposition of extracellular matrix that may result in tissue stiffness and impaired myocardium contraction. Objectives We had previously demonstrated that renal ischemia/reperfusion (I/R is able to induce development of cardiac hypertrophy in mice. Therefore, we aimed to characterize renal I/R-induced cardiac hypertrophy. Design C57BL/6 J mice were subjected to 60 minutes’ unilateral renal pedicle occlusion, followed by reperfusion (I/R for 5, 8, 12 or 15 days. Gene expression, protein abundance and morphometric analyses were performed in all time points. Results Left ventricle wall thickening was increased after eight days of reperfusion (p < 0.05. An increase in the number of heart ventricle capillaries and diameter after 12 days of reperfusion (p < 0.05 was observed; an increase in the density of capillaries starting at 5 days of reperfusion (p < 0.05 was also observed. Analyses of MMP2 protein levels showed an increase at 15 days compared to sham (p < 0.05. Moreover, TGF-β gene expression was downregulated at 12 days as well TIMP 1 and 2 (p < 0.05. The Fourier-transform infrared spectroscopy analysis showed that collagen content was altered only in the internal section of the heart (p < 0.05; such data were supported by collagen mRNA levels. Conclusions Renal I/R leads to impactful changes in heart morphology, accompanied by an increase in microvasculature. Although it is clear that I/R is able to induce cardiac remodeling, such morphological changes is present in only a section of the heart tissue.

  11. Negative feedback regulation of Homer 1a on norepinephrine-dependent cardiac hypertrophy

    Energy Technology Data Exchange (ETDEWEB)

    Chiarello, Carmelina; Bortoloso, Elena; Carpi, Andrea; Furlan, Sandra; Volpe, Pompeo, E-mail: pompeo.volpe@unipd.it

    2013-07-15

    Homers are scaffolding proteins that modulate diverse cell functions being able to assemble signalling complexes. In this study, the presence, sub-cellular distribution and function of Homer 1 was investigated. Homer 1a and Homer 1b/c are constitutively expressed in cardiac muscle of both mouse and rat and in HL-1 cells, a cardiac cell line. As judged by confocal immunofluorescence microscopy, Homer 1a displays sarcomeric and peri-nuclear localization. In cardiomyocytes and cultured HL-1 cells, the hypertrophic agonist norepinephrine (NE) induces α{sub 1}-adrenergic specific Homer 1a over-expression, with a two-to-three-fold increase within 1 h, and no up-regulation of Homer 1b/c, as judged by Western blot and qPCR. In HL-1 cells, plasmid-driven over-expression of Homer 1a partially antagonizes activation of ERK phosphorylation and ANF up-regulation, two well-established, early markers of hypertrophy. At the morphometric level, NE-induced increase of cell size is likewise and partially counteracted by exogenous Homer 1a. Under the same experimental conditions, Homer 1b/c does not have any effect on ANF up-regulation nor on cell hypertrophy. Thus, Homer 1a up-regulation is associated to early stages of cardiac hypertrophy and appears to play a negative feedback regulation on molecular transducers of hypertrophy. -- Highlights: • Homer 1a is constitutively expressed in cardiac tissue. • In HL-1 cells, norepinephrine activates signaling pathways leading to hypertrophy. • Homer 1a up-regulation is an early event of norepinephrine-induced hypertrophy. • Homer 1a plays a negative feedback regulation modulating pathological hypertrophy. • Over-expression of Homer 1a per se does not induce hypertrophy.

  12. Tanshinone-induced ERs suppresses IGFII activation to alleviate Ang II-mediated cardiac hypertrophy.

    Science.gov (United States)

    Chen, Ya-Fang; Lee, Nien-Hung; Pai, Pei-Ying; Chung, Li-Chin; Shen, Chia-Yao; Rajendran, Peramaiyan; Chen, Yu-Feng; Chen, Ray-Jade; Padma Viswanadha, Vijaya; Kuo, Wei-Wen; Huang, Chih-Yang

    2017-10-01

    Cardiomyopathy involves changes in myocardial ultrastructure and cardiac hypertrophy. Angiotensin II (AngII) has previously been shown to stimulate the expression of IGF-2 and IGF-2R in H9c2 cardiomyoblasts and increase of blood pressure, and cardiac hypertrophy. Estrogen receptors (ERs) exert protective effects, such as anti-hypertrophy in cadiomyocytes. Tanshinone IIA (TSN), a main active ingredient from a Chinese medical herb, Salvia miltiorrhiza Bunge (Danshen), was shown to protect cardiomyocytes hypertrophy by different stress signals. We aimed to investigate whether TSN protected H9c2 cardiomyocytes from AngII-induced activation of IGF-2R pathway and hypertrophy by mediating through ERs. AngII resulted in H9c2 cardiomyoblast hypertrophy and increased inflammatory molecular markers. These were down-regulated by TSN via estrogen receptors. AngII resulted in elevation in MAPKs, IGF-2R and hypertrophic protein markers. These, again, were reduced by addition of the phytoestrogen with activation of ERs. Finally, AngII induced phosphorylation of heat shock factor-1 (HSF1) and decreased sirtuin-1 (SIRT1). In addition, AngII also caused an increase in distribution of IGF-2R molecules on cell membrane. In contrast, TSN reduced HSF1 phosphorylation and cell surface IGF-2R while elevating SIRT1 via ERs. TSN was capable of attenuating AngII-induced IGF-2R pathway and hypertrophy through ERs in H9c2 cardiomyoblast cells.

  13. Pressure Overload-Induced Cardiac Hypertrophy Response Requires Janus Kinase 2-Histone Deacetylase 2 Signaling

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    Huang Ying

    2014-11-01

    Full Text Available Pressure overload induces cardiac hypertrophy through activation of Janus kinase 2 (Jak2, however, the underlying mechanisms remain largely unknown. In the current study, we tested whether histone deacetylase 2 (HDAC2 was involved in the process. We found that angiotensin II (Ang-II-induced re-expression of fetal genes (Atrial natriuretic peptide (ANP and brain natriuretic peptide (BNP in cultured cardiomyocytes was prevented by the Jak2 inhibitor AG-490 and HDAC2 inhibitor Trichostatin-A (TSA, or by Jak2/HDAC2 siRNA knockdown. On the other hand, myocardial cells with Jak2 or HDAC2 over-expression were hyper-sensitive to Ang-II. In vivo, pressure overload by transverse aorta binding (AB induced a significant cardiac hypertrophic response as well as re-expression of ANP and BNP in mice heart, which were markedly reduced by AG-490 and TSA. Significantly, AG-490, the Jak2 inhibitor, largely suppressed pressure overload-/Ang-II-induced HDAC2 nuclear exportation in vivo and in vitro. Meanwhile, TSA or HDAC2 siRNA knockdown reduced Ang-II-induced ANP/BNP expression in Jak2 over-expressed H9c2 cardiomyocytes. Together, these results suggest that HDAC2 might be a downstream effector of Jak2 to mediate cardiac hypertrophic response by pressure overload or Ang-II.

  14. Inhibition of Uncoupling Protein 2 Attenuates Cardiac Hypertrophy Induced by Transverse Aortic Constriction in Mice

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    Xiao-Bing Ji

    2015-07-01

    Full Text Available Background: Uncoupling protein 2 (UCP2 is critical in regulating energy metabolism. Due to the significant change in energy metabolism of myocardium upon pressure overload, we hypothesize that UCP2 could contribute to the etiology of cardiac hypertrophy. Methods: Adult male C57BL/6J mice were subjected to pressure overload by using transverse aortic constriction (TAC, and then received genipin (a UCP2 selective inhibitor; 25 mg/kg/d, ip or vehicle for three weeks prior to histologic assessment of myocardial hypertrophy. ATP concentration, ROS level, and myocardial apoptosis were also examined. A parallel set of experiments was also conducted in UCP2-/- mice. Results: TAC induced left ventricular hypertrophy, as reflected by increased ventricular weight/thickness and increased size of myocardial cell (vs. sham controls. ATP concentration was decreased; ROS level was increased. Apoptosis and fibrosis markers were increased. TAC increased mitochondrial UCP2 expression in the myocardium at both mRNA and protein levels. Genipin treatment attenuated cardiac hypertrophy and the histologic/biochemical changes described above. Hypertrophy and associated changes induced by TAC in UCP2-/- mice were much less pronounced than in WT mice. Conclusions: Blocking UCP2 expression attenuates cardiac hypertrophy induced by pressure overload.

  15. Cigarette Smoking-Induced Cardiac Hypertrophy, Vascular Inflammation and Injury are Attenuated by Antioxidant Supplementation in An Animal Model

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    Moustafa Al Hariri

    2016-11-01

    hypertrophy in cigarette smoke exposed animals.Conclusion Findings from this work showed that cigarette smoking exposure is associated with significant cardiovascular pathology such as cardiac hypertrophy, inflammation, pro-fibrotic and atherogenic markers and aortic calcification in an animal model as assessed 1 month post exposure. Antioxidant supplementation prevented cardiac hypertrophy and attenuated indicators of atherosclerosis markers associated with cigarette smoke exposure.Key words: Cigarette smoking, pomegranate Juice, inflammation, hypertrophy, calcification, reactive oxygen species, cardiovascular diseases.

  16. Human paraoxonase gene cluster overexpression alleviates angiotensin II-induced cardiac hypertrophy in mice.

    Science.gov (United States)

    Pei, Jian-Fei; Yan, Yun-Fei; Tang, Xiaoqiang; Zhang, Yang; Cui, Shen-Shen; Zhang, Zhu-Qin; Chen, Hou-Zao; Liu, De-Pei

    2016-11-01

    Cardiac hypertrophy is the strongest predictor of the development of heart failure, and anti-hypertrophic treatment holds the key to improving the clinical syndrome and increasing the survival rates for heart failure. The paraoxonase (PON) gene cluster (PC) protects against atherosclerosis and coronary artery diseases. However, the role of PC in the heart is largely unknown. To evaluate the roles of PC in cardiac hypertrophy, transgenic mice carrying the intact human PON1, PON2, and PON3 genes and their flanking sequences were studied. We demonstrated that the PC transgene (PC-Tg) protected mice from cardiac hypertrophy induced by Ang II; these mice had reduced heart weight/body weight ratios, decreased left ventricular wall thicknesses and increased fractional shortening compared with wild-type (WT) control. The same protective tendency was also observed with an Apoe -/- background. Mechanically, PC-Tg normalized the disequilibrium of matrix metalloproteinases (MMPs)/tissue inhibitors of MMPs (TIMPs) in hypertrophic hearts, which might contribute to the protective role of PC-Tg in cardiac fibrosis and, thus, protect against cardiac remodeling. Taken together, our results identify a novel anti-hypertrophic role for the PON gene cluster, suggesting a possible strategy for the treatment of cardiac hypertrophy through elevating the levels of the PON gene family.

  17. Nobiletin, a Polymethoxy Flavonoid, Protects Against Cardiac Hypertrophy Induced by Pressure-Overload via Inhibition of NAPDH Oxidases and Endoplasmic Reticulum Stress.

    Science.gov (United States)

    Zhang, Ning; Wei, Wen-Ying; Yang, Zheng; Che, Yan; Jin, Ya-Ge; Liao, Hai-Han; Wang, Sha-Sha; Deng, Wei; Tang, Qi-Zhu

    2017-01-01

    An increase in oxidative stress has been implicated in the pathophysiology of pressure-overload induced cardiac hypertrophy. Nobiletin (NOB), extracted from the fruit peel of citrus, possesses anti-oxidative property. Our study aimed to investigate the protective role of NOB in the progression of cardiac hypertrophy in vivo and in vitro. Mice received aortic banding (AB) operation to induce cardiac hypertrophy. Experimental groups were as follows: sham+vehicle (VEH/SH), sham+NOB (NOB/SH), AB+vehicle (VEH/AB), and AB+ NOB (NOB/AB). Animals (n = 15 per group) were treated with vehicle or NOB (50 mg/kg) for 4 weeks after disease onset. NOB prevented cardiac hypertrophy induced by aortic banding (AB), as assessed by the cross-sectional area of cardiomyocytes, heart weight-to-body weight ratio, gene expression of hypertrophic markers and cardiac function. In addition, NOB supplementation blunted the increased expression of NAPDH oxidase (NOX) 2 and NOX4 and mitigated endoplasmic reticulum (ER) stress and myocyte apoptosis in cardiac hypertrophy. Furthermore, NOB treatment attenuated the neonatal rat cardiomyocyte (NRCM) hypertrophic response stimulated by phenylephrine (PE) and alleviated ER stress. However, our data showed that NOB dramatically inhibited NOX2 expression but not NOX4 in vitro. Finally, we found that knockdown of NOX2 attenuated ER stress in NRCMs stimulated by PE. Inhibition of oxidative and ER stress by NOB in the myocardium may represent a potential therapy for cardiac hypertrophy. Moreover, there is a direct role of NOX2 in regulating ER stress stimulated by PE. © 2017 The Author(s). Published by S. Karger AG, Basel.

  18. Nobiletin, a Polymethoxy Flavonoid, Protects Against Cardiac Hypertrophy Induced by Pressure-Overload via Inhibition of NAPDH Oxidases and Endoplasmic Reticulum Stress

    Directory of Open Access Journals (Sweden)

    Ning Zhang

    2017-07-01

    Full Text Available Background/Aims: An increase in oxidative stress has been implicated in the pathophysiology of pressure-overload induced cardiac hypertrophy. Nobiletin (NOB, extracted from the fruit peel of citrus, possesses anti-oxidative property. Our study aimed to investigate the protective role of NOB in the progression of cardiac hypertrophy in vivo and in vitro. Methods: Mice received aortic banding (AB operation to induce cardiac hypertrophy. Experimental groups were as follows: sham+vehicle (VEH/SH, sham+NOB (NOB/SH, AB+vehicle (VEH/AB, and AB+ NOB (NOB/AB. Animals (n = 15 per group were treated with vehicle or NOB (50 mg/kg for 4 weeks after disease onset. Results: NOB prevented cardiac hypertrophy induced by aortic banding (AB, as assessed by the cross-sectional area of cardiomyocytes, heart weight-to-body weight ratio, gene expression of hypertrophic markers and cardiac function. In addition, NOB supplementation blunted the increased expression of NAPDH oxidase (NOX 2 and NOX4 and mitigated endoplasmic reticulum (ER stress and myocyte apoptosis in cardiac hypertrophy. Furthermore, NOB treatment attenuated the neonatal rat cardiomyocyte (NRCM hypertrophic response stimulated by phenylephrine (PE and alleviated ER stress. However, our data showed that NOB dramatically inhibited NOX2 expression but not NOX4 in vitro. Finally, we found that knockdown of NOX2 attenuated ER stress in NRCMs stimulated by PE. Conclusions: Inhibition of oxidative and ER stress by NOB in the myocardium may represent a potential therapy for cardiac hypertrophy. Moreover, there is a direct role of NOX2 in regulating ER stress stimulated by PE.

  19. Overexpression of the human angiotensin II type 1 receptor in the rat heart augments load induced cardiac hypertrophy

    NARCIS (Netherlands)

    Hoffmann, S.; Krause, T.; van Geel, P. P.; Willenbrock, R.; Pagel, I.; Pinto, Y. M.; Buikema, H.; van Gilst, W. H.; Lindschau, C.; Paul, M.; Inagami, T.; Ganten, D.; Urata, H.

    2001-01-01

    Angiotensin II is known to stimulate cardiac hypertrophy and contractility. Most angiotensin II effects are mediated via membrane bound AT1 receptors. However, the role of myocardial AT1 receptors in cardiac hypertrophy and contractility is still rarely defined. To address the hypothesis that

  20. Satellite cell depletion prevents fiber hypertrophy in skeletal muscle.

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    Egner, Ingrid M; Bruusgaard, Jo C; Gundersen, Kristian

    2016-08-15

    The largest mammalian cells are the muscle fibers, and they have multiple nuclei to support their large cytoplasmic volumes. During hypertrophic growth, new myonuclei are recruited from satellite stem cells into the fiber syncytia, but it was recently suggested that such recruitment is not obligatory: overload hypertrophy after synergist ablation of the plantaris muscle appeared normal in transgenic mice in which most of the satellite cells were abolished. When we essentially repeated these experiments analyzing the muscles by immunohistochemistry and in vivo and ex vivo imaging, we found that overload hypertrophy was prevented in the satellite cell-deficient mice, in both the plantaris and the extensor digitorum longus muscles. We attribute the previous findings to a reliance on muscle mass as a proxy for fiber hypertrophy, and to the inclusion of a significant number of regenerating fibers in the analysis. We discuss that there is currently no model in which functional, sustainable hypertrophy has been unequivocally demonstrated in the absence of satellite cells; an exception is re-growth, which can occur using previously recruited myonuclei without addition of new myonuclei. © 2016. Published by The Company of Biologists Ltd.

  1. Pathological hypertrophy and cardiac dysfunction are linked to aberrant endogenous unsaturated fatty acid metabolism

    Science.gov (United States)

    Salomé Campos, Dijon Henrique; Grippa Sant’Ana, Paula; Okoshi, Katashi; Padovani, Carlos Roberto; Masahiro Murata, Gilson; Nguyen, Son; Kolwicz, Stephen C.; Cicogna, Antonio Carlos

    2018-01-01

    Pathological cardiac hypertrophy leads to derangements in lipid metabolism that may contribute to the development of cardiac dysfunction. Since previous studies, using high saturated fat diets, have yielded inconclusive results, we investigated whether provision of a high-unsaturated fatty acid (HUFA) diet was sufficient to restore impaired lipid metabolism and normalize diastolic dysfunction in the pathologically hypertrophied heart. Male, Wistar rats were subjected to supra-valvar aortic stenosis (SVAS) or sham surgery. After 6 weeks, diastolic dysfunction and pathological hypertrophy was confirmed and both sham and SVAS rats were treated with either normolipidic or HUFA diet. At 18 weeks post-surgery, the HUFA diet failed to normalize decreased E/A ratios or attenuate measures of cardiac hypertrophy in SVAS animals. Enzymatic activity assays and gene expression analysis showed that both normolipidic and HUFA-fed hypertrophied hearts had similar increases in glycolytic enzyme activity and down-regulation of fatty acid oxidation genes. Mass spectrometry analysis revealed depletion of unsaturated fatty acids, primarily linoleate and oleate, within the endogenous lipid pools of normolipidic SVAS hearts. The HUFA diet did not restore linoleate or oleate in the cardiac lipid pools, but did maintain body weight and adipose mass in SVAS animals. Overall, these results suggest that, in addition to decreased fatty acid oxidation, aberrant unsaturated fatty acid metabolism may be a maladaptive signature of the pathologically hypertrophied heart. The HUFA diet is insufficient to reverse metabolic remodeling, diastolic dysfunction, or pathologically hypertrophy, possibly do to preferentially partitioning of unsaturated fatty acids to adipose tissue. PMID:29494668

  2. Cigarette Smoking-Induced Cardiac Hypertrophy, Vascular Inflammation and Injury Are Attenuated by Antioxidant Supplementation in an Animal Model.

    Science.gov (United States)

    Al Hariri, Moustafa; Zibara, Kazem; Farhat, Wissam; Hashem, Yasmine; Soudani, Nadia; Al Ibrahim, Farah; Hamade, Eva; Zeidan, Asad; Husari, Ahmad; Kobeissy, Firas

    2016-01-01

    smoke exposed animals. Conclusion: Findings from this work showed that cigarette smoking exposure is associated with significant cardiovascular pathology such as cardiac hypertrophy, inflammation, pro-fibrotic, and atherogenic markers and aortic calcification in an animal model as assessed 1 month post exposure. Antioxidant supplementation prevented cardiac hypertrophy and attenuated indicators of atherosclerosis markers associated with cigarette smoke exposure.

  3. Role of myocardial hypertrophy in trophic stimulation of indices of sympathetic cardiac innervation.

    Science.gov (United States)

    Lindpaintner, K; Lund, D D; Schmid, P G

    1987-01-01

    Indices of cardiac sympathetic innervation have commonly been found depressed in the failing, hypertrophied heart. In contrast, we have recently demonstrated that hemodynamically compensated, very gradually developing right ventricular hypertrophy is associated with an increase in sympathetic nervous markers. The present experiments were performed to corroborate these findings in a model of acutely induced right ventricular hypertrophy, and to further characterize changes in markers of autonomic innervation associated with cardiac hypertrophy. Male guinea pigs underwent either pulmonary artery banding (P) with an acutely constricting ligature, or bilateral stellate ganglionectomy (S), or both (PS). Appropriate sham procedures were performed in animals subjected to only one intervention; controls (C) underwent sham-S and sham-P. Groups of animals were sacrificed at 10 and 20 days after surgery. Cardiac tissues were weighed and subsequently analyzed for activities of tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH), two enzymes catalyzing the biosynthesis of catecholamines (CAs), and of choline acetyltransferase (CAT), a marker of parasympathetic activity, as well as for norepinephrine (NE). S resulted in profound depletions of cardiac NE of 88-92% and in significant decreases in the activities of DBH and TH. Marked right ventricular hypertrophy developed rapidly following P, and was not modified by S. Similar to our previous results, acute right ventricular hypertrophy was associated with moderate increases (10-20%) of sympathetic markers; following S, these increases (of presumably residual sympathetic innervation) were greatly enhanced, amounting to 171% and 105% for NE at 10 and 20 days, respectively. In contrast, sympathetic markers in the left ventricle of stellatectomized animals were not affected by P. Activity of CAT remained unaltered by the experimental interventions. Our experiments indicate that increases in markers of sympathetic

  4. Protection against cardiac hypertrophy by geniposide involves the GLP-1 receptor / AMPKα signalling pathway.

    Science.gov (United States)

    Ma, Zhen-Guo; Dai, Jia; Zhang, Wen-Bin; Yuan, Yuan; Liao, Hai-Han; Zhang, Ning; Bian, Zhou-Yan; Tang, Qi-Zhu

    2016-05-01

    Activation of glucagon-like peptide-1 (GLP-1) receptor exerts a range of cardioprotective effects. Geniposide is an agonist of GLP-1 receptor, but its role in cardiac hypertrophy remains completely unknown. Here, we have investigated its protective effects and clarified the underlying molecular mechanisms. The transverse aorta was constricted in C57/B6 mice and then geniposide was given orally for 7 weeks. Morphological changes, echocardiographic parameters, histological analyses and hypertrophic markers were used to evaluate hypertrophy. Geniposide inhibited the hypertrophic response induced by constriction of the transverse aorta or by isoprenaline. Activation of 5'-AMP-activated protein kinase-α (AMPKα) and inhibition of mammalian target of rapamycin, ERK and endoplasmic reticulum stress were observed in hypertrophic hearts that were treated with geniposide. Furthermore, Compound C (CpC) or knock-down of AMPKα restricted protection of geniposide against cell hypertrophy and activation of mammalian target of rapamycin and ERK induced by hypertrophic stimuli. CpC or shAMPKα also abolished the protection of geniposide against endoplasmic reticulum stress induced by thapsigargin or dihtiothreitol. The cardio-protective effects of geniposide were ablated in mice subjected to CpC. GLP-1receptor blockade counteracted the anti-hypertrophic response and activation of AMPKα by geniposide. Knock-down of GLP-1 receptor also offset the inhibitory effects of geniposide on cardiac hypertrophy in vivo. Geniposide protected against cardiac hypertrophy via activation of the GLP-1 receptor/AMPKα pathway. Geniposide is a potential therapeutic drug for cardiac hypertrophy. © 2016 The British Pharmacological Society.

  5. Splice variants of enigma homolog, differentially expressed during heart development, promote or prevent hypertrophy.

    Science.gov (United States)

    Yamazaki, Tomoko; Wälchli, Sébastien; Fujita, Toshitsugu; Ryser, Stephan; Hoshijima, Masahiko; Schlegel, Werner; Kuroda, Shun'ichi; Maturana, Andrés D

    2010-06-01

    Proteins with a PDZ (for PSD-95, DLG, ZO-1) and one to three LIM (for Lin11, Isl-1, Mec-3) domains are scaffolding sarcomeric and cytoskeletal elements that form structured muscle fibres and provide for the link to intracellular signalling by selectively associating protein kinases, ion channels, and transcription factors with the mechanical stress-strain sensors. Enigma homolog (ENH) is a PDZ-LIM protein with four splice variants: ENH1 with an N-terminal PDZ domain and three C-terminal LIM domains and ENH2, ENH3, and ENH4 without LIM domains. We addressed the functional role of ENH alternative splicing. We studied the expression of the four ENH isoforms in the heart during development and in a mouse model of heart hypertrophy. All four isoforms are expressed in the heart but the pattern of expression is clearly different between embryonic, neonatal, and adult stages. ENH1 appears as the embryonic isoform, whereas ENH2, ENH3, and ENH4 are predominant in adult heart. Moreover, alternative splicing of ENH was changed following induction of heart hypertrophy, producing an ENH isoform pattern similar to that of neonatal heart. Next, we tested a possible causal role of ENH1 and ENH4 in the development of cardiac hypertrophy. When overexpressed in rat neonatal cardiomyocytes, ENH1 promoted the expression of hypertrophy markers and increased cell volume, whereas, on the contrary, ENH4 overexpression prevented these changes. Antagonistic splice variants of ENH may play a central role in the adaptive changes of the link between mechanical stress-sensing and signalling occurring during embryonic development and/or heart hypertrophy.

  6. Toll-Like Receptor 4 Inhibition Improves Oxidative Stress and Mitochondrial Health in Isoproterenol-Induced Cardiac Hypertrophy in Rats

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    Parmeshwar B. Katare

    2017-06-01

    Full Text Available BackgroundInflammation remains a crucial factor for progression of cardiac diseases and cardiac hypertrophy remains an important cause of cardiac failure over all age groups. As a key regulator of inflammation, toll-like receptor 4 (TLR4 plays an important role in pathogenesis of cardiac diseases. Being an important regulator of innate immunity, the precise pathway of TLR4-mediated cardiac complications is yet to be established. Therefore, the primary objective of the present study was to find the role of TLR4 in cardiac hypertrophy and the molecular mechanism thereof.MethodsCardiac hypertrophy was induced with administration of isoproterenol (5 mg/kg/day, sc. TLR4 receptor inhibitor RS-LPS (lipopolysaccharide from the photosynthetic bacterium Rhodobacter sphaeroides; 5 μg/day and agonist lipopolysaccharide (LPS (from Escherichia coli; 3.12 μg/day were administered through osmotic pump along with isoproterenol. Cardiac hypertrophy as well as oxidative stress and mitochondrial parameters were evaluated.ResultsCardiac hypertrophy was confirmed with increased heart weight/body weight ratio as well as assessment of hypertrophic markers in heart. There was a marked increase in the TLR4 expression and oxidative stress along with mitochondrial dysfunction in ISO group. TLR4 inhibition significantly decreased heart weight/body weight ratio and ANP, collagen, and β-MHC expression and restored the disturbed cellular antioxidant flux. The mitochondrial perturbations that were observed in hypertrophy heart was normalized after administration of TLR4 inhibitor but not with the agonist. TLR4 agonism further exaggerated the oxidative stress in heart and hence accelerated the disease development and progression.ConclusionOur data show that increased TLR4 ligand pool in cardiac hypertrophy may exaggerate the disease progression. However, inhibition of TLR4 attenuated cardiac hypertrophy through reduced cardiac redox imbalance and mitochondrial

  7. Lysyl oxidase overexpression accelerates cardiac remodeling and aggravates angiotensin II-induced hypertrophy.

    Science.gov (United States)

    Galán, María; Varona, Saray; Guadall, Anna; Orriols, Mar; Navas, Miquel; Aguiló, Silvia; de Diego, Alicia; Navarro, María A; García-Dorado, David; Rodríguez-Sinovas, Antonio; Martínez-González, José; Rodriguez, Cristina

    2017-09-01

    Lysyl oxidase (LOX) controls matrix remodeling, a key process that underlies cardiovascular diseases and heart failure; however, a lack of suitable animal models has limited our knowledge with regard to the contribution of LOX to cardiac dysfunction. Here, we assessed the impact of LOX overexpression on ventricular function and cardiac hypertrophy in a transgenic LOX (TgLOX) mouse model with a strong cardiac expression of human LOX. TgLOX mice exhibited high expression of the transgene in cardiomyocytes and cardiofibroblasts, which are associated with enhanced LOX activity and H 2 O 2 production and with cardiofibroblast reprogramming. LOX overexpression promoted an age-associated concentric remodeling of the left ventricle and impaired diastolic function. Furthermore, LOX transgenesis aggravated angiotensin II (Ang II)-induced cardiac hypertrophy and dysfunction, which triggered a greater fibrotic response that was characterized by stronger collagen deposition and cross-linking and high expression of fibrotic markers. In addition, LOX transgenesis increased the Ang II-induced myocardial inflammatory infiltrate, exacerbated expression of proinflammatory markers, and decreased that of cardioprotective factors. Mechanistically, LOX overexpression enhanced oxidative stress and potentiated the Ang II-mediated cardiac activation of p38 MAPK while reducing AMPK activation. Our findings suggest that LOX induces an age-dependent disturbance of diastolic function and aggravates Ang II-induced hypertrophy, which provides novel insights into the role of LOX in cardiac performance.-Galán, M., Varona, S., Guadall, A., Orriols, M., Navas, M., Aguiló, S., de Diego, A., Navarro, M. A., García-Dorado, D., Rodríguez-Sinovas, A., Martínez-González, J., Rodriguez, C. Lysyl oxidase overexpression accelerates cardiac remodeling and aggravates angiotensin II-induced hypertrophy. © FASEB.

  8. Comparison of Nigella sativa- and exercise-induced models of cardiac hypertrophy: structural and electrophysiological features.

    Science.gov (United States)

    Al-Asoom, Lubna Ibrahim; Al-Shaikh, Basil Abdulrahman; Bamosa, Abdullah Omar; El-Bahai, Mohammad Nabil

    2014-09-01

    Exercise training is employed as supplementary therapeutic intervention for heart failure, due to its ability to induce physiological cardiac hypertrophy. In parallel, supplementation with Nigella sativa (N. sativa) was found to enhance myocardial function and induce cardiac hypertrophy. In this study, we aim to compare the morphological and electrophysiological changes associated with these patterns of cardiac hypertrophy and the possible changes upon administration of N. sativa to exercise-trained animals. Fifty-six adult Wistar rats were divided into: control, Nigella-treated (N), exercise-trained (E), and Nigella-treated-exercise-trained (NE) rats. Daily 800 mg/kg N. sativa was administered orally to N and NE. E and NE ran on treadmill, 2 h/day. At the end of 8 weeks ECG, body weight (BW), heart weight (HW), and left ventricular weight (LVW) were recorded. Hematoxylin and Eosin and periodic acid-Schiff sections were prepared to study the histology of left ventricles and to measure diameter of cardiomyocytes (Cdia). HW/BW, LVW/BW, and mean Cdia were significantly higher in all experimental animals compared to the controls. Histology showed normal cardiomyocytes with no fibrosis. ECG showed significantly lower heart rates, higher QRS amplitude, and ventricular specific potential in NE group compared to control group. Supplementation of N. sativa demonstrated a synergistic effect with exercise training as Nigella-exercise-induced cardiac hypertrophy had lower heart rate and well-matched electrical activity of the heart to its mass. Therefore, this model of cardiac hypertrophy might be introduced as a new therapeutic strategy for treatment for heart failure with superior advantages to exercise training.

  9. Sildenafil prevents the up-regulation of transient receptor potential canonical channels in the development of cardiomyocyte hypertrophy

    International Nuclear Information System (INIS)

    Kiso, Hironori; Ohba, Takayoshi; Iino, Kenji; Sato, Kazuhiro; Terata, Yutaka; Murakami, Manabu; Ono, Kyoichi; Watanabe, Hiroyuki; Ito, Hiroshi

    2013-01-01

    Highlights: •Transient receptor potential canonical (TRPC1, 3 and 6) are up-regulated by ET-1. •Sildenafil inhibited hypertrophic responses (BNP, Ca entry, NFAT activation). •Sildenafil suppressed TRPC1, 3 and 6 expression. -- Abstract: Background: Transient receptor potential canonical (TRPCs) channels are up-regulated in the development of cardiac hypertrophy. Sildenafil inhibits TRPC6 activation and expression, leading to the prevention of cardiac hypertrophy. However, the effects of sildenafil on the expression of other TRPCs remain unknown. We hypothesized that in addition to its effects of TRPC6, sildenafil blocks the up-regulation of other TRPC channels to suppress cardiomyocyte hypertrophy. Methods and results: In cultured neonatal rat cardiomyocytes, a 48 h treatment with 10 nM endothelin (ET)-1 induced hypertrophic responses characterized by nuclear factor of activated T cells activation and enhancement of brain natriuretic peptide expression and cell surface area. Co-treatment with sildenafil (1 μM, 48 h) inhibited these ET-1-induced hypertrophic responses. Although ET-1 enhanced the gene expression of TRPCs, sildenafil inhibited the enhanced gene expression of TRPC1, C3 and C6. Moreover, co-treatment with sildenafil abolished the augmentation of SOCE in the hypertrophied cardiomyocytes. Conclusions: These results suggest that sildenafil inhibits cardiomyocyte hypertrophy by suppressing the up-regulation of TRPC expression

  10. Cardiac CaM Kinase II genes δ and γ contribute to adverse remodeling but redundantly inhibit calcineurin-induced myocardial hypertrophy.

    Science.gov (United States)

    Kreusser, Michael M; Lehmann, Lorenz H; Keranov, Stanislav; Hoting, Marc-Oscar; Oehl, Ulrike; Kohlhaas, Michael; Reil, Jan-Christian; Neumann, Kay; Schneider, Michael D; Hill, Joseph A; Dobrev, Dobromir; Maack, Christoph; Maier, Lars S; Gröne, Hermann-Josef; Katus, Hugo A; Olson, Eric N; Backs, Johannes

    2014-10-07

    Ca(2+)-dependent signaling through CaM Kinase II (CaMKII) and calcineurin was suggested to contribute to adverse cardiac remodeling. However, the relative importance of CaMKII versus calcineurin for adverse cardiac remodeling remained unclear. We generated double-knockout mice (DKO) lacking the 2 cardiac CaMKII genes δ and γ specifically in cardiomyocytes. We show that both CaMKII isoforms contribute redundantly to phosphorylation not only of phospholamban, ryanodine receptor 2, and histone deacetylase 4, but also calcineurin. Under baseline conditions, DKO mice are viable and display neither abnormal Ca(2+) handling nor functional and structural changes. On pathological pressure overload and β-adrenergic stimulation, DKO mice are protected against cardiac dysfunction and interstitial fibrosis. But surprisingly and paradoxically, DKO mice develop cardiac hypertrophy driven by excessive activation of endogenous calcineurin, which is associated with a lack of phosphorylation at the auto-inhibitory calcineurin A site Ser411. Likewise, calcineurin inhibition prevents cardiac hypertrophy in DKO. On exercise performance, DKO mice show an exaggeration of cardiac hypertrophy with increased expression of the calcineurin target gene RCAN1-4 but no signs of adverse cardiac remodeling. We established a mouse model in which CaMKII's activity is specifically and completely abolished. By the use of this model we show that CaMKII induces maladaptive cardiac remodeling while it inhibits calcineurin-dependent hypertrophy. These data suggest inhibition of CaMKII but not calcineurin as a promising approach to attenuate the progression of heart failure. © 2014 American Heart Association, Inc.

  11. Estrogen deprivation aggravates cardiac hypertrophy in nonobese Type 2 diabetic Goto-Kakizaki (GK) rats.

    Science.gov (United States)

    Apaijai, Nattayaporn; Charoenphandhu, Narattaphol; Ittichaichareon, Jitjiroj; Suntornsaratoon, Panan; Krishnamra, Nateetip; Aeimlapa, Ratchaneevan; Chattipakorn, Siriporn C; Chattipakorn, Nipon

    2017-10-31

    Both Type 2 diabetes mellitus (T2DM) and estrogen deprivation have been shown to be associated with the development of cardiovascular disease and adverse cardiac remodeling. However, the role of estrogen deprivation on adverse cardiac remodeling in nonobese T2DM rats has not been clearly elucidated. We hypothesized that estrogen-deprivation aggravates adverse cardiac remodeling in Goto-Kakizaki (GK) rats. Wild-type (WT) and GK rats at the age of 9 months old were divided into two subgroups to have either a sham operation (WTS, GKS) or a bilateral ovariectomy (WTO, GKO) ( n = 6/subgroup). Four months after the operation, the rats were killed, and the heart was excised rapidly. Metabolic parameters, cardiomyocytes hypertrophy, cardiac fibrosis, and biochemical parameters were determined. GK rats had hyperglycemia with hypoinsulinemia, and estrogen deprivation did not increase the severity of T2DM. Cardiac hypertrophy, cardiac oxidative stress, and phosphor-antinuclear factor κB were higher in WTO and GKS rats than WTS rats, and they markedly increased in GKO rats compared with GKS rats. Furthermore, cardiac fibrosis, transforming growth factor-β, Bax, phosphor-p38, and peroxisome proliferator- activated receptor γ coactivator-1α expression were increased in GKS and GKO rats compared with the lean rats. However, mitochondrial dynamics proteins including dynamin-related protein 1 and mitofusin-2 were not altered by T2DM and estrogen deprivation. Although estrogen deprivation did not aggravate T2DM in GK rats, it increased the severity of cardiac hypertrophy by provoking cardiac inflammation and oxidative stress in nonobese GK rats. © 2017 The Author(s).

  12. Ca2+/Calmodulin-Dependent Protein Kinase II and Androgen Signaling Pathways Modulate MEF2 Activity in Testosterone-Induced Cardiac Myocyte Hypertrophy

    Directory of Open Access Journals (Sweden)

    Javier Duran

    2017-09-01

    Full Text Available Testosterone is known to induce cardiac hypertrophy through androgen receptor (AR-dependent and -independent pathways, but the molecular underpinnings of the androgen action remain poorly understood. Previous work has shown that Ca2+/calmodulin-dependent protein kinase II (CaMKII and myocyte-enhancer factor 2 (MEF2 play key roles in promoting cardiac myocyte growth. In order to gain mechanistic insights into the action of androgens on the heart, we investigated how testosterone affects CaMKII and MEF2 in cardiac myocyte hypertrophy by performing studies on cultured rat cardiac myocytes and hearts obtained from adult male orchiectomized (ORX rats. In cardiac myocytes, MEF2 activity was monitored using a luciferase reporter plasmid, and the effects of CaMKII and AR signaling pathways on MEF2C were examined by using siRNAs and pharmacological inhibitors targeting these two pathways. In the in vivo studies, ORX rats were randomly assigned to groups that were administered vehicle or testosterone (125 mg⋅kg-1⋅week-1 for 5 weeks, and plasma testosterone concentrations were determined using ELISA. Cardiac hypertrophy was evaluated by measuring well-characterized hypertrophy markers. Moreover, western blotting was used to assess CaMKII and phospholamban (PLN phosphorylation, and MEF2C and AR protein levels in extracts of left-ventricle tissue from control and testosterone-treated ORX rats. Whereas testosterone treatment increased the phosphorylation levels of CaMKII (Thr286 and phospholambam (PLN (Thr17 in cardiac myocytes in a time- and concentration-dependent manner, testosterone-induced MEF2 activity and cardiac myocyte hypertrophy were prevented upon inhibition of CaMKII, MEF2C, and AR signaling pathways. Notably, in the hypertrophied hearts obtained from testosterone-administered ORX rats, both CaMKII and PLN phosphorylation levels and AR and MEF2 protein levels were increased. Thus, this study presents the first evidence indicating that

  13. Kaempferol Attenuates Cardiac Hypertrophy via Regulation of ASK1/MAPK Signaling Pathway and Oxidative Stress.

    Science.gov (United States)

    Feng, Hong; Cao, Jianlei; Zhang, Guangyu; Wang, Yanggan

    2017-07-01

    Kaempferol has been demonstrated to provide benefits for the treatment of atherosclerosis, coronary heart disease, hyperlipidemia, and diabetes through its antioxidant and anti-inflammatory properties. However, its role in cardiac hypertrophy remains to be elucidated. The aim of our study was to investigate the effects of kaempferol on cardiac hypertrophy and the underlying mechanism. Mice subjected to aorta banding were treated with or without kaempferol (100 mg/kg/d, p. o.) for 6 weeks. Echocardiography was performed to evaluate cardiac function. Mice hearts were collected for pathological observation and molecular mechanism investigation. H9c2 cardiomyocytes were stimulated with or without phenylephrine for in vitro study. Kaempferol significantly attenuated cardiac hypertrophy induced by aorta banding as evidenced by decreased cardiomyocyte areas and interstitial fibrosis, accompanied with improved cardiac functions and decreased apoptosis. The ASK1/MAPK signaling pathways (JNK1/2 and p38) were markedly activated in the aorta banding mouse heart but inhibited by kaempferol treatment. In in vitro experiments, kaempferol also inhibited the activity of ASK1/JNK1/2/p38 signaling pathway and the enlargement of H9c2 cardiomyocytes. Furthermore, our study revealed that kaempferol could protect the mouse heart and H9c2 cells from pathological oxidative stress. Our investigation indicated that treatment with kaempferol protects against cardiac hypertrophy, and its cardioprotection may be partially explained by the inhibition of the ASK1/MAPK signaling pathway and the regulation of oxidative stress. Georg Thieme Verlag KG Stuttgart · New York.

  14. DDiT4L promotes autophagy and inhibits pathological cardiac hypertrophy in response to stress.

    Science.gov (United States)

    Simonson, Bridget; Subramanya, Vinita; Chan, Mun Chun; Zhang, Aifeng; Franchino, Hannabeth; Ottaviano, Filomena; Mishra, Manoj K; Knight, Ashley C; Hunt, Danielle; Ghiran, Ionita; Khurana, Tejvir S; Kontaridis, Maria I; Rosenzweig, Anthony; Das, Saumya

    2017-02-28

    Physiological cardiac hypertrophy, in response to stimuli such as exercise, is considered adaptive and beneficial. In contrast, pathological cardiac hypertrophy that arises in response to pathological stimuli such as unrestrained high blood pressure and oxidative or metabolic stress is maladaptive and may precede heart failure. We found that the transcript encoding DNA damage-inducible transcript 4-like (DDiT4L) was expressed in murine models of pathological cardiac hypertrophy but not in those of physiological cardiac hypertrophy. In cardiomyocytes, DDiT4L localized to early endosomes and promoted stress-induced autophagy through a process involving mechanistic target of rapamycin complex 1 (mTORC1). Exposing cardiomyocytes to various types of pathological stress increased the abundance of DDiT4L , which inhibited mTORC1 but activated mTORC2 signaling. Mice with conditional cardiac-specific overexpression of DDiT4L had mild systolic dysfunction, increased baseline autophagy, reduced mTORC1 activity, and increased mTORC2 activity, all of which were reversed by suppression of transgene expression. Genetic suppression of autophagy also reversed cardiac dysfunction in these mice. Our data showed that DDiT4L may be an important transducer of pathological stress to autophagy through mTOR signaling in the heart and that DDiT4L could be therapeutically targeted in cardiovascular diseases in which autophagy and mTOR signaling play a major role. Copyright © 2017, American Association for the Advancement of Science.

  15. Phosphorylation of pRb by cyclin D kinase is necessary for development of cardiac hypertrophy

    DEFF Research Database (Denmark)

    Hinrichsen, Rebecca; Hansen, A.H.; Haunsø, S.

    2008-01-01

    OBJECTIVES: A number of stimuli induce cardiac hypertrophy and may lead to cardiomyopathy and heart failure. It is believed that cardiomyocytes withdraw from the cell cycle shortly after birth and become terminally differentiated. However, cell cycle regulatory proteins take part in the development...... growth in cardiomyocytes, whereas cyclin E-cdk2 kinase is not necessary for hypertrophy but regulates endoreplication in these cells. The data support the notion that hypertrophic growth of cardiomyocytes involves a partial progression through the G1 phase of the cell cycle Udgivelsesdato: 2008/10...

  16. Zinc-finger protein 418 overexpression protects against cardiac hypertrophy and fibrosis.

    Directory of Open Access Journals (Sweden)

    Liming Pan

    Full Text Available This study aimed to investigated the effect and mechanism of zinc-finger protein 418 (ZNF418 on cardiac hypertrophy caused by aortic banding (AB, phenylephrine (PE or angiotensin II (Ang II in vivo and in vitro.The expression of ZNF418 in hearts of patients with dilated cardiomyopathy (DCM or hypertrophic cardiomyopathy (HCM and AB-induced cardiac hypertrophy mice, as well as in Ang II- or PE-induced hypertrophic primary cardiomyocytes was detected by western blotting. Then, the expression of ZNF418 was up-regulated or down-regulated in AB-induced cardiac hypertrophy mice and Ang II -induced hypertrophic primary cardiomyocytes. The hypertrophic responses and fibrosis were evaluated by echocardiography and histological analysis. The mRNA levels of hypertrophy markers and fibrotic markers were detected by RT-qPCR. Furthermore, the phosphorylation and total levels of c-Jun were measured by western blotting.ZNF418 was markedly down-regulated in hearts of cardiac hypertrophy and hypertrophic primary cardiomyocytes. Down-regulated ZNF418 exacerbated the myocyte size and fibrosis, moreover increased the mRNA levels of ANP, BNP, β-MHC, MCIP1.4, collagen 1a, collagen III, MMP-2 and fibronection in hearts of AB-treated ZNF418 knockout mice or Ang II-treated cardiomyocytes with AdshZNF418. Conversely, these hypertrophic responses were reduced in the ZNF418 transgenic (TG mice treated by AB and the AdZNF418-transfected primary cardiomyocytes treated by Ang II. Additionally, the deficiency of ZNF418 enhanced the phosphorylation level of c-jun, and overexpression of ZNF418 suppressed the phosphorylation level of c-jun in vivo and in vitro.ZNF418 maybe attenuate hypertrophic responses by inhibiting the activity of c-jun/AP-1.

  17. Zinc-finger protein 418 overexpression protects against cardiac hypertrophy and fibrosis

    Science.gov (United States)

    Huang, Zirui; Zhu, Zhilin; Xu, Chunli; Teng, Lin; He, Ling; Gu, Chen; Yi, Cai

    2017-01-01

    Background This study aimed to investigated the effect and mechanism of zinc-finger protein 418 (ZNF418) on cardiac hypertrophy caused by aortic banding (AB), phenylephrine (PE) or angiotensin II (Ang II) in vivo and in vitro. Methods The expression of ZNF418 in hearts of patients with dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM) and AB-induced cardiac hypertrophy mice, as well as in Ang II- or PE-induced hypertrophic primary cardiomyocytes was detected by western blotting. Then, the expression of ZNF418 was up-regulated or down-regulated in AB-induced cardiac hypertrophy mice and Ang II -induced hypertrophic primary cardiomyocytes. The hypertrophic responses and fibrosis were evaluated by echocardiography and histological analysis. The mRNA levels of hypertrophy markers and fibrotic markers were detected by RT-qPCR. Furthermore, the phosphorylation and total levels of c-Jun were measured by western blotting. Results ZNF418 was markedly down-regulated in hearts of cardiac hypertrophy and hypertrophic primary cardiomyocytes. Down-regulated ZNF418 exacerbated the myocyte size and fibrosis, moreover increased the mRNA levels of ANP, BNP, β-MHC, MCIP1.4, collagen 1a, collagen III, MMP-2 and fibronection in hearts of AB-treated ZNF418 knockout mice or Ang II-treated cardiomyocytes with AdshZNF418. Conversely, these hypertrophic responses were reduced in the ZNF418 transgenic (TG) mice treated by AB and the AdZNF418-transfected primary cardiomyocytes treated by Ang II. Additionally, the deficiency of ZNF418 enhanced the phosphorylation level of c-jun, and overexpression of ZNF418 suppressed the phosphorylation level of c-jun in vivo and in vitro. Conclusion ZNF418 maybe attenuate hypertrophic responses by inhibiting the activity of c-jun/AP-1. PMID:29065170

  18. An assessment of norepinephrine mediated hypertrophy to apoptosis transition in cardiac cells: a signal for cell death.

    Science.gov (United States)

    Jain, Aditi; Atale, Neha; Kohli, Shrey; Bhattacharya, Susinjan; Sharma, Manish; Rani, Vibha

    2015-01-05

    Heart is an organ which is under a constant work load that generates numerous stress responses. Heart failure is associated with increased plasma norepinephrine (NE) and hypertrophic cell death. Within the current study we try to understand the concentration dependent molecular switch from hypertrophy to apoptosis under stress. The effect of increasing concentration of NE on cell death was studied using MTT assay based on which further experimental conditions were decided. Trypan Blue staining and TUNEL assay were done at selected concentrations of NE. Cellular and nuclear morphology at these concentrations was studied using Haematoxylin-Eosin, DAPI and PI stains. The molecular switch between hypertrophy and cell death was studied by expression analysis of β-MyHC and TNF-α. Rhodamine and DCFH-DA staining were done to evaluate the role of mitochondria and ROS under these conditions. Role of caspases under these transitions was also evaluated. NE shows steep falls in cell viability at 50 μM and 100 μM concentrations. The cellular and nuclear morphology is altered at these concentrations along with alterations at molecular level showing a shift from hypertrophy towards cell death. Altered mitochondrial membrane potential and increase in ROS support this which leads to caspase dependent activation of cell death. We show that at 50 μM NE, there occurs a transition from cellular hypertrophy towards death. This could be beneficial to prevent hypertrophy induced cardiac cell death and evaluating cardio protective therapeutic targets in vitro. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  19. Construction and analysis of cardiac hypertrophy-associated lncRNA-mRNA network based on competitive endogenous RNA reveal functional lncRNAs in cardiac hypertrophy.

    Science.gov (United States)

    Song, Chao; Zhang, Jian; Liu, Yan; Pan, Hao; Qi, Han-Ping; Cao, Yong-Gang; Zhao, Jian-Mei; Li, Shang; Guo, Jing; Sun, Hong-Li; Li, Chun-Quan

    2016-03-08

    Cardiac hypertrophy (CH) could increase cardiac after-load and lead to heart failure. Recent studies have suggested that long non-coding RNA (lncRNA) played a crucial role in the process of the cardiac hypertrophy, such as Mhrt, TERMINATOR. Some studies have further found a new interacting mechanism, competitive endogenous RNA (ceRNA), of which lncRNA could interact with micro-RNAs (miRNA) and indirectly interact with mRNAs through competing interactions. However, the mechanism of ceRNA regulated by lncRNA in the CH remained unclear. In our study, we generated a global triple network containing mRNA, miRNA and lncRNA, and extracted a CH related lncRNA-mRNA network (CHLMN) through integrating the data from starbase, miRanda database and gene expression profile. Based on the ceRNA mechanism, we analyzed the characters of CHLMN and found that 3 lncRNAs (SLC26A4-AS1, RP11-344E13.3 and MAGI1-IT1) were high related to CH. We further performed cluster module analysis and random walk with restart for the CHLMN, finally 14 lncRNAs had been discovered as the potential CH related disease genes. Our results showed that lncRNA played an important role in the CH and could shed new light to the understanding underlying mechanisms of the CH.

  20. Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy

    Science.gov (United States)

    Hafner, Angela V.; Dai, Jing; Gomes, Ana P.; Xiao, Chun-Yang; Palmeira, Carlos M.; Rosenzweig, Anthony; Sinclair, David A.

    2010-01-01

    Cardiac failure is a leading cause of age-related death, though its root cause remains unknown. Mounting evidence implicates a decline in mitochondrial function due to increased opening of the mitochondrial permeability transition pore (mPTP). Here we report that the NAD+-dependent deacetylase SIRT3 deacetylates the regulatory component of the mPTP, cyclophilin D (CypD) on lysine 166, adjacent to the binding site of cyclosporine A, a CypD inhibitor. Cardiac myocytes from mice lacking SIRT3 exhibit an age-dependent increase in mitochondrial swelling due to increased mPTP opening, a phenotype that is rescued by cyclosporine A. SIRT3 knockout mice show accelerated signs of aging in the heart including cardiac hypertrophy and fibrosis at 13 months of age. SIRT3 knockout mice are also hypersensitive to heart stress induced by transverse aortic constriction (TAC), as evidenced by cardiac hypertrophy, fibrosis, and increased mortality. Together, these data show for the first time that SIRT3 activity is necessary to prevent mitochondrial dysfunction and cardiac hypertrophy during aging and shed light on new pharmacological approaches to delaying aging and treating diseases in cardiac muscle and possibly other post-mitotic tissues. PMID:21212461

  1. Isosteviol prevents the prolongation of action potential in hypertrophied cardiomyoctyes by regulating transient outward potassium and L-type calcium channels.

    Science.gov (United States)

    Fan, Zhuo; Lv, Nanying; Luo, Xiao; Tan, Wen

    2017-10-01

    Cardiac hypertrophy is a thickening of the heart muscle that is associated with cardiovascular diseases such as hypertension and myocardial infarction. It occurs initially as an adaptive process against increased workloads and often leads to sudden arrhythmic deaths. Studies suggest that the lethal arrhythmia is attributed to hypertrophy-induced destabilization of cardiac electrical activity, especially the prolongation of the action potential. The reduced activity of I to is demonstrated to be responsible for the ionic mechanism of prolonged action potential duration and arrhythmogeneity. Isosteviol (STV), a derivative of stevioside, plays a protective role in a variety of stress-induced cardiac diseases. Here we report effects of STV on rat ISO-induced hypertrophic cardiomyocytes. STV alleviated ISO-induced hypertrophy of cardiomyocytes by decreasing cell area of hypertrophied cardiomyocytes. STV application prevented the prolongation of action potential which was prominent in hypertrophied cells. The decrease and increase of current densities for I to and I CaL observed in hypertrophied myocytes were both prevented by STV application. In addition, the results of qRT-PCR suggested that the changes of electrophysiological activity of I to and I CaL are correlated to the alterations of the mRNA transcription level. Copyright © 2017. Published by Elsevier B.V.

  2. Apigenin ameliorates hypertension-induced cardiac hypertrophy and down-regulates cardiac hypoxia inducible factor-lα in rats.

    Science.gov (United States)

    Zhu, Zeng-Yan; Gao, Tian; Huang, Yan; Xue, Jie; Xie, Mei-Lin

    2016-04-01

    Apigenin is a natural flavonoid compound that can inhibit hypoxia-inducible factor (HIF)-1α expression in cultured tumor cells under hypoxic conditions. Hypertension-induced cardiac hypertrophy is always accompanied by abnormal myocardial glucolipid metabolism due to an increase of HIF-1α. However, whether or not apigenin may ameliorate the cardiac hypertrophy and abnormal myocardial glucolipid metabolism remains unknown. This study aimed to examine the effects of apigenin. Rats with cardiac hypertrophy induced by renovascular hypertension were treated with apigenin 50-100 mg kg(-1) (the doses can be achieved by pharmacological or dietary supplementation for an adult person) by gavage for 4 weeks. The results showed that after treatment with apigenin, the blood pressure, heart weight, heart weight index, cardiomyocyte cross-sectional area, serum angiotensin II, and serum and myocardial free fatty acids were reduced. It is important to note that apigenin decreased the expression level of myocardial HIF-1α protein. Moreover, apigenin simultaneously increased the expression levels of myocardial peroxisome proliferator-activated receptor (PPAR) α, carnitine palmitoyltransferase (CPT)-1, and pyruvate dehydrogenase kinase (PDK)-4 proteins and decreased the expression levels of myocardial PPARγ, glycerol-3-phosphate acyltransferase genes (GPAT), and glucose transporter (GLUT)-4 proteins. These findings demonstrated that apigenin could improve hypertensive cardiac hypertrophy and abnormal myocardial glucolipid metabolism in rats, and its mechanisms might be associated with the down-regulation of myocardial HIF-1α expression and, subsequently increasing the expressions of myocardial PPARα and its target genes CPT-1 and PDK-4, and decreasing the expressions of myocardial PPARγ and its target genes GPAT and GLUT-4.

  3. Accessory papillary muscles and papillary muscle hypertrophy are associated with sudden cardiac arrest of unknown cause.

    Science.gov (United States)

    Uhm, Jae-Sun; Youn, Jong-Chan; Lee, Hye-Jeong; Park, Junbeom; Park, Jin-Kyu; Shim, Chi Young; Hong, Geu-Ru; Joung, Boyoung; Pak, Hui-Nam; Lee, Moon-Hyoung

    2015-10-15

    The present study was performed for elucidating the associations between the morphology of the papillary muscles (PMs) and sudden cardiac arrest (SCA). We retrospectively reviewed history, laboratory data, electrocardiography, echocardiography, coronary angiography, and cardiac CT/MRI for 190 patients with SCA. The prevalence of accessory PMs and PM hypertrophy in patients with SCA of unknown cause was compared with that in patients with SCA of known causes and 98 age- and sex-matched patients without SCA. An accessory PM was defined as a PM with origins separated from the anterolateral and posteromedial PMs, or a PM that branched into two or three bellies at the base of the anterolateral or posteromedial PM. PM hypertrophy was defined as at least one of the two PMs having a diameter of ≥1.1cm. In 49 patients (age 49.9±15.9years; 38 men) the cause of SCA was unknown, whereas 141 (age 54.2±16.6years; 121 men) had a known cause. The prevalence of accessory PMs was significantly higher in the unknown-cause group than in the known-cause group (24.5% and 7.8%, respectively; p=0.002) or the no-SCA group (7.1%, p=0.003). The same was true for PM hypertrophy (unknown-cause 12.2%, known-cause 2.1%, p=0.010; no SCA group 1.0%, p=0.006). By logistic regression, accessory PM and PM hypertrophy were independently associated with sudden cardiac arrest of unknown cause. An accessory PM and PM hypertrophy are associated with SCA of unknown cause. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  4. Andrographis paniculata extract attenuates pathological cardiac hypertrophy and apoptosis in high-fat diet fed mice.

    Science.gov (United States)

    Hsieh, You-Liang; Shibu, Marthandam Asokan; Lii, Chong-Kuei; Viswanadha, Vijaya Padma; Lin, Yi-Lin; Lai, Chao-Hung; Chen, Yu-Feng; Lin, Kuan-Ho; Kuo, Wei-Wen; Huang, Chih-Yang

    2016-11-04

    Andrographis paniculata (Burm. f.) Nees (Acanthaceae) has a considerable medicinal reputation in most parts of Asia as a potent medicine in the treatment of Endocrine disorders, inflammation and hypertension. Water extract of A. paniculata and its active constituent andrographolide are known to possess anti-inflammatory and anti-apoptotic effects. Our aim is to identify whether A. paniculata extract could protect myocardial damage in high-fat diet induced obese mice. The test mice were divided into three groups fed either with normal chow or with high fat diet (obese) or with high fat diet treated with A. paniculata extract (2g/kg/day, through gavage, for a week). We found that the myocardial inflammation pathway related proteins were increased in the obese mouse which potentially contributes to cardiac hypertrophy and myocardial apoptosis. But feeding with A. paniculata extract showed significant inhibition on the effects of high fat diet. Our study strongly suggests that supplementation of A. paniculata extract can be used for prevention and treatment of cardiovascular disease in obese patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  5. Endogenous antioxidant defense induction by melon superoxide dismutase reduces cardiac hypertrophy in spontaneously hypertensive rats.

    Science.gov (United States)

    Carillon, Julie; Rugale, Caroline; Rouanet, Jean-Max; Cristol, Jean-Paul; Lacan, Dominique; Jover, Bernard

    2014-08-01

    We assessed the influence of SODB, a melon superoxide dismutase (SOD), on left ventricular (LV) hypertrophy in SHR. SODB (4 or 40U SOD) was given orally for 4 or 28 days to SHR. For each treatment period, LV weight index (LVWI) and cardiomyocytes size were measured. SOD, glutathione peroxidase (GPx) and catalase expressions, and LV production and presence of superoxide anion were determined. Pro-inflammatory markers were also measured. SODB reduced LVWI and cardiomyocytes size after 4 or 28 days. Cardiac SOD and GPx increased by 30-40% with SODB. The presence but not production of superoxide anion was significantly reduced by SODB. No effect of SODB was detected on inflammatory status in any group. The beneficial effect of SODB on cardiac hypertrophy seems to be related to the stimulation of endogenous antioxidant defense, suggesting that SODB may be of interest as a dietary supplementation during conventional antihypertensive therapy.

  6. Loss of Mouse P2Y6 Nucleotide Receptor Is Associated with Physiological Macrocardia and Amplified Pathological Cardiac Hypertrophy*

    Science.gov (United States)

    Clouet, Sophie; Di Pietrantonio, Larissa; Daskalopoulos, Evangelos-Panagiotis; Esfahani, Hrag; Horckmans, Michael; Vanorlé, Marion; Lemaire, Anne; Balligand, Jean-Luc; Beauloye, Christophe; Boeynaems, Jean-Marie; Communi, Didier

    2016-01-01

    The study of the mechanisms leading to cardiac hypertrophy is essential to better understand cardiac development and regeneration. Pathological conditions such as ischemia or pressure overload can induce a release of extracellular nucleotides within the heart. We recently investigated the potential role of nucleotide P2Y receptors in cardiac development. We showed that adult P2Y4-null mice displayed microcardia resulting from defective cardiac angiogenesis. Here we show that loss of another P2Y subtype called P2Y6, a UDP receptor, was associated with a macrocardia phenotype and amplified pathological cardiac hypertrophy. Cardiomyocyte proliferation and size were increased in vivo in hearts of P2Y6-null neonates, resulting in enhanced postnatal heart growth. We then observed that loss of P2Y6 receptor enhanced pathological cardiac hypertrophy induced after isoproterenol injection. We identified an inhibitory effect of UDP on in vitro isoproterenol-induced cardiomyocyte hyperplasia and hypertrophy. The present study identifies mouse P2Y6 receptor as a regulator of cardiac development and cardiomyocyte function. P2Y6 receptor could constitute a therapeutic target to regulate cardiac hypertrophy. PMID:27231349

  7. Western diet increases cardiac ceramide content in healthy and hypertrophied hearts.

    Science.gov (United States)

    Butler, T J; Ashford, D; Seymour, A-M

    2017-11-01

    Obesity and cardiac left ventricular hypertrophy (LVH) are recognised independent risk factors in the development of heart failure (HF). However, the combination of these factors may exacerbate the onset of cardiovascular disease by mechanisms as yet unclear. LVH leads to significant cellular remodelling, including alterations in metabolism which may result in an inappropriate accumulation of lipids and eventual lipotoxicity and apoptosis. The aim of the study was to determine the impact of dietary manipulation on cardiac metabolism in the obese and hypertrophied heart. LVH was induced via aortic constriction (AC) in an experimental model of cardiac hypertrophy and animals subjected to 9 weeks of dietary manipulation with either a standard, high fat, or a sucrose containing Western-style diet (SD, HFD and WD, respectively). This latter diet resulted in accelerated weight gain in both LVH/AC and control animals. LVH was greater in AC animals fed a WD, and both control and AC animals from this diet showed a significant reduction in cardiac fatty acid oxidation and increased triacylglycerol content. Ceramide content was significantly increased in the WD groups, with no additional effect of LVH. Comparison with a model of HF induced by exposure to Doxorubicin and WD showed exacerbated remodelling of cardiac ceramide species leading to increased C16 and C18 content. These findings highlight the inappropriate accumulation and re-distribution of cardiac ceramide species in a diet-induced model of obesity and LVH, potentially increasing susceptibility to cell death. The combination of increased fat and sugar leads to greater pathological remodelling and may explain why this diet pattern is consistently linked with poor cardiovascular outcomes. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University

  8. Pioglitazone Protected against Cardiac Hypertrophy via Inhibiting AKT/GSK3β and MAPK Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Wen-Ying Wei

    2016-01-01

    Full Text Available Peroxisome proliferator activated receptor γ (PPARγ has been closely involved in the process of cardiovascular diseases. This study was to investigate whether pioglitazone (PIO, a PPARγ agonist, could protect against pressure overload-induced cardiac hypertrophy. Mice were orally given PIO (2.5 mg/kg from 1 week after aortic banding and continuing for 7 weeks. The morphological examination and biochemical analysis were used to evaluate the effects of PIO. Neonatal rat ventricular cardiomyocytes were also used to verify the protection of PIO against hypertrophy in vitro. The results in our study demonstrated that PIO remarkably inhibited hypertrophic response induced by aortic banding in vivo. Besides, PIO also suppressed cardiac fibrosis in vivo. PIO treatment also inhibited the activation of protein kinase B (AKT/glycogen synthase kinase-3β (GSK3β and mitogen-activated protein kinase (MAPK in the heart. In addition, PIO alleviated angiotensin II-induced hypertrophic response in vitro. In conclusion, PIO could inhibit cardiac hypertrophy via attenuation of AKT/GSK3β and MAPK pathways.

  9. Effects of protein-calorie restriction on mechanical function of hypertrophied cardiac muscle

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    Antônio Carlos Cicogna

    1999-04-01

    Full Text Available OBJECTIVE: To assess the effect of food restriction (FR on hypertrophied cardiac muscle in spontaneously hypertensive rats (SHR. METHODS: Isolated papillary muscle preparations of the left ventricle (LV of 60-day-old SHR and of normotensive Wistar-Kyoto (WKY rats were studied. The rats were fed either an unrestricted diet or FR diet (50% of the intake of the control diet for 30 days. The mechanical function of the muscles was evaluated through monitoring isometric and isotonic contractions. RESULTS: FR caused: 1 reduction in the body weight and LV weight of SHR and WKY rats; 2 increase in the time to peak shortening and the time to peak developed tension (DT in the hypertrophied myocardium of the SHR; 3 diverging changes in the mechanical function of the normal cardiac muscles of WKY rats with reduction in maximum velocity of isotonic shortening and of the time for DT to decrease 50% of its maximum value, and increase of the resting tension and of the rate of tension decline. CONCLUSION: Short-term FR causes prolongation of the contraction time of hypertrophied muscles and paradoxal changes in mechanical performance of normal cardiac fibers, with worsening of the shortening indices and of the resting tension, and improvement of the isometric relaxation.

  10. High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood.

    Science.gov (United States)

    Collet, Marie; Assouline, Zahra; Bonnet, Damien; Rio, Marlène; Iserin, Franck; Sidi, Daniel; Goldenberg, Alice; Lardennois, Caroline; Metodiev, Metodi Dimitrov; Haberberger, Birgit; Haack, Tobias; Munnich, Arnold; Prokisch, Holger; Rötig, Agnès

    2016-08-01

    Acyl-CoA dehydrogenase family, member 9 (ACAD9) mutation is a frequent, usually fatal cause of early-onset cardiac hypertrophy and mitochondrial respiratory chain complex I deficiency in early childhood. We retrospectively studied a series of 20 unrelated children with cardiac hypertrophy and isolated complex I deficiency and identified compound heterozygosity for missense, splice site or frame shift ACAD9 variants in 8/20 patients (40%). Age at onset ranged from neonatal period to 9 years and 5/8 died in infancy. Heart transplantation was possible in 3/8. Two of them survived and one additional patient improved spontaneously. Importantly, the surviving patients later developed delayed-onset neurologic or muscular symptoms, namely cognitive impairment, seizures, muscle weakness and exercise intolerance. Other organ involvement included proximal tubulopathy, renal failure, secondary ovarian failure and optic atrophy. We conclude that ACAD9 mutation is the most frequent cause of cardiac hypertrophy and isolated complex I deficiency. Heart transplantation in children surviving neonatal period should be considered with caution, as delayed-onset muscle and brain involvement of various severity may occur, even if absent prior to transplantation.

  11. Cardiac hypertrophy in chick embryos induced by hypothermia

    International Nuclear Information System (INIS)

    Boehm, C.; Johnson, T.R.; Caston, J.D.; Przybylski, R.J.

    1987-01-01

    A decrease in incubation temperature from 38 to 32 0 C elicits a decrease in chicken embryo size and weight with concomitant heart enlargement if done after day 10 of incubation. When assayed at day 18 of incubation with the hypothermia started on day 11 or 14, evidence is presented that the heart enlargement is an hypertrophy with no detectable hyperplasia. Supporting data are presented for various physical parameters showing increases in heart wet and dry weight, volume, area, wall thickness, and cell size. There was little difference in DNA content and nuclear [ 3 H]thymidine labeling index between hearts of control and hypothermic embryos. Hearts of hypothermic embryos showed a slight increase in water content and considerable increases in RNA, protein, and glycogen content per unit DNA. The average size of polysomes isolated from hypothermic hearts was larger than that of polysomes isolated from controls. Microscopic studies showed no obvious increase in amount of capillary beds, connective tissue, and myocardial cells. Annulate lamellae were found only in myocardial cells of hypothermic embryos in sparse amounts and low frequency but always associated with large deposits of glycogen

  12. A novel urotensin II receptor antagonist, KR-36996, improved cardiac function and attenuated cardiac hypertrophy in experimental heart failure.

    Science.gov (United States)

    Oh, Kwang-Seok; Lee, Jeong Hyun; Yi, Kyu Yang; Lim, Chae Jo; Park, Byung Kil; Seo, Ho Won; Lee, Byung Ho

    2017-03-15

    Urotensin II and its receptor are thought to be involved in various cardiovascular diseases such as heart failure, pulmonary hypertension and atherosclerosis. Since the regulation of the urotensin II/urotensin II receptor offers a great potential for therapeutic strategies related to the treatment of cardiovascular diseases, the study of selective and potent antagonists for urotensin II receptor is more fascinating. This study was designed to determine the potential therapeutic effects of a newly developed novel urotensin II receptor antagonist, N-(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)benzo[b]thiophene-3-carboxamide (KR-36996), in experimental models of heart failure. KR-36996 displayed a high binding affinity (Ki=4.44±0.67nM) and selectivity for urotensin II receptor. In cell-based study, KR-36996 significantly inhibited urotensin II-induced stress fiber formation and cellular hypertrophy in H9c2 UT cells. In transverse aortic constriction-induced cardiac hypertrophy model in mice, the daily oral administration of KR-36996 (30mg/kg) for 14 days significantly decreased left ventricular weight by 40% (Pheart failure model in rats, repeated echocardiography and hemodynamic measurements demonstrated remarkable improvement of the cardiac performance by KR-36996 treatment (25 and 50mg/kg/day, p.o.) for 12 weeks. Moreover, KR-36996 decreased interstitial fibrosis and cardiomyocyte hypertrophy in the infarct border zone. These results suggest that potent and selective urotensin II receptor antagonist could efficiently attenuate both cardiac hypertrophy and dysfunction in experimental heart failure. KR-36996 may be useful as an effective urotensin II receptor antagonist for pharmaceutical or clinical applications. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Novel Sulfur Metabolites of Garlic Attenuate Cardiac Hypertrophy and Remodeling through Induction of Na+/K+-ATPase Expression.

    Science.gov (United States)

    Khatua, Tarak N; Borkar, Roshan M; Mohammed, Soheb A; Dinda, Amit K; Srinivas, R; Banerjee, Sanjay K

    2017-01-01

    Epidemiologic studies show an inverse correlation between garlic consumption and progression of cardiovascular disease. However, the molecular basis for the beneficial effect of garlic on the heart is not known. Therefore, the objective of the present study was to (1) investigate the effect of raw garlic on isoproterenol (Iso) induced cardiac hypertrophy (2) find the active metabolites of garlic responsible for the beneficial effect. Cardiac hypertrophy was induced in rats by subcutaneous single injection of Iso 5 mg kg -1 day -1 for 15 days and the effect of garlic (250 mg/kg/day orally) was evaluated. Garlic metabolites in in vivo were identified by LC/MS study. The effect of garlic and its metabolites were evaluated against hypertrophy in H9C2 cells. Garlic normalized cardiac oxidative stress after Iso administration. Cardiac pathology and mitochondrial enzyme activities were improved in hypertrophy heart after garlic administration. Decreased Na + /K + -ATPase protein level that observed in hypertrophy heart was increased after garlic administration. We identified three garlic metabolites in rat serum. To confirm the role of garlic metabolites on cardiac hypertrophy, Na + /K + -ATPase expression and intracellular calcium levels were measured after treating H9C2 cells with raw garlic and two of its active metabolites, allyl methyl sulfide and allyl methyl sulfoxide. Raw garlic and both metabolites increased Na + /K + -ATPase protein level and decreased intracellular calcium levels and cell size in Iso treated H9C2 cells. This antihypertrophic effect of garlic and its sulfur metabolites were lost in H9C2 cells in presence of Na + /K + -ATPase inhibitor. In conclusion, garlic and its active metabolites increased Na + /K + -ATPase in rat heart, and attenuated cardiac hypertrophy and associated remodeling. Our data suggest that identified new garlic metabolites may be useful for therapeutic intervention against cardiac hypertrophy.

  14. Inhibition of Cardiac Hypertrophy Effects in D-Galactose-Induced Senescent Hearts by Alpinate Oxyphyllae Fructus Treatment

    Directory of Open Access Journals (Sweden)

    Yung-Ming Chang

    2017-01-01

    Full Text Available Aging is a complex physiological phenomenon accelerated by ROS accumulation, with multisystem decline and increasing vulnerability to degenerative diseases and death. Cardiac hypertrophy is a key pathophysiological component that accompanies the aging process. Alpinate Oxyphyllae Fructus (Alpinia oxyphylla MIQ, AOF is a traditional Chinese medicine, which provides cardioprotective activity against aging, hypertension, and cerebrovascular disorders. In this study, we found the protective effect of AOF against cardiac hypertrophy in D-galactose-induced aging rat model. The results showed that treating rats with D-galactose resulted in pathological hypertrophy as evident from the morphology change, increased left ventricular weight/whole heart weight, and expression of hypertrophy-related markers (MYH7 and BNP. Both concentric and eccentric cardiac hypertrophy signaling proteins were upregulated in aging rat model. However, these pathological changes were significantly improved in AOF treated group (AM and AH in a dose-dependent manner. AOF negatively modulated D-galactose-induced cardiac hypertrophy signaling mechanism to attenuate ventricular hypertrophy. These enhanced cardioprotective activities following oral administration of AOF reflect the potential use of AOF for antiaging treatments.

  15. Role of Oxidative Stress in Thyroid Hormone-Induced Cardiomyocyte Hypertrophy and Associated Cardiac Dysfunction: An Undisclosed Story

    Directory of Open Access Journals (Sweden)

    Mohammad T. Elnakish

    2015-01-01

    Full Text Available Cardiac hypertrophy is the most documented cardiomyopathy following hyperthyroidism in experimental animals. Thyroid hormone-induced cardiac hypertrophy is described as a relative ventricular hypertrophy that encompasses the whole heart and is linked with contractile abnormalities in both right and left ventricles. The increase in oxidative stress that takes place in experimental hyperthyroidism proposes that reactive oxygen species are key players in the cardiomyopathy frequently reported in this endocrine disorder. The goal of this review is to shed light on the effects of thyroid hormones on the development of oxidative stress in the heart along with the subsequent cellular and molecular changes. In particular, we will review the role of thyroid hormone-induced oxidative stress in the development of cardiomyocyte hypertrophy and associated cardiac dysfunction, as well as the potential effectiveness of antioxidant treatments in attenuating these hyperthyroidism-induced abnormalities in experimental animal models.

  16. Vitamin D deficiency induces cardiac hypertrophy and inflammation in epicardial adipose tissue in hypercholesterolemic swine.

    Science.gov (United States)

    Gupta, Gaurav K; Agrawal, Tanupriya; DelCore, Michael G; Mohiuddin, Syed M; Agrawal, Devendra K

    2012-08-01

    Vitamin D is a sectosteroid that functions through Vitamin D receptor (VDR), a transcription factor, which controls the transcription of many targets genes. Vitamin D deficiency has been linked with cardiovascular diseases, including heart failure and coronary artery disease. Suppressor of cytokine signaling (SOCS)3 regulates different biological processes such as inflammation and cellular differentiation and is an endogenous negative regulator of cardiac hypertrophy. The purpose of this study was to test the hypothesis that vitamin D deficiency causes cardiomyocyte hypertrophy and increased proinflammatory profile in epicardial adipose tissue (EAT), and this correlates with decreased expression of SOCS3 in cardiomyocytes and EAT. Eight female Yucatan miniswine were fed vitamin D-sufficient (900 IU/d) or vitamin D-deficient hypercholesterolemic diet. Lipid profile, metabolic panel, and serum 25(OH)D levels were regularly measured. After 12 months animals were euthanized and histological, immunohistochemical and qPCR studies were performed on myocardium and epicardial fat. Histological studies showed cardiac hypertrophy, as judged by cardiac myocyte cross sectional area, in the vitamin D-deficient group. Immunohistochemical and qPCR analyses showed significantly decreased mRNA and protein expression of VDR and SOCS3 in cardiomyocytes of vitamin D-deficient animals. EAT from vitamin D-deficient group had significantly higher expression of TNF-α, IL-6, MCP-1, and decreased adiponectin in association with increased inflammatory cellular infiltrate. Interestingly, EAT from vitamin D-deficient group had significantly decreased expression of SOCS3. These data suggest that vitamin D deficiency induces hypertrophy in cardiomyocytes which is associated with decreased expression of VDR and SOCS3. Vitamin D deficiency is also associated with increased inflammatory markers in EAT. Activity of VDR in the body is controlled through regulation of vitamin D metabolites. Therefore

  17. Cardiac structural and hemodynamic changes associated with physiological heart hypertrophy of pregnancy are reversed postpartum.

    Science.gov (United States)

    Umar, Soban; Nadadur, Rangarajan; Iorga, Andrea; Amjedi, Marjan; Matori, Humann; Eghbali, Mansoureh

    2012-10-15

    Pregnancy is associated with ventricular hypertrophy and volume overload. Here we investigated whether late pregnancy is associated with cardiac structural and hemodynamic changes, and if these changes are reversed postpartum. Female mice (C57BL/6) were used in nonpregnant diestrus (NP), late-pregnant (LP), or 7-day postpartum (PP7) stages. Echocardiography and cardiac catheterization were performed to monitor cardiac hemodynamics. Transcript expression of proangiogenic vascular endothelial growth factor, cardiac fetal gene osteopontin, cardiac extracellular matrix-degrading enzymes matrix metalloproteinase-2, and a disintegrin and metalloproteinase-15 and -17 were assessed by RT-PCR. Masson trichrome staining for cardiac fibrosis and endothelial marker CD31 immunostaining for angiogenesis were performed. Heart hypertrophy in LP was fully reversed in PP7 (heart weight: NP = 114 ± 4 mg; LP = 147 ± 2 mg; PP7 = 117 ± 8 mg, P vs. PP7). LP had elevated left ventricular (LV) pressure (119 ± 5 mmHg in LP vs. 92 ± 7 mmHg in NP, P P vs. LP). LP had increased LV contractility (maximal rate of increase of LV pressure = 6,664 ± 297 mmHg/s in LP vs. 4,294 ± 568 mmHg/s in NP, P P vs. LP). LV ejection fraction was reduced in LP (LP = 58 ± 1% vs. NP = 70 ± 4%, P P vs. LP). Myocardial angiogenesis was significantly increased in LP (capillary density = 1.25 ± 0.02 vs. 0.95 ± 0.01 capillaries/myocyte in NP, P P vs. LP). Vascular endothelial growth factor was upregulated in LP (LP = 1.4 ± 0.1 vs. NP = 1 ± 0.1, normalized to NP, P P vs. LP). There was no increase in cardiac fibrosis in LP. Matrix metalloproteinase-2 transcript levels were downregulated in LP (LP = 0.47 ± 0.03 vs. NP = 1 ± 0.01, normalized to NP, P P vs. LP). In conclusion, pregnancy-induced heart hypertrophy is associated with transient cardiac dysfunction, increased cardiac angiogenesis, lack of fibrosis, and decreased expression of remodeling enzymes that are reversed postpartum.

  18. Empagliflozin lessened cardiac injury and reduced visceral adipocyte hypertrophy in prediabetic rats with metabolic syndrome.

    Science.gov (United States)

    Kusaka, Hiroaki; Koibuchi, Nobutaka; Hasegawa, Yu; Ogawa, Hisao; Kim-Mitsuyama, Shokei

    2016-11-11

    The potential benefit of SGLT2 inhibitors in metabolic syndrome is with prediabetic stage unclear. This work was undertaken to investigate the non-glycemic effect of empagliflozin on metabolic syndrome rats with prediabetes. SHR/NDmcr-cp(+/+) rats (SHRcp), a model of metabolic syndrome with prediabetes, were given empagliflozin for 10 weeks to examine the effects on urinary sodium and water balance, visceral and subcutaneous adipocyte, and cardiac injury. Further, the effect of empagliflozin on blood pressure and autonomic nervous system was continuously investigated by using radiotelemetry system. Empagliflozin significantly reduced urinary sodium and water balance of SHRcp only within 1 week of the treatment, but later than 1 week did not alter them throughout the treatment. Empagliflozin significantly reduced body weight of SHRcp, which was mainly attributed to the significant reduction of subcutaneous fat mass. Empagliflozin significantly reduced the size of visceral adipocytes and increased the number of smaller size of adipocytes, which was associated with the attenuation of oxidative stress. Empagliflozin ameliorated cardiac hypertrophy and fibrosis of SHRcp, in association with the attenuation of cardiac oxidative stress and inflammation. However, empagliflozin did not significantly change blood pressure, heart rate, sympathetic activity, or baroreceptor function, as evidenced by radiotelemetry analysis. Our present work provided the evidence that SGLT2 inhibition reduced visceral adipocytes hypertrophy and ameliorated cardiac injury in prediabetic metabolic syndrome rat, independently of diuretic effect or blood pressure lowering effect. Thus, SGLT2 inhibition seems to be a promising therapeutic strategy for prediabetic metabolic syndrome.

  19. Cardiac morphology in left ventricular hypertrophy using thallium-201 myocardial scintigraphy

    Energy Technology Data Exchange (ETDEWEB)

    Torii, Yukio; Adachi, Haruhiko; Katsume, Hiroshi; Ochiai, Masakazu; Ijichi, Hamao

    1985-06-01

    To evaluate cardiac morphology in the patients with various cases of hypertrophy, we measured left ventricular (LV) size using thallium-201 myocardial scintigraphy in 29 normal subjects and in 90 patients. Cardiac shape and dimension were assessed by measuring the wall thickness and external length in the short and long axis of LV image in LAO projection. In aortic stenosis and hypertensive heart disease the shape was spherical and the wall was thickened. In both mitral (MR) and aortic (AR) regurgitations, LV dilatation were shown; spherical shape in chronic MR but ellipsoid shape in acute MR and AR. Decreased LV size but normal shape was observed in mitral stenosis and cor pulmonale. In hypertrophic cardiomyopathy the LV wall was asymmetrically hypertrophied, while in congestive cardiomyopathy the wall is thin with marked LV dilatation and the shape was spherical. We concluded that the heart had characteristic configuration which might reflect cardiac performance or compensate for the load to the heart, and that thallium-201 myocardial scintigraphy is useful in the evaluation of cardiac morphology as well as in diagnosis of myocardial ischemia. (author).

  20. Mitoprotective antioxidant EUK-134 stimulates fatty acid oxidation and prevents hypertrophy in H9C2 cells.

    Science.gov (United States)

    Purushothaman, Sreeja; Nair, R Renuka

    2016-09-01

    Oxidative stress is an important contributory factor for the development of cardiovascular diseases like hypertension-induced hypertrophy. Mitochondrion is the major source of reactive oxygen species. Hence, protecting mitochondria from oxidative damage can be an effective therapeutic strategy for the prevention of hypertensive heart disease. Conventional antioxidants are not likely to be cardioprotective, as they cannot protect mitochondria from oxidative damage. EUK-134 is a salen-manganese complex with superoxide dismutase and catalase activity. The possible role of EUK-134, a mitoprotective antioxidant, in the prevention of hypertrophy of H9C2 cells was examined. The cells were stimulated with phenylephrine (50 μM), and hypertrophy was assessed based on cell volume and expression of brain natriuretic peptide and calcineurin. Enhanced myocardial lipid peroxidation and protein carbonyl content, accompanied by nuclear factor-kappa B gene expression, confirmed the presence of oxidative stress in hypertrophic cells. Metabolic shift was evident from reduction in the expression of medium-chain acyl-CoA dehydrogenase. Mitochondrial oxidative stress was confirmed by the reduced expression of mitochondria-specific antioxidant peroxiredoxin-3 and enhanced mitochondrial superoxide production. Compromised mitochondrial function was apparent from reduced mitochondrial membrane potential. Pretreatment with EUK-134 (10 μM) was effective in the prevention of hypertrophic changes in H9C2 cells, reduction of oxidative stress, and prevention of metabolic shift. EUK-134 treatment improved the oxidative status of mitochondria and reversed hypertrophy-induced reduction of mitochondrial membrane potential. Supplementation with EUK-134 is therefore identified as a novel approach to attenuate cardiac hypertrophy and lends scope for the development of EUK-134 as a therapeutic agent in the management of human cardiovascular disease.

  1. Phosphorylation of pRb by cyclin D kinase is necessary for development of cardiac hypertrophy

    DEFF Research Database (Denmark)

    Hinrichsen, R.; Hansen, A.H.; Busk, P.K.

    2008-01-01

    of hypertrophy, and it is important to elucidate the mechanisms of how these proteins are involved in the hypertrophic response in cardiomyocytes. MATERIALS AND METHODS, AND RESULTS: In the present study, by immunohistochemistry with a phosphorylation-specific antibody, we found that cyclin D-cdk4....../6-phosphorylated retinoblastoma protein (pRb) during hypertrophy and expression of an unphosphorylatable pRb mutant impaired hypertrophic growth in cardiomyocytes. Transcription factor E2F was activated by hypertrophic elicitors but activation was impaired by pharmacological inhibition of cyclin D-cdk4....../6. Inhibition of cyclin E-cdk2 complex only partly impaired E2F activity and did not prevent hypertrophic growth, but diminished endoreplication during hypertrophy. CONCLUSIONS: These results indicate that cyclin D-cdk4/6-dependent phosphorylation of pRb and activation of E2F is necessary for hypertrophic...

  2. Hypertrophy of neurons within cardiac ganglia in human, canine, and rat heart failure: the potential role of nerve growth factor.

    Science.gov (United States)

    Singh, Sanjay; Sayers, Scott; Walter, James S; Thomas, Donald; Dieter, Robert S; Nee, Lisa M; Wurster, Robert D

    2013-08-19

    Autonomic imbalances including parasympathetic withdrawal and sympathetic overactivity are cardinal features of heart failure regardless of etiology; however, mechanisms underlying these imbalances remain unknown. Animal model studies of heart and visceral organ hypertrophy predict that nerve growth factor levels should be elevated in heart failure; whether this is so in human heart failure, though, remains unclear. We tested the hypotheses that neurons in cardiac ganglia are hypertrophied in human, canine, and rat heart failure and that nerve growth factor, which we hypothesize is elevated in the failing heart, contributes to this neuronal hypertrophy. Somal morphology of neurons from human (579.54±14.34 versus 327.45±9.17 μm(2); Phearts (767.80±18.37 versus 650.23±9.84 μm(2); Phearts (327.98±3.15 versus 271.29±2.79 μm(2); Phuman heart are 250% greater than levels in healthy donor hearts. Neurons from cardiac ganglia cultured with nerve growth factor are significantly larger and have greater dendritic arborization than neurons in control cultures. Hypertrophied neurons are significantly less excitable than smaller ones; thus, hypertrophy of vagal postganglionic neurons in cardiac ganglia would help to explain the parasympathetic withdrawal that accompanies heart failure. Furthermore, our observations suggest that nerve growth factor, which is elevated in the failing human heart, causes hypertrophy of neurons in cardiac ganglia.

  3. Comparative Analysis of mRNA Isoform Expression in Cardiac Hypertrophy and Development Reveals Multiple Post-Transcriptional Regulatory Modules

    Science.gov (United States)

    Park, Ji Yeon; Li, Wencheng; Zheng, Dinghai; Zhai, Peiyong; Zhao, Yun; Matsuda, Takahisa; Vatner, Stephen F.; Sadoshima, Junichi; Tian, Bin

    2011-01-01

    Cardiac hypertrophy is enlargement of the heart in response to physiological or pathological stimuli, chiefly involving growth of myocytes in size rather than in number. Previous studies have shown that the expression pattern of a group of genes in hypertrophied heart induced by pressure overload resembles that at the embryonic stage of heart development, a phenomenon known as activation of the “fetal gene program”. Here, using a genome-wide approach we systematically defined genes and pathways regulated in short- and long-term cardiac hypertrophy conditions using mice with transverse aortic constriction (TAC), and compared them with those regulated at different stages of embryonic and postnatal development. In addition, exon-level analysis revealed widespread mRNA isoform changes during cardiac hypertrophy resulting from alternative usage of terminal or internal exons, some of which are also developmentally regulated and may be attributable to decreased expression of Fox-1 protein in cardiac hypertrophy. Genes with functions in certain pathways, such as cell adhesion and cell morphology, are more likely to be regulated by alternative splicing. Moreover, we found 3′UTRs of mRNAs were generally shortened through alternative cleavage and polyadenylation in hypertrophy, and microRNA target genes were generally de-repressed, suggesting coordinated mechanisms to increase mRNA stability and protein production during hypertrophy. Taken together, our results comprehensively delineated gene and mRNA isoform regulation events in cardiac hypertrophy and revealed their relations to those in development, and suggested that modulation of mRNA isoform expression plays an importance role in heart remodeling under pressure overload. PMID:21799842

  4. Quercetin prevents left ventricular hypertrophy in the Apo E knockout mouse

    Directory of Open Access Journals (Sweden)

    Elena Ulasova

    2013-01-01

    Full Text Available Hypercholesterolemia is a risk factor for the development of hypertrophic cardiomyopathy. Nevertheless, there are few studies aimed at determining the effects of dietary compounds on early or mild cardiac hypertrophy associated with dyslipidemia. Here we describe left ventricular (LV hypertrophy in 12 week-old Apo E−/− hypercholesterolemic mice. The LV end diastolic posterior wall thickness and overall LV mass were significantly increased in Apo E−/− mice compared with wild type (WT controls. Fractional shortening, LV end diastolic diameter, and hemodynamic parameters were unchanged from WT mice. Oral low dose quercetin (QCN; 0.1 µmol QCN/kg body weight for 6 weeks significantly reduced total cholesterol and very low density lipoprotein in the plasma of Apo E−/− mice. QCN treatment also significantly decreased LV posterior wall thickness and LV mass in Apo E−/− mice. Myocardial geometry and function were unaffected in WT mice by QCN treatment. These data suggest that dietary polyphenolic compounds such as QCN may be effective modulators of plasma cholesterol and could prevent maladaptive myocardial remodeling.

  5. Mitochondria-Targeted Antioxidant Prevents Cardiac Dysfunction Induced by Tafazzin Gene Knockdown in Cardiac Myocytes

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    Quan He

    2014-01-01

    Full Text Available Tafazzin, a mitochondrial acyltransferase, plays an important role in cardiolipin side chain remodeling. Previous studies have shown that dysfunction of tafazzin reduces cardiolipin content, impairs mitochondrial function, and causes dilated cardiomyopathy in Barth syndrome. Reactive oxygen species (ROS have been implicated in the development of cardiomyopathy and are also the obligated byproducts of mitochondria. We hypothesized that tafazzin knockdown increases ROS production from mitochondria, and a mitochondria-targeted antioxidant prevents tafazzin knockdown induced mitochondrial and cardiac dysfunction. We employed cardiac myocytes transduced with an adenovirus containing tafazzin shRNA as a model to investigate the effects of the mitochondrial antioxidant, mito-Tempo. Knocking down tafazzin decreased steady state levels of cardiolipin and increased mitochondrial ROS. Treatment of cardiac myocytes with mito-Tempo normalized tafazzin knockdown enhanced mitochondrial ROS production and cellular ATP decline. Mito-Tempo also significantly abrogated tafazzin knockdown induced cardiac hypertrophy, contractile dysfunction, and cell death. We conclude that mitochondria-targeted antioxidant prevents cardiac dysfunction induced by tafazzin gene knockdown in cardiac myocytes and suggest mito-Tempo as a potential therapeutic for Barth syndrome and other dilated cardiomyopathies resulting from mitochondrial oxidative stress.

  6. Fetal-adult cardiac transcriptome analysis in rats with contrasting left ventricular mass reveals new candidates for cardiac hypertrophy.

    Directory of Open Access Journals (Sweden)

    Katja Grabowski

    Full Text Available Reactivation of fetal gene expression patterns has been implicated in common cardiac diseases in adult life including left ventricular (LV hypertrophy (LVH in arterial hypertension. Thus, increased wall stress and neurohumoral activation are discussed to induce the return to expression of fetal genes after birth in LVH. We therefore aimed to identify novel potential candidates for LVH by analyzing fetal-adult cardiac gene expression in a genetic rat model of hypertension, i.e. the stroke-prone spontaneously hypertensive rat (SHRSP. To this end we performed genome-wide transcriptome analysis in SHRSP to identify differences in expression patterns between day 20 of fetal development (E20 and adult animals in week 14 in comparison to a normotensive rat strain with contrasting low LV mass, i.e. Fischer (F344. 15232 probes were detected as expressed in LV tissue obtained from rats at E20 and week 14 (p < 0.05 and subsequently screened for differential expression. We identified 24 genes with SHRSP specific up-regulation and 21 genes with down-regulation as compared to F344. Further bioinformatic analysis presented Efcab6 as a new candidate for LVH that showed only in the hypertensive SHRSP rat differential expression during development (logFC = 2.41, p < 0.001 and was significantly higher expressed in adult SHRSP rats compared with adult F344 (+ 76% and adult normotensive Wistar-Kyoto rats (+ 82%. Thus, it represents an interesting new target for further functional analyses and the elucidation of mechanisms leading to LVH. Here we report a new approach to identify candidate genes for cardiac hypertrophy by combining the analysis of gene expression differences between strains with a contrasting cardiac phenotype with a comparison of fetal-adult cardiac expression patterns.

  7. Fetal-Adult Cardiac Transcriptome Analysis in Rats with Contrasting Left Ventricular Mass Reveals New Candidates for Cardiac Hypertrophy

    Science.gov (United States)

    Grabowski, Katja; Riemenschneider, Mona; Schulte, Leonard; Witten, Anika; Schulz, Angela; Stoll, Monika; Kreutz, Reinhold

    2015-01-01

    Reactivation of fetal gene expression patterns has been implicated in common cardiac diseases in adult life including left ventricular (LV) hypertrophy (LVH) in arterial hypertension. Thus, increased wall stress and neurohumoral activation are discussed to induce the return to expression of fetal genes after birth in LVH. We therefore aimed to identify novel potential candidates for LVH by analyzing fetal-adult cardiac gene expression in a genetic rat model of hypertension, i.e. the stroke-prone spontaneously hypertensive rat (SHRSP). To this end we performed genome-wide transcriptome analysis in SHRSP to identify differences in expression patterns between day 20 of fetal development (E20) and adult animals in week 14 in comparison to a normotensive rat strain with contrasting low LV mass, i.e. Fischer (F344). 15232 probes were detected as expressed in LV tissue obtained from rats at E20 and week 14 (p < 0.05) and subsequently screened for differential expression. We identified 24 genes with SHRSP specific up-regulation and 21 genes with down-regulation as compared to F344. Further bioinformatic analysis presented Efcab6 as a new candidate for LVH that showed only in the hypertensive SHRSP rat differential expression during development (logFC = 2.41, p < 0.001) and was significantly higher expressed in adult SHRSP rats compared with adult F344 (+ 76%) and adult normotensive Wistar-Kyoto rats (+ 82%). Thus, it represents an interesting new target for further functional analyses and the elucidation of mechanisms leading to LVH. Here we report a new approach to identify candidate genes for cardiac hypertrophy by combining the analysis of gene expression differences between strains with a contrasting cardiac phenotype with a comparison of fetal-adult cardiac expression patterns. PMID:25646840

  8. Secoisolariciresinol diglucoside attenuates cardiac hypertrophy and oxidative stress in monocrotaline-induced right heart dysfunction.

    Science.gov (United States)

    Puukila, Stephanie; Fernandes, Rafael Oliveira; Türck, Patrick; Carraro, Cristina Campos; Bonetto, Jéssica Hellen Poletto; de Lima-Seolin, Bruna Gazzi; da Rosa Araujo, Alex Sander; Belló-Klein, Adriane; Boreham, Douglas; Khaper, Neelam

    2017-08-01

    Pulmonary arterial hypertension (PAH) occurs when remodeling of pulmonary vessels leads to increased pulmonary vascular resistance resulting in increased pulmonary arterial pressure. Increased pulmonary arterial pressure results in right ventricle hypertrophy and eventually heart failure. Oxidative stress has been implicated in the pathogenesis of PAH and may play a role in the regulation of cellular signaling involved in cardiac response to pressure overload. Secoisolariciresinol diglucoside (SDG), a component from flaxseed, has been shown to reduce cardiac oxidative stress in various pathophysiological conditions. We investigated the potential protective effects of SDG in a monocrotaline-induced model of PAH. Five- to six-week-old male Wistar rats were given a single intraperitoneal injection of monocrotaline (60 mg/kg) and sacrificed 21 days later where heart, lung, and plasma were collected. SDG (25 mg/kg) was given via gavage as either a 21-day co-treatment or pre-treatment of 14 days before monocrotaline administration and continued for 21 days. Monocrotaline led to right ventricle hypertrophy, increased lipid peroxidation, and elevated plasma levels of alanine transaminase (ALT) and aspartate transaminase (AST). Co-treatment with SDG did not attenuate hypertrophy or ALT and AST levels but decreased reactive oxygen species (ROS) levels and catalase and superoxide dismutase activity compared to the monocrotaline-treated group. Pre-treatment with SDG decreased right ventricle hypertrophy, ROS levels, lipid peroxidation, catalase, superoxide dismutase, and glutathione peroxidase activity and plasma levels of ALT and AST when compared to the monocrotaline group. These findings indicate that pre-treatment with SDG provided better protection than co-treatment in this model of right heart dysfunction, suggesting an important role for SDG in PAH and right ventricular remodeling.

  9. Hypertension is a conditional factor for the development of cardiac hypertrophy in type 2 diabetic mice.

    Directory of Open Access Journals (Sweden)

    Marc van Bilsen

    Full Text Available BACKGROUND: Type 2 diabetes is frequently associated with co-morbidities, including hypertension. Here we investigated if hypertension is a critical factor in myocardial remodeling and the development of cardiac dysfunction in type 2 diabetic db/db mice. METHODS: Thereto, 14-wks-old male db/db mice and non-diabetic db/+ mice received vehicle or angiotensin II (AngII for 4 wks to induce mild hypertension (n = 9-10 per group. Left ventricular (LV function was assessed by serial echocardiography and during a dobutamine stress test. LV tissue was subjected to molecular and (immunohistochemical analysis to assess effects on hypertrophy, fibrosis and inflammation. RESULTS: Vehicle-treated diabetic mice neither displayed marked myocardial structural remodeling nor cardiac dysfunction. AngII-treatment did not affect body weight and fasting glucose levels, and induced a comparable increase in blood pressure in diabetic and control mice. Nonetheless, AngII-induced LV hypertrophy was significantly more pronounced in diabetic than in control mice as assessed by LV mass (increase +51% and +34%, respectively, p<0.01 and cardiomyocyte size (+53% and +31%, p<0.001. This was associated with enhanced LV mRNA expression of markers of hypertrophy and fibrosis and reduced activation of AMP-activated protein kinase (AMPK, while accumulation of Advanced Glycation End products (AGEs and the expression levels of markers of inflammation were not altered. Moreover, AngII-treatment reduced LV fractional shortening and contractility in diabetic mice, but not in control mice. CONCLUSIONS: Collectively, the present findings indicate that type 2 diabetes in its early stage is not yet associated with adverse cardiac structural changes, but already renders the heart more susceptible to hypertension-induced hypertrophic remodeling.

  10. Modulation of impact of obesity in pathological and physiological cardiac hypertrophy by orlistat

    OpenAIRE

    Singh, Manjeet; Singh, Randhir; Krishan, Pawan

    2010-01-01

    High fat diet (30 % fat) was used to induce obesity in rats. Male wistar rats were kept at high fat diet for 90 days and subjected to partial abdominal aortic constriction (PAAC) at 62nd day and continued upto 90th day. Similarly rats were kept at high fat diet for 90 days and subjected to chronic swimming training (CST) at 46th day and continued upto 90th day. Obesity was assessed by measuring body weight, WHR ratio, obesity index and adiposity index. Cardiac hypertrophy was asse...

  11. Myocyte-Derived Hsp90 Modulates Collagen Upregulation via Biphasic Activation of STAT-3 in Fibroblasts during Cardiac Hypertrophy

    Science.gov (United States)

    Datta, Ritwik; Bansal, Trisha; Rana, Santanu; Datta, Kaberi; Datta Chaudhuri, Ratul; Chawla-Sarkar, Mamta

    2016-01-01

    ABSTRACT Signal transducer and activator of transcription 3 (STAT-3)-mediated signaling in relation to upregulated collagen expression in fibroblasts during cardiac hypertrophy is well defined. Our recent findings have identified heat shock protein 90 (Hsp90) to be a critical modulator of fibrotic signaling in cardiac fibroblasts in this disease milieu. The present study was therefore intended to analyze the role of Hsp90 in the STAT-3-mediated collagen upregulation process. Our data revealed a significant difference between in vivo and in vitro results, pointing to a possible involvement of myocyte-fibroblast cross talk in this process. Cardiomyocyte-targeted knockdown of Hsp90 in rats (Rattus norvegicus) in which the renal artery was ligated showed downregulated collagen synthesis. Furthermore, the results obtained with cardiac fibroblasts conditioned with Hsp90-inhibited hypertrophied myocyte supernatant pointed toward cardiomyocytes' role in the regulation of collagen expression in fibroblasts during hypertrophy. Our study also revealed a novel signaling mechanism where myocyte-derived Hsp90 orchestrates not only p65-mediated interleukin-6 (IL-6) synthesis but also its release in exosomal vesicles. Such myocyte-derived exosomes and myocyte-secreted IL-6 are responsible in unison for the biphasic activation of STAT-3 signaling in cardiac fibroblasts that culminates in excess collagen synthesis, leading to severely compromised cardiac function during cardiac hypertrophy. PMID:28031326

  12. Renin angiotensin system and cardiac hypertrophy after sinoaortic denervation in rats

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    Aline Cristina Piratello

    2010-01-01

    Full Text Available OBJECTIVE: The aim of this study was to evaluate the role of angiotensin I, II and 1-7 on left ventricular hypertrophy of Wistar and spontaneously hypertensive rats submitted to sinoaortic denervation. METHODS: Ten weeks after sinoaortic denervation, hemodynamic and morphofunctional parameters were analyzed, and the left ventricle was dissected for biochemical analyses. RESULTS: Hypertensive groups (controls and denervated showed an increase on mean blood pressure compared with normotensive ones (controls and denervated. Blood pressure variability was higher in denervated groups than in their respective controls. Left ventricular mass and collagen content were increased in the normotensive denervated and in both spontaneously hypertensive groups compared with Wistar controls. Both hypertensive groups presented a higher concentration of angiotensin II than Wistar controls, whereas angiotensin 1-7 concentration was decreased in the hypertensive denervated group in relation to the Wistar groups. There was no difference in angiotensin I concentration among groups. CONCLUSION: Our results suggest that not only blood pressure variability and reduced baroreflex sensitivity but also elevated levels of angiotensin II and a reduced concentration of angiotensin 1-7 may contribute to the development of left ventricular hypertrophy. These data indicate that baroreflex dysfunction associated with changes in the renin angiotensin system may be predictive factors of left ventricular hypertrophy and cardiac failure.

  13. Angiotensin II Stimulation of Cardiac Hypertrophy and Functional Decompensation in Osteoprotegerin-Deficient Mice.

    Science.gov (United States)

    Tsuruda, Toshihiro; Sekita-Hatakeyama, Yoko; Hao, Yilin; Sakamoto, Sumiharu; Kurogi, Syuji; Nakamura, Midori; Udagawa, Nobuyuki; Funamoto, Taro; Sekimoto, Tomohisa; Hatakeyama, Kinta; Chosa, Etsuo; Kato, Johji; Asada, Yujiro; Kitamura, Kazuo

    2016-05-01

    Circulating and myocardial expressions of receptor activator of nuclear factor-κb ligand and osteoprotegerin are activated in heart failure; however, it remains to be determined their pathophysiological roles on left ventricular structure and function in interaction with renin-angiotensin system. We conducted experiments using 8-week-old osteoprotegerin(-/-) mice and receptor activator of nuclear factor-κb ligand-transgenic mice to assess whether they affect the angiotensin II-induced left ventricular remodeling. Subcutaneous infusion of angiotensin II to osteoprotegerin(-/-) mice progressed the eccentric hypertrophy, resulting in left ventricular systolic dysfunction for 28 days, and this was comparable with wild-type mice, showing concentric hypertrophy, irrespective of equivalent elevation of systolic blood pressure. The structural alteration was associated with reduced interstitial fibrosis, decreased procollagen α1 and syndecan-1 expressions, and the increased number of apoptotic cells in the left ventricle, compared with wild-type mice. In contrast, angiotensin II infusion to the receptor activator of nuclear factor-κb ligand-transgenic mice revealed the concentric hypertrophy with preserved systolic contractile function. Intraperitoneal administration of human recombinant osteoprotegerin, but not subcutaneous injection of anti-receptor activator of nuclear factor-κb ligand antibody, to the angiotensin II-infused osteoprotegerin(-/-) mice for 28 days ameliorated the progression of heart failure without affecting systolic blood pressure. These results underscore the biological activity of osteoprotegerin in preserving myocardial structure and function during the angiotensin II-induced cardiac hypertrophy, independent of receptor activator of nuclear factor-κb ligand activity. In addition, the antiapoptotic and profibrotic actions of osteoprotegerin that emerged from our data might be involved in the mechanisms. © 2016 American Heart Association, Inc.

  14. Duration-controlled swimming exercise training induces cardiac hypertrophy in mice.

    Science.gov (United States)

    Evangelista, F S; Brum, P C; Krieger, J E

    2003-12-01

    Exercise training associated with robust conditioning can be useful for the study of molecular mechanisms underlying exercise-induced cardiac hypertrophy. A swimming apparatus is described to control training regimens in terms of duration, load, and frequency of exercise. Mice were submitted to 60- vs 90-min session/day, once vs twice a day, with 2 or 4% of the weight of the mouse or no workload attached to the tail, for 4 vs 6 weeks of exercise training. Blood pressure was unchanged in all groups while resting heart rate decreased in the trained groups (8-18%). Skeletal muscle citrate synthase activity, measured spectrophotometrically, increased (45-58%) only as a result of duration and frequency-controlled exercise training, indicating that endurance conditioning was obtained. In groups which received duration and endurance conditioning, cardiac weight (14-25%) and myocyte dimension (13-20%) increased. The best conditioning protocol to promote physiological hypertrophy, our primary goal in the present study, was 90 min, twice a day, 5 days a week for 4 weeks with no overload attached to the body. Thus, duration- and frequency-controlled exercise training in mice induces a significant conditioning response qualitatively similar to that observed in humans.

  15. Duration-controlled swimming exercise training induces cardiac hypertrophy in mice

    Directory of Open Access Journals (Sweden)

    F.S. Evangelista

    2003-12-01

    Full Text Available Exercise training associated with robust conditioning can be useful for the study of molecular mechanisms underlying exercise-induced cardiac hypertrophy. A swimming apparatus is described to control training regimens in terms of duration, load, and frequency of exercise. Mice were submitted to 60- vs 90-min session/day, once vs twice a day, with 2 or 4% of the weight of the mouse or no workload attached to the tail, for 4 vs 6 weeks of exercise training. Blood pressure was unchanged in all groups while resting heart rate decreased in the trained groups (8-18%. Skeletal muscle citrate synthase activity, measured spectrophotometrically, increased (45-58% only as a result of duration and frequency-controlled exercise training, indicating that endurance conditioning was obtained. In groups which received duration and endurance conditioning, cardiac weight (14-25% and myocyte dimension (13-20% increased. The best conditioning protocol to promote physiological hypertrophy, our primary goal in the present study, was 90 min, twice a day, 5 days a week for 4 weeks with no overload attached to the body. Thus, duration- and frequency-controlled exercise training in mice induces a significant conditioning response qualitatively similar to that observed in humans.

  16. Serum uric acid is associated with left ventricular hypertrophy independent of serum parathyroid hormone in male cardiac patients.

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    Shu-ichi Fujita

    Full Text Available BACKGROUND: Several studies have shown that serum uric acid (UA is associated with left ventricular (LV hypertrophy. Serum levels of parathyroid hormone (PTH, which has bbe shown to be correlated with UA, is also known to be associated with cardiac hypertrophy; however, whether the association between UA and cardiac hypertrophy is independent of PTH remains unknown. PURPOSE: We investigated whether the relationship between serum uric acid (UA and LV hypertrophy is independent of intact PTH and other calcium-phosphate metabolism-related factors in cardiac patients. METHODS AND RESULTS: In a retrospective study, the association between UA and left ventricular mass index was assessed among 116 male cardiac patients (mean age 65 ± 12 years who were not taking UA lowering drugs. The median UA value was 5.9 mg/dL. Neither age nor body mass index differed significantly among the UA quartile groups. Patients with higher UA levels were more likely to be taking loop diuretics. UA showed a significant correlation with intact PTH (R = 0.34, P<0.001 but not with other calcium-phosphate metabolism-related factors. Linear regression analysis showed that log-transformed UA showed a significant association with left ventricular mass index, and this relationship was found to be significant exclusively in patients who were not taking loop and/or thiazide diuretics. Multivariate logistic regression analysis showed that log-transformed UA was independently associated with LV hypertrophy with an odds ratio of 2.79 (95% confidence interval 1.48-5.28, P = 0.002 per one standard deviation increase. CONCLUSIONS: Among cardiac patients, serum UA was associated with LV hypertrophy, and this relationship was, at least in part, independent of intact PTH levels, which showed a significant correlation with UA in the same population.

  17. Effects of pressure- or volume-overload hypertrophy on passive stiffness in isolated adult cardiac muscle cells

    Science.gov (United States)

    Kato, S.; Koide, M.; Cooper, G. 4th; Zile, M. R.

    1996-01-01

    It has been hypothesized that the changes in myocardial stiffness induced by chronic hemodynamic overloading are dependent on changes in the passive stiffness of the cardiac muscle cell (cardiocyte). However, no previous studies have examined the passive constitutive properties of cardiocytes isolated from animals with myocardial hypertrophy. Accordingly, changes in relative passive stiffness of cardiocytes isolated from animals with chronic pressure- or volume-overload hypertrophy were determined by examining the effects of anisosmotic stress on cardiocyte size. Anisosmotic stress was produced by altering superfusate osmolarity. Hypertrophied cardiocytes were enzymatically isolated from 16 adult cats with right ventricular (RV) pressure-overload hypertrophy induced by pulmonary artery banding (PAB) and from 6 adult cats with RV volume-overload hypertrophy induced by creating an atrial septal defect (ASD). Left ventricular (LV) cardiocytes from each cat served as nonhypertrophied, normally loaded, same-animal controls. Superfusate osmolarity was decreased from 305 +/- 3 to 135 +/- 5 mosM and increased to 645 +/- 4 mosM. During anisosmotic stress, there were no significant differences between hypertrophied RV and normal LV cardiocytes in pressure overload PAB cats with respect to percent change in cardiocyte area (47 +/- 2% in RV vs. 48 +/- 2% in LV), diameter (46 +/- 3% in RV vs. 48 +/- 2% in LV), or length (2.4 +/- 0.2% in RV vs. 2.0 +/- 0.3% in LV), or sarcomere length (1.5 +/- 0.1% in RV vs. 1.3 +/- 0.3% in LV). Likewise, there were no significant differences in cardiocyte strain between hypertrophied RV and normal LV cardiocytes from ASD cats. In conclusion, chronic pressure-overload hypertrophy and chronic volume-overload hypertrophy did not alter the cardiocyte response to anisosmotic stress. Thus chronic overload hypertrophy did not alter relative passive cardiocyte stiffness.

  18. Electrophysiological characteristics of pressure overload-induced cardiac hypertrophy and its influence on ventricular arrhythmias.

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    Xiaowei Chen

    Full Text Available To explore the cardiac electrophysiological characteristics of cardiac hypertrophy and its influence on the occurrence of ventricular tachyarrhythmias.Adult C57BL6 mice were randomly divided into a surgery group and a control group. Thoracic aortic constriction was performed on mice in the surgery group, and cardiac anatomical and ultrasonic evaluations were performed to confirm the success of the cardiac hypertrophy model 4 weeks after the operation. Using the Langendorff method of isolated heart perfusion, monophasic action potentials (MAPs and the effective refractory period (ERP at different parts of the heart (including the epi- and endo-myocardium of the left and right ventricles were measured, and the induction rate of ventricular tachyarrhythmias was observed under programmed electrical stimulus (PES and burst stimulus. Whole-cell patch-clamp was used to obtain the I-V characteristics of voltage-gated potassium channels in cardiomyocytes of different parts of the heart (including the epi- and endo-myocardium of the left and right ventricles as well as the channels' properties of steady-state inactivation and recovery from inactivation.The ratio of heart weight to body weight and the ratio of left ventricular weight to body weight in the surgery group were significantly higher than those in the control group (P < 0.05. Ultrasonic evaluation revealed that both interventricular septal diameter (IVSD and left ventricle posterior wall diameter (LVPWD in the surgery group were significantly larger than those in the control group (P < 0.05. Under PES and burst stimuli, the induction rates of arrhythmias in the surgery group significantly increased, reaching 41.2% and 23.5%, respectively. Both the QT interval and action potential duration (APD in the surgery group were significantly longer than in the control group (P<0.01, and the changes showed obvious spatial heterogeneity. Whole-cell patch-clamp recordings demonstrated that the surgery group

  19. Relationship between plasma xanthine oxidoreductase activity and left ventricular ejection fraction and hypertrophy among cardiac patients.

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    Yuki Fujimura

    Full Text Available Xanthine oxidoreductase (XOR, which catalyzes purine catabolism, has two interconvertible forms, xanthine dehydrogenase and xanthine oxidase, the latter of which produces superoxide during uric acid (UA synthesis. An association between plasma XOR activity and cardiovascular and renal outcomes has been previously suggested. We investigated the potential association between cardiac parameters and plasma XOR activity among cardiology patients.Plasma XOR activity was measured by [13C2,15N2]xanthine coupled with liquid chromatography/triplequadrupole mass spectrometry. Among 270 patients who were not taking UA-lowering drugs, XOR activity was associated with body mass index (BMI, alanine aminotransferase (ALT, HbA1c and renal function. Although XOR activity was not associated with serum UA overall, patients with chronic kidney disease (CKD, those with higher XOR activity had higher serum UA among patients without CKD. Compared with patients with the lowest XOR activity quartile, those with higher three XOR activity quartiles more frequently had left ventricular hypertrophy. In addition, plasma XOR activity showed a U-shaped association with low left ventricular ejection fraction (LVEF and increased plasma B-type natriuretic peptide (BNP levels, and these associations were independent of age, gender, BMI, ALT, HbA1C, serum UA, and CKD stages.Among cardiac patients, left ventricular hypertrophy, low LVEF, and increased BNP were significantly associated with plasma XOR activity independent of various confounding factors. Whether pharmaceutical modification of plasma XOR activity might inhibit cardiac remodeling and improve cardiovascular outcome should be investigated in future studies.

  20. Polarization-resolved SHG microscopy in cardiac hypertrophy study (Conference Presentation)

    Science.gov (United States)

    Wang, Zhonghai; Yuan, Cai; Shao, Yonghong; Bradshaw, Amy D.; Borg, Thomas K.; Gao, Bruce Z.

    2017-02-01

    Cardiac hypertrophy, a process initiated by mechanical alterations, is hypothesized to cause long-term molecular-level alteration in the sarcomere lattice, which is the main force-generating component in the heart muscle. This molecular-level alteration is beyond the resolving capacity of common light microscopy. Second harmonic generation (SHG) microscopy has unique capability for visualizing ordered molecular structures in biological tissues without labeling. Combined with polarization imaging technique, SHG microscopy is able to extract structural details of myosin at the molecular level so as to reveal molecular-level alterations that occur during hypertrophy. The myosin filaments are believed to possess C6 symmetry; thus, the nonlinear polarization response relationship between generated second harmonic light I^2ωand incident fundamental light I^ω is determined by nonlinear coefficients, χ_15, χ_31 and χ_33. χ_31/χ_15 is believed to be an indicator of the molecular symmetry of myosin filament, whileχ_33/χ_15represents the intramyosin orientation angle of the double helix. By changing the polarization of the incident light and evaluating the corresponding SHG signals, the molecular structure of the myosin, reflected by the χ coefficients, can be revealed. With this method, we studied the structural properties of heart tissues in different conditions, including those in normal, physiologically hypertrophic (heart tissue from postpartum female rats), and pathologically hypertrophic (heart tissue from transverse-aorta constricted rats) conditions. We found that ratios of χ_31/χ_15 showed no significant difference between heart tissues from different conditions; their values were all close to 1, which demonstrated that Kleinman symmetry held for all conditions. Ratios of χ_33/χ_15 from physiologically or pathologically hypertrophic heart tissues were raised and showed significant difference from those from normal heart tissues, which indicated that

  1. Severe Left Ventricular Hypertrophy, Small Pericardial Effusion, and Diffuse Late Gadolinium Enhancement by Cardiac Magnetic Resonance Suspecting Cardiac Amyloidosis: Endomyocardial Biopsy Reveals an Unexpected Diagnosis

    Directory of Open Access Journals (Sweden)

    Nina P. Hofmann

    2016-01-01

    Full Text Available Left ventricular (LV hypertrophy can be related to a multitude of cardiac disorders, such as hypertrophic cardiomyopathy (HCM, cardiac amyloidosis, and hypertensive heart disease. Although the presence of LV hypertrophy is generally associated with poorer cardiac outcomes, the early differentiation between these pathologies is crucial due to the presence of specific treatment options. The diagnostic process with LV hypertrophy requires the integration of clinical evaluation, electrocardiography (ECG, echocardiography, biochemical markers, and if required CMR and endomyocardial biopsy in order to reach the correct diagnosis. Here, we present a case of a patient with severe LV hypertrophy (septal wall thickness of 23 mm, LV mass of 264 g, and LV mass index of 147 g/m2, severely impaired longitudinal function, and preserved radial contractility (ejection fraction = 55%, accompanied by small pericardial effusion and diffuse late gadolinium enhancement (LGE by cardiac magnetic resonance (CMR. Due to the imaging findings, an infiltrative cardiomyopathy, such as cardiac amyloidosis, was suspected. However, amyloid accumulation was excluded by endomyocardial biopsy, which revealed the presence of diffuse myocardial fibrosis in an advanced hypertensive heart disease.

  2. C-Myc Induced Compensated Cardiac Hypertrophy Increases Free Fatty Acid Utilization for the Citric Acid Cycle

    Energy Technology Data Exchange (ETDEWEB)

    Olson, Aaron; Ledee, Dolena; Iwamoto, Kate; Kajimoto, Masaki; O' Kelly-Priddy, Colleen M.; Isern, Nancy G.; Portman, Michael A.

    2013-02-01

    The protooncogene C-Myc (Myc) regulates cardiac hypertrophy. Myc promotes compensated cardiac function, suggesting that the operative mechanisms differ from those leading to heart failure. Myc regulation of substrate metabolism is a reasonable target, as Myc alters metabolism in other tissues. We hypothesize that Myc-induced shifts in substrate utilization signal and promote compensated hypertrophy. We used cardiac specific Myc-inducible C57/BL6 male mice between 4-6 months old that develop hypertrophy with tamoxifen (tam). Isolated working hearts and 13Carbon (13C )-NMR were used to measure function and fractional contributions (Fc) to the citric acid cycle by using perfusate containing 13C-labeled free fatty acids, acetoacetate, lactate, unlabeled glucose and insulin. Studies were performed at pre-hypertrophy (3-days tam, 3dMyc), established hypertrophy (7-days tam, 7dMyc) or vehicle control (cont). Non-transgenic siblings (NTG) received 7-days tam or vehicle to assess drug effect. Hypertrophy was confirmed by echocardiograms and heart weights. Western blots were performed on key metabolic enzymes. Hypertrophy occurred in 7dMyc only. Cardiac function did not differ between groups. Tam alone did not affect substrate contribution in NTG. Substrate utilization was not significantly altered in 3dMyc versus cont. The free fatty acid FC was significantly greater in 7dMyc vs cont with decreased unlabeled Fc, which is predominately exogenous glucose. Free fatty acid flux to the citric acid cycle increased while lactate flux was diminished in 7dMyc compared to cont. Total protein levels of a panel of key metabolic enzymes were unchanged; however total protein O-GlcNAcylation was increased in 7dMyc. Substrate utilization changes did not precede hypertrophy; therefore they are not the primary signal for cardiac growth in this model. Free fatty acid utilization and oxidation increase at established hypertrophy. Understanding the mechanisms whereby this change maintained

  3. Genetic polymorphisms ofUTS2rs2890565 Ser89Asn in cardiac hypertrophy in Chinese Han population.

    Science.gov (United States)

    Zhao, Jing; Jiang, Jie; Wang, Jie; Liu, Lin; Han, Xiao-Ning; Chu, Song-Yun; Xue, Lin; Ding, Wen-Hui

    2017-07-01

    Cardiac hypertrophy is the heart's response to a variety of extrinsic and intrinsic stimuli, some of which might finally lead up to a maladaptive state. Clinical evidence, in vitro and in vivo studies have implicated urotensin II (U-II/UTS2) in the development of cardiac hypertrophy, contributing to the (patho)-physiological regulation of cardiovascular homeostasis in humans. Several genes are associated with left ventricular hypertrophy; considering these, our objective was to evaluate the possible role of UTS2 gene polymorphisms (Thr21Met and Ser89Asn) in the genetic susceptibility to cardiac hypertrophy in a Chinese population. A case-control study was designed to compare the distribution of alleles and genotypes between three groups: case group 1 (subjects with hypertension and cardiac hypertrophy, n=265), case group 2 (subjects with hypertension, without cardiac hypertrophy, n=768), and the control group (subjects neither with hypertension nor with cardiac hypertrophy, n=416). The detection of UTS2 gene polymorphisms was achieved with the PCR restriction fragment length polymorphism technique. We did not identify statistically significant differences between the three groups, neither with regard to the frequency of genotype/variant at the Ser89Asn locus nor at the Thr21Met locus. When stratified by sex, differences in genotype distribution of polymorphism Ser89Asn were only seen in female subjects in both the additive tested inheritance model (OR=0.507, 95% CI 0.249 to 1.032, p=0.032) and the recessive tested inheritance model (OR=0.475, 95% CI 0.239 to 0.945, p=0.034) between case group 2 (subjects with hypertension, without cardiac hypertrophy) and the control group (subjects neither with hypertension nor with cardiac hypertrophy). When stratified by sex, for female subjects with cardiac hypertrophy, we identified statistically significant differences in left ventricular posterior wall thickness for variant genotypes at the Ser89Asn locus (AA vs GG: 1

  4. TRPV1 Activation Attenuates High-Salt Diet-Induced Cardiac Hypertrophy and Fibrosis through PPAR-δ Upregulation

    OpenAIRE

    Gao, Feng; Liang, Yi; Wang, Xiang; Lu, Zongshi; Li, Li; Zhu, Shanjun; Liu, Daoyan; Yan, Zhencheng; Zhu, Zhiming

    2014-01-01

    High-salt diet-induced cardiac hypertrophy and fibrosis are associated with increased reactive oxygen species production. Transient receptor potential vanilloid type 1 (TRPV1), a specific receptor for capsaicin, exerts a protective role in cardiac remodeling that resulted from myocardial infarction, and peroxisome proliferation-activated receptors δ (PPAR-δ) play an important role in metabolic myocardium remodeling. However, it remains unknown whether activation of TRPV1 could alleviate cardi...

  5. Nitrite exerts antioxidant effects, inhibits the mTOR pathway and reverses hypertension-induced cardiac hypertrophy.

    Science.gov (United States)

    Guimaraes, Danielle A; Dos Passos, Madla A; Rizzi, Elen; Pinheiro, Lucas C; Amaral, Jefferson H; Gerlach, Raquel F; Castro, Michele M; Tanus-Santos, Jose E

    2018-03-09

    Cardiac hypertrophy is a common consequence of chronic hypertension and leads to heart failure and premature death. The anion nitrite is now considered as a bioactive molecule able to exert beneficial cardiovascular effects. Previous results showed that nitrite attenuates hypertension-induced increases in reactive oxygen species (ROS) production in the vasculature. Whether antioxidant effects induced by nitrite block critical signaling pathways involved in cardiac hypertrophy induced by hypertension has not been determined yet. The Akt/mTOR signaling pathway is responsible to activate protein synthesis during cardiac remodeling and is activated by increased ROS production, which is commonly found in hypertension. Here, we investigated the effects of nitrite treatment on cardiac remodeling and activation of this hypertrophic signaling pathway in 2 kidney-1 clip (2K1C) hypertension. Sham and 2K1C rats were treated with oral nitrite at 1 or 15mg/kg for four weeks. Nitrite treatment (15mg/kg) reduced systolic blood pressure and decreased ROS production in the heart tissue from hypertensive rats. This nitrite dose also blunted hypertension-induced activation of mTOR pathway and cardiac hypertrophy. While the lower nitrite dose (1mg/kg) did not affect blood pressure, it exerted antioxidant effects and tended to attenuate mTOR pathway activation and cardiac hypertrophy induced by hypertension. Our findings provide strong evidence that nitrite treatment decreases cardiac remodeling induced by hypertension as a result of its antioxidants effects and downregulation of mTOR signaling pathway. This study may help to establish nitrite as an effective therapy in hypertension-induced cardiac hypertrophic remodeling. Copyright © 2018. Published by Elsevier Inc.

  6. Cardioprotective Effect of Ulmus wallichiana Planchon in β-Adrenergic Agonist Induced Cardiac Hypertrophy

    Science.gov (United States)

    Syed, Anees A.; Lahiri, Shibani; Mohan, Divya; Valicherla, Guru R.; Gupta, Anand P.; Kumar, Sudhir; Maurya, Rakesh; Bora, Himanshu K.; Hanif, Kashif; Gayen, Jiaur R.

    2016-01-01

    Ulmus wallichiana Planchon (Family: Ulmaceae), a traditional medicinal plant, was used in fracture healing in the folk tradition of Uttarakhand, Himalaya, India. The present study investigated the cardioprotective effect of ethanolic extract (EE) and butanolic fraction (BF) of U. wallichiana in isoprenaline (ISO) induced cardiac hypertrophy in Wistar rats. Cardiac hypertrophy was induced by ISO (5 mg/kg/day, subcutaneously) in rats. Treatment was performed by oral administration of EE and BF of U. wallichiana (500 and 50 mg/kg/day). The blood pressure (BP) and heart rate (HR) were measured by non-invasive blood pressure measurement technique. Plasma renin, Ang II, NO, and cGMP level were estimated using an ELISA kit. Angiotensin converting enzyme activity was estimated. BP and HR were significantly increased in ISO group (130.33 ± 1.67 mmHg vs. 111.78 ± 1.62 mmHg, p < 0.001 and 450.51 ± 4.90 beats/min vs. 347.82 ± 6.91 beats/min, respectively, p < 0.001). The BP and HR were significantly reduced (EE: 117.53 ± 2.27 mmHg vs. 130.33 ± 1.67 mmHg, p < 0.001, BF: 119.74 ± 3.32 mmHg vs. 130.33 ± 1.67 mmHg, p < 0.001); HR: (EE: 390.22 ± 8.24 beats/min vs. 450.51 ± 4.90 beats/min, p < 0.001, BF: 345.38 ± 6.79 beats/min vs. 450.51 ± 4.90 beats/min, p < 0.001) after the treatment of EE and BF of U. wallichiana, respectively. Plasma renin, Ang II, ACE activity was decreased and NO, cGMP level were increased. The EE and BF of U. wallichiana down regulated the expression of ANP, BNP, TNF-α, IL-6, MMP9, β1-AR, TGFβ1 and up regulated NOS3, ACE2 and Mas expression level, respectively. Thus, this study demonstrated that U. wallichiana has cardioprotective effect against ISO induced cardiac hypertrophy. PMID:28066255

  7. Pregestational type 2 diabetes mellitus induces cardiac hypertrophy in the murine embryo through cardiac remodeling and fibrosis.

    Science.gov (United States)

    Lin, Xue; Yang, Penghua; Reece, E Albert; Yang, Peixin

    2017-08-01

    Cardiac hypertrophy is highly prevalent in patients with type 2 diabetes mellitus. Experimental evidence has implied that pregnant women with type 2 diabetes mellitus and their children are at an increased risk of cardiovascular diseases. Our previous mouse model study revealed that maternal type 2 diabetes mellitus induces structural heart defects in their offspring. This study aims to determine whether maternal type 2 diabetes mellitus induces embryonic heart hypertrophy in a murine model of diabetic embryopathy. The type 2 diabetes mellitus embryopathy model was established by feeding 4-week-old female C57BL/6J mice with a high-fat diet for 15 weeks. Cardiac hypertrophy in embryos at embryonic day 17.5 was characterized by measuring heart size and thickness of the right and left ventricle walls and the interventricular septum, as well as the expression of β-myosin heavy chain, atrial natriuretic peptide, insulin-like growth factor-1, desmin, and adrenomedullin. Cardiac remodeling was determined by collagen synthesis and fibronectin synthesis. Fibrosis was evaluated by Masson staining and determining the expression of connective tissue growth factor, osteopontin, and galectin-3 genes. Cell apoptosis also was measured in the developing heart. The thicknesses of the left ventricle walls and the interventricular septum of embryonic hearts exposed to maternal diabetes were significantly thicker than those in the nondiabetic group. Maternal diabetes significantly increased β-myosin heavy chain, atrial natriuretic peptide, insulin-like growth factor-1, and desmin expression, but decreased expression of adrenomedullin. Moreover, collagen synthesis was significantly elevated, whereas fibronectin synthesis was suppressed, in embryonic hearts from diabetic dams, suggesting that cardiac remodeling is a contributing factor to cardiac hypertrophy. The cardiac fibrosis marker, galectin-3, was induced by maternal diabetes. Furthermore, maternal type 2 diabetes mellitus

  8. Serelaxin treatment promotes adaptive hypertrophy but does not prevent heart failure in experimental peripartum cardiomyopathy.

    Science.gov (United States)

    Nonhoff, Justus; Ricke-Hoch, Melanie; Mueller, Mirco; Stapel, Britta; Pfeffer, Tobias; Kasten, Martina; Scherr, Michaela; von Kaisenberg, Constantin; Bauersachs, Johann; Haghikia, Arash; Hilfiker-Kleiner, Denise

    2017-05-01

    Peripartum cardiomyopathy (PPCM) is a systolic left ventricular dysfunction developing in the peripartum phase in previously healthy women. Relaxin-2 is a pregnancy hormone with potential beneficial effects in heart failure patients. We evaluated Relaxin-2 as a potential diagnostic marker and/or a therapeutic agent in PPCM. In healthy peripartum women, serum Relaxin-2 levels (measured by ELISA in the second half of pregnancy) were elevated showing a decreasing trend in the first postpartum week and returned to non-pregnant levels thereafter. In PPCM patients diagnosed in the first postpartum week, serum Relaxin-2 levels were lower compared to healthy postpartum stage-matched controls. In PPCM patients diagnosed later (0.5-10 months postpartum) Relaxin-2 levels were in the range of non-pregnant controls and not different from healthy postpartum stage-matched controls. In mice, serum Relaxin-1 (functional equivalent of human Relaxin-2) was increased late in pregnancy and rapidly cleared in the first postpartum week. In mice with PPCM due to a cardiomyocyte-specific knockout of STAT3 (CKO) neither low nor high dose of recombinant Relaxin-2 (serelaxin, sRlx-LD: 30 µg/kg/day; sRlx-HD: 300 µg/kg/day) affected cardiac fibrosis, inflammation and heart failure but sRlx-HD increased capillary/cardiomyocyte ratio. sRlx-HD significantly increased heart/body weight ratio and cardiomyocyte cross-sectional area in postpartum CKO and wild-type mice without changing the foetal gene expression program (ANP or β-MHC). sRlx-HD augmented plasma Prolactin levels in both genotypes, which induced cardiac activation of STAT5. In vitro analyses showed that Prolactin induces cardiomyocyte hypertrophy via activation of STAT5. Although Relaxin-2 levels seemed lower in PPCM patients diagnosed early postpartum, we observed a high pregnancy-related variance of serum Relaxin-2 levels peripartum making it unsuitable as a biomarker for this condition. Supplementation with sRlx may contribute to

  9. Investigation of the relationship between regression of hypertensive cardiac hypertrophy and improvement of cardiac sympathetic nervous dysfunction using iodine-123 metaiodobenzylguanidine myocardial imaging

    International Nuclear Information System (INIS)

    Morimoto, Satoshi; Terada, Koji; Keira, Natsuya; Satoda, Masahiko; Inoue, Keiji; Tatsukawa, Hirotaka; Katoh, Shuji; Ida, Kazunori; Sugihara, Hiroki; Takeda, Kazuo; Nakagawa, Masao

    1996-01-01

    Although many theories exist on the subject, the mechanisms responsible for a reduction of hypertensive cardiac hypertrophy in response to antihypertensive therapy are still unclear. In order to investigate the relationship between regression of hypertensive cardiac hypertrophy and cardiac nervous function, we studied ten patients with untreated essential hypertension (six men and four women, 62±12 years old). Both echocardiography and iodine-123 metaiodobenzylguanidine (MIBG) myocardial imaging were performed before and after antihypertensive therapy. Left ventricular mass (LVM) was significantly reduced in conjunction with the reduction of blood pressure following treatment. MIBG myocardial images showed that the heart-to-mediastinum activity ratio (H/M) was significantly increased while the washout ratio was significantly decreased. Patients were divided into two groups according to the ratio of the LVM values before and after therapy (LVM ratio). Patients with an LVM ratio of less than 0.75 were classified as group A and those with values higher than 0.75 as group B. Neither the change in blood pressure nor the length of treatment was significantly different between these two groups. On the other hand, both the increase in H/M and the decrease in the washout ratio were significantly greater in group A than in group B. These results indicate that an improvement in cardiac sympathetic nervous function may be related to the regression of hypertensive cardiac hypertrophy. Increasing the subject base in these studies and a more precise analysis of the relevance of the data obtained from MIBG myocardial images are recommended to clarify how changes in cardiac sympathetic nervous function relate to the regression of hypertensive cardiac hypertrophy. (orig.)

  10. IGF-2R-Gαq signaling and cardiac hypertrophy in the low-birth-weight lamb

    OpenAIRE

    Wang, Kimberley C. W.; Tosh, Darran N.; Zhang, Song; McMillen, I. Caroline; Duffield, Jaime A.; Brooks, Doug A.; Morrison, Janna L.

    2015-01-01

    The cardiac insulin-like growth factor 2 receptor (IGF-2R) can induce cardiomyocyte hypertrophy in a heterotrimeric G protein receptor-coupled manner involving αq (Gαq) or αs (Gαs). We have previously shown increased left ventricular weight and cardiac IGF-2 and IGF-2R gene expression in low-birth-weight (LBW) compared with average-birth-weight (ABW) lambs. Here, we have investigated the cardiac expression of IGF-2 gene variants, the degree of histone acetylation, and the abundance of protein...

  11. With great power comes great responsibility: using mouse genetics to study cardiac hypertrophy and failure.

    Science.gov (United States)

    Molkentin, Jeffery D; Robbins, Jeffrey

    2009-02-01

    Over the past 20 years generation and subsequent characterization of genetically modified mouse models has revolutionized our understanding of disease-gene relationships and suggested numerous therapeutic targets for human disease. Cardiac biology has perhaps benefited more than most fields from the advent of modern genetic approaches in the mouse by providing a 3-dimensional integrated platform for phenotypic dissection of single gene function, largely replacing the unitary relationships derived from 2-dimensional cell culture-based platforms. Indeed, cardiac hypertrophy and end-stage heart failure are whole organ phenomena that occur within a dynamic neuroendocrine milieu, a backdrop that cannot be adequately modeled in cultured myocytes. Here we advocate the use of genetically modified mouse models for studying cardiac biology and show how, if employed properly, these models will continue to provide highly reliable data sets that suggest disease-gene relationships and novel therapeutic targets. In addition to a discussion of proper technique and controls, we will highlight examples of genetic approaches in the mouse that suggest novel disease relationships and therapeutic treatments for human heart failure, insights not possible with other experimental systems. In the preceding review/editorial by Cook, Clerk and Sugden, a number of strong arguments are made detailing the potential short comings associated with genetic approaches in the mouse as a means of unraveling cardiac disease mechanisms. We take very little issue with these arguments per se, although here we attempt to put these shortcomings into a greater context that extends beyond a single experimental setting, as well as to carefully construct a counterpoint that delineates the advantages of genetic approaches in the mouse compared with any other system currently in use in cardiovascular biology.

  12. Salt-Sensitive Hypertension and Cardiac Hypertrophy in Transgenic Mice Expressing a Corin Variant Identified in African Americans

    Science.gov (United States)

    Wang, Wei; Cui, Yujie; Shen, Jianzhong; Jiang, Jingjing; Chen, Shenghan; Peng, Jianhao; Wu, Qingyu

    2012-01-01

    African Americans represent a high risk population for salt-sensitive hypertension and heart disease but the underlying mechanism remains unclear. Corin is a cardiac protease that regulates blood pressure by activating natriuretic peptides. A corin gene variant (T555I/Q568P) was identified in African Americans with hypertension and cardiac hypertrophy. In this study, we test the hypothesis that the corin variant contributes to the hypertensive and cardiac hypertrophic phenotype in vivo. Transgenic mice were generated to express wild-type or T555I/Q568P variant corin in the heart under the control of α-myosin heavy chain promoter. The mice were crossed into a corin knockout background to create KO/TgWT and KO/TgV mice that expressed WT or variant corin, respectively, in the heart. Functional studies showed that KO/TgV mice had significantly higher levels of pro-atrial natriuretic peptide in the heart compared with that in control KO/TgWT mice, indicating that the corin variant was defective in processing natriuretic peptides in vivo. By radiotelemetry, corin KO/TgV mice were found to have hypertension that was sensitive to dietary salt loading. The mice also developed cardiac hypertrophy at 12–14 months of age when fed a normal salt diet or at a younger age when fed a high salt diet. The phenotype of salt-sensitive hypertension and cardiac hypertrophy in KO/TgV mice closely resembles the pathological findings in African Americans who carry the corin variant. The results indicate that corin defects may represent an important mechanism in salt-sensitive hypertension and cardiac hypertrophy in African Americans. PMID:22987923

  13. Tempol inhibits TGF-β and MMPs upregulation and prevents cardiac hypertensive changes.

    Science.gov (United States)

    Rizzi, Elen; Castro, Michele M; Ceron, Carla S; Neto-Neves, Evandro M; Prado, Cibele M; Rossi, Marcos A; Tanus-Santos, Jose E; Gerlach, Raquel F

    2013-04-30

    Increased oxidative stress upregulates matrix metalloproteinases (MMPs) and transforming grow factor (TGF-β), which are involved in hypertensive cardiac remodeling. We tested the hypothesis that tempol (an antioxidant) could prevent these alterations in two-kidney, one-clip (2K1C) hypertension. Sham-operated or hypertensive rats were treated with tempol (18 mg.kg(-1)day(-1) or vehicle) for 8 weeks. Systolic blood pressure was monitored weekly. At the end of the treatment, a catheter was inserted into the left carotid artery and into the left ventricle (LV) to assess arterial blood pressure and contractile function. Morphometry of the LV was carried out in hematoxylin/eosin sections and fibrosis was assessed in picrosirius red-stained sections. Cardiac TGF-β level was evaluated by immunofluorescence. Cardiac MMP-2 levels and activity were determined by gelatin zymography, in situ zymography, and immunofluorescence. Cardiac superoxide production was evaluated by dihydroethidium probe. Tempol treatment attenuated 2K1C-induced hypertension and reversed the contractile dysfunction in 2K1C rats. Cardiac hypertrophy was ameliorated by antioxidant treatment. Hypertensive rats showed increased cardiac MMP-2 levels, however tempol did not decrease MMP-2 levels. Increased TGF-β level, total gelatinolytic activity and oxidative stress were found in untreated 2K1C rats. Tempol treatment decreased oxidative stress, TGF-β levels, and gelatinolytic activity in 2K1C rats to control levels. Tempol blunted the increases in TGF-β, the proteolytic imbalance, and the morphological and functional alterations found in 2K1C-induced cardiac hypertrophy. These findings are consistent with the idea that antioxidants may help to prevent hypertension-induced cardiac hypertrophy. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  14. Elevated Levels of Asymmetric Dimethylarginine (ADMA in the Pericardial Fluid of Cardiac Patients Correlate with Cardiac Hypertrophy.

    Directory of Open Access Journals (Sweden)

    Zoltan Nemeth

    Full Text Available Pericardial fluid (PF contains several biologically active substances, which may provide information regarding the cardiac conditions. Nitric oxide (NO has been implicated in cardiac remodeling. We hypothesized that L-arginine (L-Arg precursor of NO-synthase (NOS and asymmetric dimethylarginine (ADMA, an inhibitor of NOS, are present in PF of cardiac patients and their altered levels may contribute to altered cardiac morphology.L-Arg and ADMA concentrations in plasma and PF, and echocardiographic parameters of patients undergoing coronary artery bypass graft (CABG, n = 28 or valve replacement (VR, n = 25 were determined.We have found LV hypertrophy in 35.7% of CABG, and 80% of VR patients. In all groups, plasma and PF L-Arg levels were higher than that of ADMA. Plasma L-Arg level was higher in CABG than VR (75.7 ± 4.6 μmol/L vs. 58.1 ± 4.9 μmol/L, p = 0.011, whereas PF ADMA level was higher in VR than CABG (0.9 ± 0.0 μmol/L vs. 0.7 ± 0.0 μmol/L, p = 0.009. L-Arg/ADMA ratio was lower in the VR than CABG (VRplasma: 76.1 ± 6.6 vs. CABGplasma: 125.4 ± 10.7, p = 0.004; VRPF: 81.7 ± 4.8 vs. CABGPF: 110.4 ± 7.2, p = 0.009. There was a positive correlation between plasma L-Arg and ADMA in CABG (r = 0.539, p = 0.015; and plasma and PF L-Arg in CABG (r = 0.357, p = 0.031; and plasma and PF ADMA in VR (r = 0.529, p = 0.003; and PF L-Arg and ADMA in both CABG and VR (CABG: r = 0.468, p = 0.006; VR: r = 0.371, p = 0.034. The following echocardiographic parameters were higher in VR compared to CABG: interventricular septum (14.7 ± 0.5 mm vs. 11.9 ± 0.4 mm, p = 0.000; posterior wall thickness (12.6 ± 0.3 mm vs. 11.5 ± 0.2 mm, p = 0.000; left ventricular (LV mass (318.6 ± 23.5 g vs. 234.6 ± 12.3 g, p = 0.007; right ventricular (RV (33.9 ± 0.9 cm2 vs. 29.7 ± 0.7 cm2, p = 0.004; right atrial (18.6 ± 1.0 cm2 vs. 15.4 ± 0.6 cm2, p = 0.020; left atrial (19.8 ± 1.0 cm2 vs. 16.9 ± 0.6 cm2, p = 0.033 areas. There was a positive correlation

  15. GATA4-mediated cardiac hypertrophy induced by D-myo-inositol 1,4,5-tris-phosphate

    International Nuclear Information System (INIS)

    Zhu Zhiming; Zhu Shanjun; Liu Daoyan; Yu Zengping; Yang Yongjian; Giet, Markus van der; Tepel, Martin

    2005-01-01

    We evaluated the effects of D-myo-inositol 1,4,5-tris-phosphate on cardiac hypertrophy. D-myo-inositol 1,4,5-tris-phosphate augmented cardiac hypertrophy as evidenced by its effects on DNA synthesis, protein synthesis, and expression of immediate-early genes c-myc and c-fos, β-myosin heavy chain, and α-actin. The administration of D-myo-inositol 1,4,5-tris-phosphate increased the expression of nuclear factor of activated T-cells and cardiac-restricted zinc finger transcription factor (GATA4). Real-time quantitative RT-PCR showed that D-myo-inositol 1,4,5-tris-phosphate-induced GATA4 mRNA was significantly enhanced even in the presence of the calcineurin inhibitor, cyclosporine A. The effect of D-myo-inositol 1,4,5-tris-phosphate was blocked after inhibition of inositol-trisphosphate receptors but not after inhibition of c-Raf/mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (ERK) or p38 mitogen-activated protein kinase pathways. The study shows that D-myo-inositol 1,4,5-tris-phosphate-induced cardiac hypertrophy is mediated by GATA4 but independent from the calcineurin pathway

  16. Regression of cardiac hypertrophy in the SHR by combined renin-angiotensin system blockade and dietary sodium restriction

    Directory of Open Access Journals (Sweden)

    Emad Abro

    2001-03-01

    Full Text Available Altered operation of the renin-angiotensin-aldosterone system (RAAS and dietary sodium intake have been identified as independent risk factors for cardiac hypertrophy. The way in which sodium intake and the operation of the renin-angiotensin-aldosterone system interact in the pathogenesis of cardiac hypertrophy is poorly understood. The aims of this study were to investigate the cardiac effects of the renin-angiotensin system (RAS blockade in the spontaneously hypertensive rat (SHR, using co-treatment with an angiotensin II receptor blocker (ARB and an angiotensin-converting enzyme (ACE inhibitor with different sodium intakes. Our experiments with SHR show that, at high levels of sodium intake (4.0%, aggressive RAS blockade treatment with candesartan (3 mg/kg and perindopril (6 mg/kg does not result in regression of cardiac hypertrophy. In contrast, RAS blockade coupled with reduced sodium diet (0.2% significantly regresses cardiac hypertrophy, impairs animal growth and is associated with elevated plasma renin and dramatically suppressed plasma angiotensinogen levels. Histological analyses indicate that the differential effect of reduced sodium on heart growth during RAS blockade is not associated with any change in myocardial interstitial collagen, but reflects modification of cellular geometry. Dimensional measurements of enzymatically-isolated ventricular myocytes show that, in the RAS blocked, reduced sodium group, myocyte length and width were decreased by about 16—19% compared with myocytes from the high sodium treatment group. Our findings highlight the importance of `titrating' sodium intake with combined RAS blockade in the clinical setting to optimise therapeutic benefit.

  17. Neurotransmission to parasympathetic cardiac vagal neurons in the brain stem is altered with left ventricular hypertrophy-induced heart failure.

    Science.gov (United States)

    Cauley, Edmund; Wang, Xin; Dyavanapalli, Jhansi; Sun, Ke; Garrott, Kara; Kuzmiak-Glancy, Sarah; Kay, Matthew W; Mendelowitz, David

    2015-10-01

    Hypertension, cardiac hypertrophy, and heart failure (HF) are widespread and debilitating cardiovascular diseases that affect nearly 23 million people worldwide. A distinctive hallmark of these cardiovascular diseases is autonomic imbalance, with increased sympathetic activity and decreased parasympathetic vagal tone. Recent device-based approaches, such as implantable vagal stimulators that stimulate a multitude of visceral sensory and motor fibers in the vagus nerve, are being evaluated as new therapeutic approaches for these and other diseases. However, little is known about how parasympathetic activity to the heart is altered with these diseases, and this lack of knowledge is an obstacle in the goal of devising selective interventions that can target and selectively restore parasympathetic activity to the heart. To identify the changes that occur within the brain stem to diminish the parasympathetic cardiac activity, left ventricular hypertrophy was elicited in rats by aortic pressure overload using a transaortic constriction approach. Cardiac vagal neurons (CVNs) in the brain stem that generate parasympathetic activity to the heart were identified with a retrograde tracer and studied using patch-clamp electrophysiological recordings in vitro. Animals with left cardiac hypertrophy had diminished excitation of CVNs, which was mediated both by an augmented frequency of spontaneous inhibitory GABAergic neurotransmission (with no alteration of inhibitory glycinergic activity) as well as a diminished amplitude and frequency of excitatory neurotransmission to CVNs. Opportunities to alter these network pathways and neurotransmitter receptors provide future targets of intervention in the goal to restore parasympathetic activity and autonomic balance to the heart in cardiac hypertrophy and other cardiovascular diseases. Copyright © 2015 the American Physiological Society.

  18. Experimental and Human Evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin [NGAL]) in the Development of Cardiac Hypertrophy and heart failure.

    Science.gov (United States)

    Marques, Francine Z; Prestes, Priscilla R; Byars, Sean G; Ritchie, Scott C; Würtz, Peter; Patel, Sheila K; Booth, Scott A; Rana, Indrajeetsinh; Minoda, Yosuke; Berzins, Stuart P; Curl, Claire L; Bell, James R; Wai, Bryan; Srivastava, Piyush M; Kangas, Antti J; Soininen, Pasi; Ruohonen, Saku; Kähönen, Mika; Lehtimäki, Terho; Raitoharju, Emma; Havulinna, Aki; Perola, Markus; Raitakari, Olli; Salomaa, Veikko; Ala-Korpela, Mika; Kettunen, Johannes; McGlynn, Maree; Kelly, Jason; Wlodek, Mary E; Lewandowski, Paul A; Delbridge, Lea M; Burrell, Louise M; Inouye, Michael; Harrap, Stephen B; Charchar, Fadi J

    2017-06-14

    Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants. We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2 -knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2 -knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis -eQTL for LCN2 expression. Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  19. Toll‐Like Receptor‐2 Mediates Adaptive Cardiac Hypertrophy in Response to Pressure Overload Through Interleukin‐1β Upregulation via Nuclear Factor κB Activation

    Science.gov (United States)

    Higashikuni, Yasutomi; Tanaka, Kimie; Kato, Megumi; Nureki, Osamu; Hirata, Yasunobu; Nagai, Ryozo; Komuro, Issei; Sata, Masataka

    2013-01-01

    Background Inflammation is induced in the heart during the development of cardiac hypertrophy. The initiating mechanisms and the role of inflammation in cardiac hypertrophy, however, remain unclear. Toll‐like receptor‐2 (TLR2) recognizes endogenous molecules that induce noninfectious inflammation. Here, we examined the role of TLR2‐mediated inflammation in cardiac hypertrophy. Methods and Results At 2 weeks after transverse aortic constriction, Tlr2−/− mice showed reduced cardiac hypertrophy and fibrosis with greater left ventricular dilatation and impaired systolic function compared with wild‐type mice, which indicated impaired cardiac adaptation in Tlr2−/− mice. Bone marrow transplantation experiment revealed that TLR2 expressed in the heart, but not in bone marrow–derived cells, is important for cardiac adaptive response to pressure overload. In vitro experiments demonstrated that TLR2 signaling can induce cardiomyocyte hypertrophy and fibroblast and vascular endothelial cell proliferation through nuclear factor–κB activation and interleukin‐1β upregulation. Systemic administration of a nuclear factor–κB inhibitor or anti–interleukin‐1β antibodies to wild‐type mice resulted in impaired adaptive cardiac hypertrophy after transverse aortic constriction. We also found that heat shock protein 70, which was increased in murine plasma after transverse aortic constriction, can activate TLR2 signaling in vitro and in vivo. Systemic administration of anti–heat shock protein 70 antibodies to wild‐type mice impaired adaptive cardiac hypertrophy after transverse aortic constriction. Conclusions Our results demonstrate that TLR2‐mediated inflammation induced by extracellularly released heat shock protein 70 is essential for adaptive cardiac hypertrophy in response to pressure overload. Thus, modulation of TLR2 signaling in the heart may provide a novel strategy for treating heart failure due to inadequate adaptation to hemodynamic

  20. Smoothelin-B deficiency results in reduced arterial contractility, hypertension, and cardiac hypertrophy in mice.

    Science.gov (United States)

    Rensen, Sander S; Niessen, Petra M; van Deursen, Jan M; Janssen, Ben J; Heijman, Edwin; Hermeling, Evelien; Meens, Merlijn; Lie, Natascha; Gijbels, Marion J; Strijkers, Gustav J; Doevendans, Pieter A; Hofker, Marten H; De Mey, Jo G R; van Eys, Guillaume J

    2008-08-19

    Smoothelins are actin-binding proteins that are abundantly expressed in healthy visceral (smoothelin-A) and vascular (smoothelin-B) smooth muscle. Their expression is strongly associated with the contractile phenotype of smooth muscle cells. Analysis of mice lacking both smoothelins (Smtn-A/B(-/-) mice) previously revealed a critical role for smoothelin-A in intestinal smooth muscle contraction. Here, we report on the generation and cardiovascular phenotype of mice lacking only smoothelin-B (Smtn-B(-/-)). Myograph studies revealed that the contractile capacity of the saphenous and femoral arteries was strongly reduced in Smtn-B(-/-) mice, regardless of the contractile agonist used to trigger contraction. Arteries from Smtn-A/B(-/-) compound mutant mice exhibited a similar contractile deficit. Smtn-B(-/-) arteries had a normal architecture and expressed normal levels of other smooth muscle cell-specific genes, including smooth muscle myosin heavy chain, alpha-smooth muscle actin, and smooth muscle-calponin. Decreased contractility of Smtn-B(-/-) arteries was paradoxically accompanied by increased mean arterial pressure (20 mm Hg) and concomitant cardiac hypertrophy despite normal parasympathetic and sympathetic tone in Smtn-B(-/-) mice. Magnetic resonance imaging experiments revealed that cardiac function was not changed, whereas distension of the proximal aorta during the cardiac cycle was increased in Smtn-B(-/-) mice. However, isobaric pulse wave velocity and pulse pressure measurements indicated normal aortic distensibility. Collectively, our results identify smoothelins as key determinants of arterial smooth muscle contractility and cardiovascular performance. Studies on mutations in the Smtn gene or alterations in smoothelin levels in connection to hypertension in humans are warranted.

  1. Pulmonary hypertension and cardiac hypertrophy in children recipients of orthotopic living related liver transplantation

    Directory of Open Access Journals (Sweden)

    Magd A. Kotb

    2017-11-01

    Full Text Available Surgical stress, liberation of cytokines associated with re-perfusion injury, and long standing use of immune suppressive medications in children recipients of orthotopic living related liver transplantation (OLRLT pose cardiovascular risk. Reported cardiovascular adverse effects vary from left ventricular wall thickening, hypertrophic cardiomyopathy to resting ECG abnormalities, asymptomatic ST depression following increased heart rate and ventricular arrhythmias. Twenty-five consecutive children recipients of OLRLT were assessed by conventional 2-D, M-mode echocardiography and Doppler. The mean age ± SD at transplantation and at enrollment in study was 6.3 ± 4.5 and 13.5 ± 5.6 years respectively. All children were on immunosuppressive medications, with tacrolimus being constant among all. Long-term post-transplant echocardiography revealed statistically significant interventricular septal hypertrophy among all (mean thickness 0.89 ± 0.16 cm, (P = 0.0001 in comparison to reference range for age, 24 had pulmonary hypertension (mean mPAP 36.43 ± 5.60 mm Hg, P = 0.0001, and early diastolic dysfunction with a mean Tei index of 0.40 ± 0.10. However cardiac function was generally preserved. Children recipients of OLRLT have cardiac structural and functional abnormalities that can be asymptomatic. Pulmonary hypertension, increased cardiac mass, de novo aortic stenosis and diastolic heart failure were among abnormalities encountered in the studied population. Echocardiography is indispensible in follow-up of children recipients of OLRLT.

  2. Trpm4 gene invalidation leads to cardiac hypertrophy and electrophysiological alterations.

    Directory of Open Access Journals (Sweden)

    Marie Demion

    Full Text Available RATIONALE: TRPM4 is a non-selective Ca2+-activated cation channel expressed in the heart, particularly in the atria or conduction tissue. Mutations in the Trpm4 gene were recently associated with several human conduction disorders such as Brugada syndrome. TRPM4 channel has also been implicated at the ventricular level, in inotropism or in arrhythmia genesis due to stresses such as ß-adrenergic stimulation, ischemia-reperfusion, and hypoxia re-oxygenation. However, the physiological role of the TRPM4 channel in the healthy heart remains unclear. OBJECTIVES: We aimed to investigate the role of the TRPM4 channel on whole cardiac function with a Trpm4 gene knock-out mouse (Trpm4-/- model. METHODS AND RESULTS: Morpho-functional analysis revealed left ventricular (LV eccentric hypertrophy in Trpm4-/- mice, with an increase in both wall thickness and chamber size in the adult mouse (aged 32 weeks when compared to Trpm4+/+ littermate controls. Immunofluorescence on frozen heart cryosections and qPCR analysis showed no fibrosis or cellular hypertrophy. Instead, cardiomyocytes in Trpm4-/- mice were smaller than Trpm4+/+with a higher density. Immunofluorescent labeling for phospho-histone H3, a mitosis marker, showed that the number of mitotic myocytes was increased 3-fold in the Trpm4-/-neonatal stage, suggesting hyperplasia. Adult Trpm4-/- mice presented multilevel conduction blocks, as attested by PR and QRS lengthening in surface ECGs and confirmed by intracardiac exploration. Trpm4-/-mice also exhibited Luciani-Wenckebach atrioventricular blocks, which were reduced following atropine infusion, suggesting paroxysmal parasympathetic overdrive. In addition, Trpm4-/- mice exhibited shorter action potentials in atrial cells. This shortening was unrelated to modifications of the voltage-gated Ca2+ or K+ currents involved in the repolarizing phase. CONCLUSIONS: TRPM4 has pleiotropic roles in the heart, including the regulation of conduction and cellular

  3. Adiponectin ameliorates hyperglycemia-induced cardiac hypertrophy and dysfunction by concomitantly activating Nrf2 and Brg1.

    Science.gov (United States)

    Li, Haobo; Yao, Weifeng; Irwin, Michael G; Wang, Tingting; Wang, Shuang; Zhang, Liangqing; Xia, Zhengyuan

    2015-07-01

    Hyperglycemia-induced oxidative stress is implicated in the development of cardiomyopathy in diabetes that is associated with reduced adiponectin (APN) and heme oxygenase-1 (HO-1). Brahma-related gene 1 (Brg1) assists nuclear factor-erythroid-2-related factor-2 (Nrf2) to activate HO-1 to increase myocardial antioxidant capacity in response to oxidative stress. We hypothesized that reduced adiponectin (APN) impairs HO-1 induction which contributes to the development of diabetic cardiomyopathy, and that supplementation of APN may ameliorate diabetic cardiomyopathy by activating HO-1 through Nrf2 and Brg1 in diabetes. Control (C) and streptozotocin-induced diabetic (D) rats were untreated or treated with APN adenovirus (1×10(9) pfu) 3 weeks after diabetes induction and examined and terminated 1 week afterward. Rat left ventricular functions were assessed by a pressure-volume conductance system, before the rat hearts were removed to perform histological and biochemical assays. Four weeks after diabetes induction, D rats developed cardiac hypertrophy evidenced as increased ratio of heart weight to body weight, elevated myocardial collagen I content, and larger cardiomyocyte cross-sectional area (all Psupplementation of recombined globular APN (gAd, 2μg/mL) reversed HG-induced reductions of HO-1, Brg1, and nuclear Nrf2 protein expression and attenuated cellular oxidative stress, myocyte size, and apoptotic cells. Inhibition of HO-1 by ZnPP (10μM) or small interfering RNA (siRNA) canceled all the above gAd beneficial effects. Moreover, inhibition of Nrf2 (either by the Nrf2 inhibitor luteolin or siRNA) or Brg1 (by siRNA) canceled gAd-induced HO-1 induction and cellular protection in CMs and in H9C2 cells incubated with HG. In summary, our present study demonstrated that APN reduced cardiac oxidative stress, ameliorated cardiomyocyte hypertrophy, and prevented left ventricular dysfunction in diabetes by concomitantly activating Nrf2 and Brg1 to facilitate HO-1 induction

  4. Connective Tissue Growth Factor Transgenic Mouse Develops Cardiac Hypertrophy, Lean Body Mass and Alopecia.

    Science.gov (United States)

    Nuglozeh, Edem

    2017-07-01

    compelled us to work at the level of hemizygosity. The histological characterisation of left ventricle shows cardiac hypertrophy together with decrease in body mass and alopecia, this compared to the wild type. The immunohistochemical staining of aorta root showed hyperplasia with increased expression and colocalisation of renin and CTGF demonstrating that CTGF may be involved in vascular tone control. Genetic engineering is a noble avenue to investigate the function of new or existing genes. Our data have shown that CTGF transgenic mouse has cardiac and aorta root hypertrophy and abnormal renin accumulation in aorta root as compared to the wild-type animals. The transgenic animals developed alopecia and lean body mass adding two new functions on pre-existing CTGF multiple functions.

  5. Increased natriuretic peptide receptor A and C gene expression in rats with pressure-overload cardiac hypertrophy

    DEFF Research Database (Denmark)

    Christoffersen, Tue E.H.; Aplin, Mark; Strom, Claes C.

    2006-01-01

    Both atrial (ANP) and brain (BNP) natriuretic peptide affect development of cardiac hypertrophy and fibrosis via binding to natriuretic peptide receptor (NPR)-A in the heart. A putative clearance receptor, NPR-C, is believed to regulate cardiac levels of ANP and BNP. The renin-angiotensin system...... in regulation of natriuretic peptide and NPR gene expression. The ascending aorta was banded in 84 rats during Hypnorm/Dormicum-isoflurane anesthesia; after 4 wk the rats were randomized to treatment with losartan or placebo. The left ventricle of the heart was removed 1, 2, or 4 wk later. Aortic banding...

  6. Effects of exercise and other nonpharmacological measures on blood pressure and cardiac hypertrophy.

    Science.gov (United States)

    Jennings, G; Dart, A; Meredith, I; Korner, P; Laufer, E; Dewar, E

    1991-01-01

    Reversal of left ventricular hypertrophy (LVH) is an important target of antihypertensive therapy. Nonpharmacological approaches such as weight reduction and exercise training have favorable effects on other risk factors. However, there are few data on their effects on LVH. Athletes have eccentric rather than concentric LVH. A 12-month exercise program in 13 unmedicated hypertensive subjects altered LV geometry, reducing LV wall thickness and increasing LV internal diameters (LVID). LV mass was unchanged, and the thickness/radius fell by 9%. Shorter-term studies have shown that the cardiac structural changes with a moderate exercise program occur rapidly and their onset lags only about 2 weeks behind blood pressure (BP) effects. Assessment of weight loss effects on LVH is complicated by the strong relationship between body weight and ventricular wall thickness. LVID, and LV mass. To some extent, this can be overcome by arbitrarily indexing to body surface area or height. The wall thickness/radius ratio is not related to body size. Weight reduction reduces BP and thickness/radius by 10% in controlled trials. Small studies have also reported reduction in LV mass after sodium restriction in hypertensive subjects. Studies with other nonpharmacological measures could make a substantial contribution to knowledge of their efficacy.

  7. Regression of Copper-Deficient Heart Hypertrophy: Reduction in the Size of Hypertrophic Cardiomyocytes

    Science.gov (United States)

    Dietary copper deficiency causes cardiac hypertrophy and its transition to heart failure in a mouse model. Copper repletion results in a rapid regression of cardiac hypertrophy and prevention of heart failure. The present study was undertaken to understand dynamic changes of cardiomyocytes in the hy...

  8. Left ventricular function and cardiac hypertrophy in the cases of mild hypertension with marked ST-T changes in electrocardiogram

    Energy Technology Data Exchange (ETDEWEB)

    Ryono, M. (Wakayama Medical Coll. (Japan))

    1981-08-01

    The characteristics of the hemodynamic pattern and cardiac hypertrophy of mild hypertensive patients with giant negative T waves in electrocardiogram (ECG) (group I, 12 patients) were examined by the radionuclide methods, the cardiac catheterization and the echocardiogram. As control groups, the patients of essential hypertension (EH) with high voltage in ECG (group II, 36 patients), those with high voltage and mild ST-T changes in ECG (group III, 9 patients), and the patients with normotensive hypertrophic cardiomyopathy (group IV, 8 patients) were studied. Ejection fraction and cardiac index in group I were increased compared with those in group II (p < 0.01) or group III (p < 0.001). Peak systolic dV/dt and peak diastolic dV/dt in group I were also greater than those in EH (p < 0.001 and p < 0.01, respectively). While total peripheral resistance in group I was higher than in group IV (p < 0.001), but lower than in group II (p < 0.01) or group III (p < 0.01). The ratio of left ventricular radius to wall thickness (R/Th) in group I measured by thallium-201 (/sup 201/Tl) myocardial images was significantly lower than in group II and III (p < 0.001). The /sup 201/Tl-uptake index in cardiac apex determined by apical/total counts was increased in group I compared with other groups. These results suggest that group I is hyperkinetic state and has marked apical hypertrophy. The possibility exists that the increased afterload might be a trigger of apical hypertrophy in predisposed individuals.

  9. IGF-2R-Gαq signaling and cardiac hypertrophy in the low-birth-weight lamb.

    Science.gov (United States)

    Wang, Kimberley C W; Tosh, Darran N; Zhang, Song; McMillen, I Caroline; Duffield, Jaime A; Brooks, Doug A; Morrison, Janna L

    2015-04-01

    The cardiac insulin-like growth factor 2 receptor (IGF-2R) can induce cardiomyocyte hypertrophy in a heterotrimeric G protein receptor-coupled manner involving αq (Gαq) or αs (Gαs). We have previously shown increased left ventricular weight and cardiac IGF-2 and IGF-2R gene expression in low-birth-weight (LBW) compared with average-birth-weight (ABW) lambs. Here, we have investigated the cardiac expression of IGF-2 gene variants, the degree of histone acetylation, and the abundance of proteins in the IGF-2R downstream signaling pathway in ABW and LBW lambs. Samples from the left ventricle of ABW and LBW lambs were collected at 21 days of age. There was increased phospho-CaMKII protein with decreased HDAC 4 abundance in the LBW compared with ABW lambs. There was increased GATA 4 and decreased phospho-troponin I abundance in LBW compared with ABW lambs, which are markers of pathological cardiac hypertrophy and impaired or reduced contractility, respectively. There was increased histone acetylation of H3K9 at IGF-2R promoter and IGF-2R intron 2 differentially methylated region in the LBW lamb. In conclusion, histone acetylation of IGF-2R may lead to increased IGF-2R mRNA expression and subsequently mediate Gαq signaling early in life via CaMKII, resulting in an increased risk of left ventricular hypertrophy and cardiovascular disease in adult life. Copyright © 2015 the American Physiological Society.

  10. Effect of siRNA silencing of inducible co-stimulatory molecule on myocardial cell hypertrophy after cardiac infarction in rats.

    Science.gov (United States)

    Wang, W M; Liu, Z; Chen, G

    2016-05-20

    As the most common cardiac disease, myocardial infarction is followed by hypertrophy of cardiac myocytes and reconstruction of ventricular structure. The up-regulation of a series of factors including metalloproteinases, inflammatory factors, and growth factors after primary infarction lead to the hypertrophy, apoptosis, necrosis, and fibroblast proliferation in cardiac muscle tissues. Recent studies have reported on the potency of small interfering RNA (siRNA) in treating cardiac diseases. We thus investigated the efficacy of inducible co-stimulatory molecule (ICOS)-specific siRNA silencing in myocardial hypertrophy in a cardiac infarction rat model. This cardiac infarction model was prepared by ligating the left anterior descending coronary artery. ICOS-siRNA treatment was administered in parallel with non-sense siRNA. After 18 days, the cross-sectional area of cardiac muscle tissues and the left ventricle weight index were measured, along with ICOS mRNA and protein expression levels, and pathological staining. Compared to those in the control groups, in myocardial infarcted rats, the application of ICOS-siRNA effectively decreased the left ventricle weight index, as well as the surface area of cardiac myocytes. Both mRNA and protein levels of ICOS were also significantly decreased. HE staining was consistent with these results. In conclusion, ICOS-targeted siRNA can effectively silence gene expression of ICOS, and provided satisfactory treatment efficacy for myocardial cell hypertrophy after infarction.

  11. Comparison of echocardiographic and cardiac magnetic resonance imaging in hypertrophic cardiomyopathy sarcomere mutation carriers without left ventricular hypertrophy.

    Science.gov (United States)

    Valente, Anne Marie; Lakdawala, Neal K; Powell, Andrew J; Evans, Sarah P; Cirino, Allison L; Orav, E John; MacRae, Calum A; Colan, Steven D; Ho, Carolyn Y

    2013-06-01

    Left ventricular hypertrophy (LVH) typically manifests during or after adolescence in sarcomere mutation carriers at risk for developing hypertrophic cardiomyopathy. Guidelines recommend serial imaging of mutation carriers without LVH (G+/LVH-) to monitor for phenotypic evolution, but the optimal strategy is undefined. Compared with echocardiography (echo), cardiac MRI (CMR) offers improved endocardial visualization and potential to assess scar. However, the incremental advantage offered by CMR for early diagnosis of hypertrophic cardiomyopathy is unclear. Therefore, we systematically compared echo and CMR in G+/LVH- subjects. A total of 40 sarcomere mutation carriers with normal echo wall thickness (hypertrophic cardiomyopathy, including 1 with mild LVH by CMR at baseline. Echo is unlikely to miss substantial LVH; however, CMR identified mild hypertrophy in ≈10% of mutation carriers with normal echo wall thickness. CMR may be a useful adjunct in hypertrophic cardiomyopathy family screening, particularly in higher risk situations, or if echocardiographic images are suboptimal or suggest borderline LVH.

  12. Deficiency of cardiac Acyl-CoA synthetase-1 induces diastolic dysfunction, but pathologic hypertrophy is reversed by rapamycin

    DEFF Research Database (Denmark)

    Paul, David S; Grevengoed, Trisha J; Pascual, Florencia

    2014-01-01

    and increased phosphorylated S6 kinase (S6K), a substrate of the mechanistic target of rapamycin, mTOR. Doppler echocardiography revealed evidence of significant diastolic dysfunction, indicated by a reduced E/A ratio and increased mean performance index, although the deceleration time and the expression...... of sarco/endoplasmic reticulum calcium ATPase and phospholamban showed no difference between genotypes. To determine the role of mTOR in the development of cardiac hypertrophy, we treated Acsl1(H-/-) mice with rapamycin. Six to eight week old Acsl1(H-/-) mice and their littermate controls were given i...... and B-type natriuretic peptide. mTOR activation of the related Acsl3 gene, usually associated with pathologic hypertrophy, was also attenuated in the Acsl1(H-/-) hearts, indicating that alternative pathways of fatty acid activation did not compensate for the loss of Acsl1. Compared to controls, Acsl1(H...

  13. Selenium downregulates oxidative stress-induced activation of leukotriene pathway in experimental rats with diabetic cardiac hypertrophy.

    Science.gov (United States)

    Dhanya, B L; Swathy, R P; Indira, M

    2014-10-01

    Cardiac hypertrophy has been considered as an important risk factor of morbidity and mortality. It is characterized as thickening of ventricle wall of the heart and consequent reduction in the contracting ability of the heart to pump the blood. Hyperglycemia-induced reactive oxygen species act as major mediators of diabetic complications. Inflammation plays an essential role in the development of diabetic cardiac hypertrophy. Selenium has been shown to induce insulin-like and anti-inflammatory effects in human and experimental animals. But, its mechanism of action has not been elucidated. Hence, in order to probe into its mechanism at molecular level, we designed an experiment to study the effect of selenium as sodium selenite in streptozotocin-induced diabetic rats. The rats were divided into four groups and maintained as follows: (1) controls, (2) sodium selenite-treated controls, (3) diabetic, and (4) sodium selenite-treated diabetic rats. Duration of the experiment was 30 days. Selenium supplementation enhanced the streptozotocin-induced reduction in the activities of antioxidant enzymes, decreased the serum glucose level, glycated hemoglobin content, concentration of high-sensitivity C-reactive protein, levels of lipid peroxidation products, as well as inflammatory parameters. Decrease in the phospholipase activity by selenium supplementation also contributed to the downregulation of leukotriene pathway. It also downregulated the expressions of nuclear transcription factor κB (NFκB), lipoxygenase, cyclooxygenase, 5-lipoxygenase-activating protein, and receptor for leukotriene B4. Hence, selenium decreased the production of reactive oxygen species and inhibited the activation of NFκB-mediated transcription of pro-inflammatory mediators which resulted in the downregulation of leukotriene pathway in diabetic cardiac hypertrophy.

  14. Effects of kimchi supplementation on blood pressure and cardiac hypertrophy with varying sodium content in spontaneously hypertensive rats.

    Science.gov (United States)

    Lee, Seung-Min; Cho, Yoonsu; Chung, Hye-Kyung; Shin, Dong-Hyuk; Ha, Woel-Kyu; Lee, Sang-Chul; Shin, Min-Jeong

    2012-08-01

    We tested the effects of dietary intake of freeze-dried Korean traditional fermented cabbage (generally known as kimchi) with varying amounts of sodium on blood pressure and cardiac hypertrophy in spontaneously hypertensive rats (SHRs). Wistar-Kyoto rats (WKY), as a control group, received a regular AIN-76 diet, and the SHRs were divided into four groups. The SHR group was fed a regular diet without kimchi supplementation, the SHR-L group was fed the regular diet supplemented with low sodium kimchi containing 1.4% salt by wet weight, which was provided in a freeze-dried form, the SHR-M group was supplemented with medium levels of sodium kimchi containing 2.4% salt, and the SHR-H group was supplemented with high sodium kimchi containing 3.0% salt. Blood pressure was measured over 6 weeks, and cardiac hypertrophy was examined by measuring heart and left ventricle weights and cardiac histology. SHRs showed higher blood pressure compared to that in WKY rats, which was further elevated by consuming high sodium containing kimchi but was not influenced by supplementing with low sodium kimchi. None of the SHR groups showed significant differences in cardiac and left ventricular mass or cardiomyocyte size. Levels of serum biochemical parameters, including blood urea nitrogen, creatinine, glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, sodium, and potassium were not different among the groups. Elevations in serum levels of aldosterone in SHR rats decreased in the low sodium kimchi group. These results suggest that consuming low sodium kimchi may not adversely affect blood pressure and cardiac function even under a hypertensive condition.

  15. Daily sesame oil supplementation attenuates local renin-angiotensin system via inhibiting MAPK activation and oxidative stress in cardiac hypertrophy.

    Science.gov (United States)

    Liu, Chuan-Teng; Liu, Ming-Yie

    2017-04-01

    The renin-angiotensin system (RAS) is involved in the development of left ventricular hypertrophy (LVH) by which increases cardiac morbidity and mortality. Activation of mitogen-activated protein kinases (MAPKs) and oxidative stress are important in RAS-mediated cardiac hypertrophy. Sesame oil, a potent antioxidant, attenuates hypertension-dependent LVH. We examined the protective role of sesame oil on RAS-mediated MAPK activation and oxidative stress in rats. We induced LVH using a hypertensive model by subcutaneously injecting deoxycorticosterone acetate (DOCA; 15 mg/ml/kg in mineral oil; twice weekly for 5 weeks) and supplementing with 1% sodium chloride drinking water (DOCA/salt) to uninephrectomized rats. Sesame oil was gavaged (0.5 or 1 ml/kg/day for 7 days) after 4 weeks of DOCA/salt treatment. Cardiac histopathology, RAS parameters, expression of MAPKs, reactive oxygen species and lipid peroxidation were assessed 24 h after the last dose of sesame oil. Sesame oil significantly decreased the size of cardiomyocytes and the levels of cardiac renin, angiotensin-converting enzyme and angiotensin II. In addition, sesame oil down-regulated the expression of angiotensin type 1 receptor, JNK and p38 MAPK and apoptosis signal regulating kinase 1, c-Fos and c-Jun in rats receiving DOCA/salt. Furthermore, the induction of nicotinamide adenine dinucleotide phosphate oxidase, superoxide anion and hydroxyl radical and lipid peroxidation by DOCA/salt were inhibited by sesame oil. Sesame oil modulates cardiac RAS to ameliorate LVH by inhibiting MAPK activation and lowering oxidative stress. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Vigabatrin Therapy for Infantile Spasms in a Case of Cardiofaciocutaneous Syndrome with Cardiac Hypertrophy Developing during Adrenocorticotropic Hormone Treatment.

    Science.gov (United States)

    Hatori, Takayuki; Sugiyama, Yohei; Yamashita, Shinichiro; Hirakubo, Yuka; Nonaka, Kazuhito; Ichihashi, Ko

    2016-01-01

    In a patient with cardiofaciocutaneous syndrome complicated by intractable infantile spasms (West syndrome), cardiac hypertrophy developed during adrenocorticotropic hormone treatment. Various types of antiepileptic drugs, intravenous immunoglobulin, thyrotropin releasing hormone, and a ketogenic diet were ineffective in this case. However, vigabatrin both decreased clinical seizures and improved electroencephalogram findings. Although vigabatrin has not been approved for use in Japan, the results in the present case suggest that this drug should be considered as an alternative therapy for cases of infantile spasms associated with syndromes involving cardiomyopathy or its potential risk factors, such as cardiofaciocutaneous syndrome.

  17. Metabolic Modulation by Medium-Chain Triglycerides Reduces Oxidative Stress and Ameliorates CD36-Mediated Cardiac Remodeling in Spontaneously Hypertensive Rat in the Initial and Established Stages of Hypertrophy.

    Science.gov (United States)

    Saifudeen, Ismael; Subhadra, Lakshmi; Konnottil, Remani; Nair, R Renuka

    2017-03-01

    Left ventricular hypertrophy (LVH) is characterized by a decrease in oxidation of long-chain fatty acids, possibly mediated by reduced expression of the cell-surface protein cluster of differentiation 36 (CD36). Spontaneously hypertensive rats (SHRs) were therefore supplemented with medium-chain triglycerides (MCT), a substrate that bypasses CD36, based on the assumption that the metabolic modulation will ameliorate ventricular remodeling. The diet of 2-month-old and 6-month-old SHRs was supplemented with 5% MCT (Tricaprylin), for 4 months. Metabolic modulation was assessed by mRNA expression of peroxisome proliferator-activated receptor α and medium-chain acyl-CoA dehydrogenase. Blood pressure was measured noninvasively. LVH was assessed with the use of hypertrophy index, cardiomyocyte cross-sectional area, mRNA expression of B-type natriuretic peptide, cardiac fibrosis, and calcineurin-A levels. Oxidative stress indicators (cardiac malondialdehyde, protein carbonyl, and 3-nitrotyrosine levels), myocardial energy level (ATP, phosphocreatine), and lipid profile were determined. Supplementation of MCT stimulated fatty acid oxidation in animals of both age groups, reduced hypertrophy and oxidative stress along with the maintenance of energy level. Blood pressure, body weight, and lipid profile were unaffected by the treatment. The results indicate that modulation of myocardial fatty acid metabolism by MCT prevents progressive cardiac remodeling in SHRs, possibly by maintenance of energy level and decrease in oxidative stress. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Ouabain Attenuates Cardiac Hypertrophy of Male Rat Offspring Exposed to Intrauterine Growth Restriction Following High-Salt Diet Challenge.

    Science.gov (United States)

    Chen, Liang; Yue, Jing; Wu, Han; Yang, Jun; Han, Xiaojuan; Li, Juan; Hu, Yali

    2015-12-01

    Ouabain can normalize the blood pressure of the adult intrauterine growth restriction (IUGR) offspring through retaining the number of glomeruli of the IUGR newborn. However, the melioration of hemodynamic features coinciding with the improvement in cardiac structure and function is poorly understood. Intrauterine growth restriction was induced in pregnant rats with protein intake restriction, and ouabain was administrated using osmotic mini pumps from the second gestational day. The male offspring of the mothers with normal diet, low-protein diet, and low-protein diet added with ouabain treatment were randomly divided into 2 groups, one of which received normal diet and the other was treated with isocaloric 8% high-salt diet. We found that maternal malnutrition caused fetal growth retardation. At the end of a 40-week research, the offspring of the IUGR group presented high blood pressure and deteriorative cardiac performance and even worse in the offspring fed with 8% high-salt diet. Ouabain can normalize the blood pressure and improve the cardiac performance, even if following 8% high-salt diet challenge. Pathological and molecular analyses showed IUGR following 8% high-salt diet significantly increased the cardiac hypertrophy, whereas the unfavorable effects were ameliorated in the offspring treated with ouabain. Results suggest that the effects of ouabain on restoration of glomerular number in newborn and normalization of blood pressure during adulthood in IUGR male offspring can benefit the cardiac structure and function, especially under high-salt diet challenge. © The Author(s) 2015.

  19. Cold stress accentuates pressure overload-induced cardiac hypertrophy and contractile dysfunction: role of TRPV1/AMPK-mediated autophagy.

    Science.gov (United States)

    Lu, Songhe; Xu, Dezhong

    2013-12-06

    Severe cold exposure and pressure overload are both known to prompt oxidative stress and pathological alterations in the heart although the interplay between the two remains elusive. Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel activated in response to a variety of exogenous and endogenous physical and chemical stimuli including heat and capsaicin. The aim of this study was to examine the impact of cold exposure on pressure overload-induced cardiac pathological changes and the mechanism involved. Adult male C57 mice were subjected to abdominal aortic constriction (AAC) prior to exposure to cold temperature (4 °C) for 4 weeks. Cardiac geometry and function, levels of TRPV1, mitochondrial, and autophagy-associated proteins including AMPK, mTOR, LC3B, and P62 were evaluated. Sustained cold stress triggered cardiac hypertrophy, compromised depressed myocardial contractile capacity including lessened fractional shortening, peak shortening, and maximal velocity of shortening/relengthening, enhanced ROS production, and mitochondrial injury, the effects of which were negated by the TRPV1 antagonist SB366791. Western blot analysis revealed upregulated TRPV1 level and AMPK phosphorylation, enhanced ratio of LC3II/LC3I, and downregulated P62 following cold exposure. Cold exposure significantly augmented AAC-induced changes in TRPV1, phosphorylation of AMPK, LC3 isoform switch, and p62, the effects of which were negated by SB366791. In summary, these data suggest that cold exposure accentuates pressure overload-induced cardiac hypertrophy and contractile defect possibly through a TRPV1 and autophagy-dependent mechanism. Copyright © 2013. Published by Elsevier Inc.

  20. Genome-Wide Gene Expression Analysis Shows AKAP13-Mediated PKD1 Signaling Regulates the Transcriptional Response to Cardiac Hypertrophy.

    Directory of Open Access Journals (Sweden)

    Keven R Johnson

    Full Text Available In the heart, scaffolding proteins such as A-Kinase Anchoring Proteins (AKAPs play a crucial role in normal cellular function by serving as a signaling hub for multiple protein kinases including protein kinase D1 (PKD1. Under cardiac hypertrophic conditions AKAP13 anchored PKD1 activates the transcription factor MEF2 leading to subsequent fetal gene activation and hypertrophic response. We used an expression microarray to identify the global transcriptional response in the hearts of wild-type mice expressing the native form of AKAP13 compared to a gene-trap mouse model expressing a truncated form of AKAP13 that is unable to bind PKD1 (AKAP13-ΔPKD1. Microarray analysis showed that AKAP13-ΔPKD1 mice broadly failed to exhibit the transcriptional profile normally associated with compensatory cardiac hypertrophy following trans-aortic constriction (TAC. The identified differentially expressed genes in WT and AKAP13-ΔPKD1 hearts are vital for the compensatory hypertrophic response to pressure-overload and include myofilament, apoptotic, and cell growth/differentiation genes in addition to genes not previously identified as affected by AKAP13-anchored PKD1. Our results show that AKAP13-PKD1 signaling is critical for transcriptional regulation of key contractile, cell death, and metabolic pathways during the development of compensatory hypertrophy in vivo.

  1. Vagus nerve stimulation mitigates intrinsic cardiac neuronal remodeling and cardiac hypertrophy induced by chronic pressure overload in guinea pig

    Science.gov (United States)

    Beaumont, Eric; Wright, Gary L.; Southerland, Elizabeth M.; Li, Ying; Chui, Ray; KenKnight, Bruce H.; Armour, J. Andrew

    2016-01-01

    Our objective was to determine whether chronic vagus nerve stimulation (VNS) mitigates pressure overload (PO)-induced remodeling of the cardioneural interface. Guinea pigs (n = 48) were randomized to right or left cervical vagus (RCV or LCV) implant. After 2 wk, chronic left ventricular PO was induced by partial (15–20%) aortic constriction. Of the 31 animals surviving PO induction, 10 were randomized to RCV VNS, 9 to LCV VNS, and 12 to sham VNS. VNS was delivered at 20 Hz and 1.14 ± 0.03 mA at a 22% duty cycle. VNS commenced 10 days after PO induction and was maintained for 40 days. Time-matched controls (n = 9) were evaluated concurrently. Echocardiograms were obtained before and 50 days after PO. At termination, intracellular current-clamp recordings of intrinsic cardiac (IC) neurons were studied in vitro to determine effects of therapy on soma characteristics. Ventricular cardiomyocyte sizes were assessed with histology along with immunoblot analysis of selected proteins in myocardial tissue extracts. In sham-treated animals, PO increased cardiac output (34%, P < 0.004), as well as systolic (114%, P < 0.04) and diastolic (49%, P < 0.002) left ventricular volumes, a hemodynamic response prevented by VNS. PO-induced enhancements of IC synaptic efficacy and muscarinic sensitivity of IC neurons were mitigated by chronic VNS. Increased myocyte size, which doubled in PO (P < 0.05), was mitigated by RCV. PO hypertrophic myocardium displayed decreased glycogen synthase (GS) protein levels and accumulation of the phosphorylated (inactive) form of GS. These PO-induced changes in GS were moderated by left VNS. Chronic VNS targets IC neurons accompanying PO to obtund associated adverse cardiomyocyte remodeling. PMID:26993230

  2. Inhibition of angiotensin II-induced cardiac hypertrophy and associated ventricular arrhythmias by a p21 activated kinase 1 bioactive peptide.

    Science.gov (United States)

    Wang, Rui; Wang, Yanwen; Lin, Wee K; Zhang, Yanmin; Liu, Wei; Huang, Kai; Terrar, Derek A; Solaro, R John; Wang, Xin; Ke, Yunbo; Lei, Ming

    2014-01-01

    Cardiac hypertrophy increases the risk of morbidity and mortality of cardiovascular disease and thus inhibiting such hypertrophy is beneficial. In the present study, we explored the effect of a bioactive peptide (PAP) on angiotensin II (Ang II)-induced hypertrophy and associated ventricular arrhythmias in in vitro and in vivo models. PAP enhances p21 activated kinase 1 (Pak1) activity by increasing the level of phosphorylated Pak1 in cultured neonatal rat ventricular myocytes (NRVMs). Such PAP-induced Pak1 activation is associated with a significant reduction of Ang II-induced hypertrophy in NRVMs and C57BL/6 mice, in vitro and in vivo, respectively. Furthermore, PAP antagonizes ventricular arrhythmias associated with Ang II-induced hypertrophy in mice. Its antiarrhythmic effect is likely to be involved in multiple mechanisms to affect both substrate and trigger of ventricular arrhythmogenesis. Thus our results suggest that Pak1 activation achieved by specific bioactive peptide represents a potential novel therapeutic strategy for cardiac hypertrophy and associated ventricular arrhythmias.

  3. Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction

    NARCIS (Netherlands)

    Sharma, Umesh C.; Pokharel, Saraswati; van Brakel, Thomas J.; van Berlo, Jop H.; Cleutjens, Jack P. M.; Schroen, Blanche; André, Sabine; Crijns, Harry J. G. M.; Gabius, Hans-J.; Maessen, Jos; Pinto, Yigal M.

    2004-01-01

    BACKGROUND: Inflammatory mechanisms have been proposed to be important in heart failure (HF), and cytokines have been implicated to add to the progression of HF. However, it is unclear whether such mechanisms are already activated when hypertrophied hearts still appear well-compensated and whether

  4. Caveolae-specific activation loop between CaMKII and L-type Ca2+channel aggravates cardiac hypertrophy in α1-adrenergic stimulation.

    Science.gov (United States)

    Tonegawa, Kota; Otsuka, Wataru; Kumagai, Shohei; Matsunami, Sachi; Hayamizu, Nao; Tanaka, Shota; Moriwaki, Kazumasa; Obana, Masanori; Maeda, Makiko; Asahi, Michio; Kiyonari, Hiroshi; Fujio, Yasushi; Nakayama, Hiroyuki

    2017-03-01

    Activation of CaMKII induces a myriad of biological processes and plays dominant roles in cardiac hypertrophy. Caveolar microdomain contains many calcium/calmodulin-dependent kinase II (CaMKII) targets, including L-type Ca 2+ channel (LTCC) complex, and serves as a signaling platform. The location of CaMKII activation is thought to be critical; however, the roles of CaMKII in caveolae are still elusive due to lack of methodology for the assessment of caveolae-specific activation. Our aim was to develop a novel tool for the specific analysis of CaMKII activation in caveolae and to determine the functional role of caveolar CaMKII in cardiac hypertrophy. To assess the caveolae-specific activation of CaMKII, we generated a fusion protein composed of phospholamban and caveolin-3 (cPLN-Cav3) and GFP fusion protein with caveolin-binding domain fused to CaMKII inhibitory peptide (CBD-GFP-AIP), which inhibits CaMKII activation specifically in caveolae. Caveolae-specific activation of CaMKII was detected using phosphospecific antibody for PLN (Thr 17 ). Furthermore, adenoviral overexpression of LTCC β 2a -subunit (β 2a ) in NRCMs showed its constitutive phosphorylation by CaMKII, which induces hypertrophy, and that both phosphorylation and hypertrophy are abolished by CBD-GFP-AIP expression, indicating that β 2a phosphorylation occurs specifically in caveolae. Finally, β 2a phosphorylation was observed after phenylephrine stimulation in β 2a -overexpressing mice, and attenuation of cardiac hypertrophy after chronic phenylephrine stimulation was observed in nonphosphorylated mutant of β 2a -overexpressing mice. We developed novel tools for the evaluation and inhibition of caveolae-specific activation of CaMKII. We demonstrated that phosphorylated β 2a dominantly localizes to caveolae and induces cardiac hypertrophy after α 1 -adrenergic stimulation in mice. NEW & NOTEWORTHY While signaling in caveolae is thought to be important in cardiac hypertrophy, direct evidence

  5. Impact of alcohol intake on the relationships of uric acid with blood pressure and cardiac hypertrophy in essential hypertension.

    Science.gov (United States)

    Seki, Shingo; Oki, Yoshitsugu; Tsunoda, Seiko; Takemoto, Tomoyuki; Koyama, Tatsuya; Yoshimura, Michihiro

    2016-11-01

    Hyperuricemia, which is frequently associated with hypertension, can be caused by alcohol intake. To date, limited data have shown the link between alcohol intake and hyperuricemic hypertension. We retrospectively examined the influence of alcohol intake on the relationship between the uric acid level and blood pressure or cardio-metabolic parameters in 171 untreated non-failing hypertensive patients (mean 59.3±10.7 years). Cross-sectional analysis was separately performed in regular alcohol drinkers (more than 25g/day ethanol, n=74, 82.4% men) and non-drinkers (n=97, 33.0% men). Diastolic blood pressure was significantly higher in drinkers than in non-drinkers (101.6±11.5mmHg vs. 96.8±8.2mmHg, puric acid level (mean 6.3±1.7mg/dL) was positively correlated with both systolic and diastolic blood pressures (r=0.270/p=0.020 and r=0.354/p=0.0020, respectively), and with the markers of cardiac hypertrophy, including electrocardiographic voltage (V 1 S+V 5 R, r=0.244/p=0.042) and echocardiographic left ventricular mass index (r=0.270/p=0.026). These correlations were also observed in the male drinker sub-group. In the non-drinkers, the uric acid level (mean 5.0±1.4mg/dL) was positively correlated with BMI (r=0.369/p=0.0002) but not with blood pressure or the markers of cardiac hypertrophy. The results suggest that the role of uric acid in blood pressure might differ between hypertensive drinkers and non-drinkers. In regular alcohol drinkers, there was a positive association of uric acid level with blood pressure and the severity of cardiac hypertrophy. In non-regular drinkers, an increased uric acid level is likely to be closely associated with increased BMI. Copyright © 2016. Published by Elsevier Ltd.

  6. Exposure to low dose benzo[a]pyrene during early life stages causes symptoms similar to cardiac hypertrophy in adult zebrafish.

    Science.gov (United States)

    Huang, Lixing; Gao, Dongxu; Zhang, Youyu; Wang, Chonggang; Zuo, Zhenghong

    2014-07-15

    Growing evidence indicates that polycyclic aromatic hydrocarbons (PAHs) can lead to cardiac hypertrophy and recent research indicates that exposure to low dose crude oil during early embryonic development may lead to impacts on heart health at later life stages. The aim of this study was to evaluate whether exposure during early life stages to low dose benzo[a]pyrene (BaP), as a high-ring PAH, would lead to cardiac hypertrophy at later life stages. Zebrafish were exposed to low dose BaP until 96 hpf, then transferred to clean water and maintained for a year before histological and molecular biological analysis. Our results showed that exposure to low level BaP during early life stages increased heart weight to body weight ratios and deposited collagen in the heart of adult zebrafish. ANP, BNP and c-Myc were also induced in the heart of adult zebrafish by BaP. These results proved that low level BaP exposure during early life stages caused symptoms similar to cardiac hypertrophy in adult zebrafish. Our results displayed an elevated expression of CdC42, RhoA, p-ERK1, 2 and Rac1. Therefore, the mechanism of the cardiac hypertrophy caused by BaP exposure during early life stages may be through inducing the expression of CdC42, RhoA and Rac1, together with activating ERK1, 2. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Astragaloside IV Prevents Cardiac Remodeling in the Apolipoprotein E-Deficient Mice by Regulating Cardiac Homeostasis and Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Xiong-Zhi Li

    2017-12-01

    Full Text Available Background: Hypercholesterolemia is a risk factor for the development of cardiac hypertrophy. Astragaloside IV (AST-IV possesses cardiovascular protective properties. We hypothesize that AST-IV prevents cardiac remodeling with hypercholesterolemia via modulating tissue homeostasis and alleviating oxidative stress. Methods: The ApoE-/- mice were treated with AST-IV at 1 or 10 mg/kg for 8 weeks. The blood lipids tests, echocardiography, and TUNEL were performed. The mRNA expression profile was detected by real-time PCR. The myocytes size and number, and the expressions of proliferation (ki67, senescence (p16INK4a, oxidant (NADPH oxidase 4, NOX4 and antioxidant (superoxide dismutase, SOD were observed by immunofluorescence staining. Results: Neither 1 mg/kg nor 10 mg/kg AST-IV treatment could decrease blood lipids in ApoE-/- mice. However, the decreased left ventricular ejection fraction (LVEF and fractional shortening (FS in ApoE–/– mice were significantly improved after AST-IV treatment. The cardiac collagen volume fraction declined nearly in half after AST-IV treatment. The enlarged myocyte size was suppressed, and myocyte number was recovered, and the alterations of genes expressions linked to cell cycle, proliferation, senescence, p53-apoptosis pathway and oxidant-antioxidants in the hearts of ApoE-/- mice were reversed after AST-IV treatment. The decreased ki67 and increased p16INK4a in the hearts of ApoE-/- mice were recovered after AST-IV treatment. The percentages of apoptotic myocytes and NOX4-positive cells in AST-IV treated mice were decreased, which were consistent with the gene expressions. Conclusion: AST-IV treatment could prevent cardiac remodeling and recover the impaired ventricular function induced by hypercholesterolemia. The beneficial effect of AST-IV might partly be through regulating cardiac homeostasis and anti-oxidative stress.

  8. Cardiac remodelling: concentric versus eccentric hypertrophy in strength and endurance athletes

    OpenAIRE

    Mihl, C.; Dassen, W.R.M.; Kuipers, H.

    2008-01-01

    Cardiac remodelling is commonly defined as a physiological or pathological state that may occur after conditions such as myocardial infarction, pressure overload, idiopathic dilated cardiomyopathy or volume overload. When training excessively, the heart develops several myocardial adaptations causing a physiological state of cardiac remodelling. These morphological changes depend on the kind of training and are clinically characterised by modifications in cardiac size and shape due to increas...

  9. Tanshinone IIA Prevents Leu27IGF-II-Induced Cardiomyocyte Hypertrophy Mediated by Estrogen Receptor and Subsequent Akt Activation.

    Science.gov (United States)

    Weng, Yueh-Shan; Wang, Hsueh-Fang; Pai, Pei-Ying; Jong, Gwo-Ping; Lai, Chao-Hung; Chung, Li-Chin; Hsieh, Dennis Jine-Yuan; HsuanDay, Cecilia; Kuo, Wei-Wen; Huang, Chih-Yang

    2015-01-01

    IGF-IIR plays important roles as a key regulator in myocardial pathological hypertrophy and apoptosis, which subsequently lead to heart failure. Salvia miltiorrhiza Bunge (Danshen) is a traditional Chinese medicinal herb used to treat cardiovascular diseases. Tanshinone IIA is an active compound in Danshen and is structurally similar to 17[Formula: see text]-estradiol (E[Formula: see text]. However, whether tanshinone IIA improves cardiomyocyte survival in pathological hypertrophy through estrogen receptor (ER) regulation remains unclear. This study investigates the role of ER signaling in mediating the protective effects of tanshinone IIA on IGF-IIR-induced myocardial hypertrophy. Leu27IGF-II (IGF-II analog) was shown in this study to specifically activate IGF-IIR expression and ICI 182,780 (ICI), an ER antagonist used to investigate tanshinone IIA estrogenic activity. We demonstrated that tanshinone IIA significantly enhanced Akt phosphorylation through ER activation to inhibit Leu27IGF-II-induced calcineurin expression and subsequent NFATc3 nuclear translocation to suppress myocardial hypertrophy. Tanshinone IIA reduced the cell size and suppressed ANP and BNP, inhibiting antihypertrophic effects induced by Leu27IGF-II. The cardioprotective properties of tanshinone IIA that inhibit Leu27IGF-II-induced cell hypertrophy and promote cell survival were reversed by ICI. Furthermore, ICI significantly reduced phospho-Akt, Ly294002 (PI3K inhibitor), and PI3K siRNA significantly reduced the tanshinone IIA-induced protective effect. The above results suggest that tanshinone IIA inhibited cardiomyocyte hypertrophy, which was mediated through ER, by activating the PI3K/Akt pathway and inhibiting Leu27IGF-II-induced calcineurin and NFATC3. Tanshinone IIA exerted strong estrogenic activity and therefore represented a novel selective ER modulator that inhibits IGF-IIR signaling to block cardiac hypertrophy.

  10. Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function

    Czech Academy of Sciences Publication Activity Database

    McDermott-Roe, Ch.; Ye, J.; Ahmed, R.; Sun, X. M.; Serafín, A.; Ware, J.; Bottolo, L.; Muckett, P.; Caňas, X.; Zhang, J.; Rowe, G. C.; Buchan, R.; Lu, H.; Braithwaite, A.; Mancini, M.; Hauton, D.; Martí, R.; García-Arumí, E.; Hubner, N.; Jacob, H.; Serikawa, T.; Zídek, Václav; Papoušek, František; Kolář, František; Cardona, M.; Ruiz-Meana, M.; García-Dorado, D.; Comella, J. X.; Felkin, L. E.; Barton, P. J. R.; Arany, Z.; Pravenec, Michal; Petretto, E.; Sanchis, D.; Cook, S.A.

    2011-01-01

    Roč. 478, č. 7367 (2011), s. 114-118 ISSN 0028-0836 R&D Projects: GA MŠk(CZ) 1M0520; GA ČR(CZ) GA301/08/0166 Institutional research plan: CEZ:AV0Z50110509 Keywords : left ventricular hypertrophy * endonuclease G * mitochondrial dysfunction Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 36.280, year: 2011

  11. AKAP13 Rho-GEF and PKD-binding domain deficient mice develop normally but have an abnormal response to β-adrenergic-induced cardiac hypertrophy.

    Directory of Open Access Journals (Sweden)

    Matthew J Spindler

    Full Text Available A-kinase anchoring proteins (AKAPs are scaffolding molecules that coordinate and integrate G-protein signaling events to regulate development, physiology, and disease. One family member, AKAP13, encodes for multiple protein isoforms that contain binding sites for protein kinase A (PKA and D (PKD and an active Rho-guanine nucleotide exchange factor (Rho-GEF domain. In mice, AKAP13 is required for development as null embryos die by embryonic day 10.5 with cardiovascular phenotypes. Additionally, the AKAP13 Rho-GEF and PKD-binding domains mediate cardiomyocyte hypertrophy in cell culture. However, the requirements for the Rho-GEF and PKD-binding domains during development and cardiac hypertrophy are unknown.To determine if these AKAP13 protein domains are required for development, we used gene-trap events to create mutant mice that lacked the Rho-GEF and/or the protein kinase D-binding domains. Surprisingly, heterozygous matings produced mutant mice at Mendelian ratios that had normal viability and fertility. The adult mutant mice also had normal cardiac structure and electrocardiograms. To determine the role of these domains during β-adrenergic-induced cardiac hypertrophy, we stressed the mice with isoproterenol. We found that heart size was increased similarly in mice lacking the Rho-GEF and PKD-binding domains and wild-type controls. However, the mutant hearts had abnormal cardiac contractility as measured by fractional shortening and ejection fraction.These results indicate that the Rho-GEF and PKD-binding domains of AKAP13 are not required for mouse development, normal cardiac architecture, or β-adrenergic-induced cardiac hypertrophic remodeling. However, these domains regulate aspects of β-adrenergic-induced cardiac hypertrophy.

  12. The role of cytochrome P450 1B1 and its associated mid-chain hydroxyeicosatetraenoic acid metabolites in the development of cardiac hypertrophy induced by isoproterenol.

    Science.gov (United States)

    Maayah, Zaid H; Althurwi, Hassan N; El-Sherbeni, Ahmed A; Abdelhamid, Ghada; Siraki, Arno G; El-Kadi, Ayman O S

    2017-05-01

    Numerous experimental studies have demonstrated the role of cytochrome P450 1B1 (CYP1B1) and its associated mid-chain hydroxyeicosatetraenoic acids (mid-chain HETEs) metabolite in the pathogenesis of cardiac hypertrophy. However, the ability of isoproterenol (ISO) to induce cardiac hypertrophy through mid-chain HETEs has not been investigated yet. Therefore, we hypothesized that ISO induces cardiac hypertrophy through the induction of CYP1B1 and its associated mid-chain HETE metabolites. To test our hypothesis, Sprague-Dawley rats were treated with ISO (5 mg/kg i.p.) for 12 and 72 h whereas, human ventricular cardiomyocytes RL-14 cells were exposed to 100 μM ISO in the presence and absence of 0.5 μM tetramethoxystilbene (TMS) a selective CYP1B1 inhibitor, or 25 nM CYP1B1-siRNA. Moreover, RL-14 cells were transiently transfected with the CRISPR-CYP1B1 plasmid. Thereafter, real-time PCR, western blot analysis, and liquid chromatography-electrospray ionization mass spectroscopy were used to determine the level of gene expression, protein expression, and mid-chain HETEs, respectively. Our results showed that ISO induced CYP1B1 protein expression and the level of cardiac mid-chain HETEs in vivo at pre-hypertrophic and hypertrophic stage. In vitro, inhibition of CYP1B1 using TMS or CYP1B1-siRNA significantly attenuates ISO-induced hypertrophy. Furthermore, overexpression of CYP1B1 significantly induced cellular hypertrophy and mid-chain HETEs metabolite. Mechanistically, the protective effect of TMS against cardiac hypertrophy was mediated through the modulation of superoxide anion, mitogen-activated protein kinases (MAPKs), and nuclear factor-κB (NF-κB). In conclusion, our study provides the first evidence that CYP1B1 and its associated mid-chain HETE metabolites are directly involved in the ISO-induced cardiac hypertrophy.

  13. Usefulness of diastolic phase index by gated cardiac blood pool imaging in patients with left ventricular hypertrophy

    Energy Technology Data Exchange (ETDEWEB)

    Narita, Michihiro; Kurihara, Tadashi; Murano, Kenichi; Usami, Masahisa; Honda, Minoru

    1983-09-01

    To assess the left ventricular (LV) diastolic filling rate in patients with LV hypertrophy, we analyzed LV time activity curves obtained from gated cardiac blood pool imaging. Gated cardiac blood pool imaging with Tc-99m were obtained at rest in 20 normal subjects, 20 patients with hypertrophic cardiomyopathy (HCM) and 10 patients with hypertensive hypertrophy (HT). As systolic indices we obtained LV ejection fraction (EF) and mean first third ejection rate (1/3 ER/sub mean/). And as diastolic indices, mean filling rate during the first third of diastole (1/3 FR/sub mean/) and maximal filling rate during the whole diastole (FRmax) were calculated. LVEF and 1/3 ER/sub mean/ in patients with HT were not different significantly from normal, but those in patients with HCM were significantly greater than normal, besides 1/3 ER/sub mean/ in patients with HCM was greater than that in HT. Among diastolic phase indices, FRmax was not different significantly between 3 groups, but 1/3 FR/sub mean/ in HCM (1.47 +- 0.30 sec/sup 1/) and HT (1.34 +- 0.38 sec/sup 1/) was significantly lower than normal (2.10 +- 0.27 sec/sup 1/). Abnormal 1/3 FR/sub mean/ (<1.56 sec/sup 1/) was found in 65% of HCM and 80% of HT. Besides, in patients with HCM, 10 patients who had exertional dyspnea and anginal chest pain (NYHA Class II or III) showed significantly lower 1/3 FR/sub mean/ values than 10 patients without symptoms (1.25 +- 0.15 sec/sup 1/ vs 1.70 +- 0.25 sec/sup 1/. 1/3 FR/sub mean/ did not correlated well with LV wall thickness (summation of septal and posterior wall thickness) which was measured by ecohocardiography. But the ratio of 1/3 FR/sub mean/ to 1/3 ER/sub mean/ correlated well (r=-0.77 wall thickness in patients with LV hypertrophy. (J.P.N.).

  14. Global Transcriptomic Profiling of Cardiac Hypertrophy and Fatty Heart Induced by Long-Term High-Energy Diet in Bama Miniature Pigs.

    Directory of Open Access Journals (Sweden)

    Jihan Xia

    Full Text Available A long-term high-energy diet affects human health and leads to obesity and metabolic syndrome in addition to cardiac steatosis and hypertrophy. Ectopic fat accumulation in the heart has been demonstrated to be a risk factor for heart disorders, but the molecular mechanism of heart disease remains largely unknown. Bama miniature pigs were fed a high-fat, high-sucrose diet (HFHSD for 23 months. These pigs developed symptoms of metabolic syndrome and showed cardiac steatosis and hypertrophy with a greatly increased body weight (2.73-fold, P<0.01, insulin level (4.60-fold, P<0.01, heart weight (1.82-fold, P<0.05 and heart volume (1.60-fold, P<0.05 compared with the control pigs. To understand the molecular mechanisms of cardiac steatosis and hypertrophy, nine pig heart cRNA samples were hybridized to porcine GeneChips. Microarray analyses revealed that 1,022 genes were significantly differentially expressed (P<0.05, ≥1.5-fold change, including 591 up-regulated and 431 down-regulated genes in the HFHSD group relative to the control group. KEGG analysis indicated that the observed heart disorder involved the signal transduction-related MAPK, cytokine, and PPAR signaling pathways, energy metabolism-related fatty acid and oxidative phosphorylation signaling pathways, heart function signaling-related focal adhesion, axon guidance, hypertrophic cardiomyopathy and actin cytoskeleton signaling pathways, inflammation and apoptosis pathways, and others. Quantitative RT-PCR assays identified several important differentially expressed heart-related genes, including STAT3, ACSL4, ATF4, FADD, PPP3CA, CD74, SLA-8, VCL, ACTN2 and FGFR1, which may be targets of further research. This study shows that a long-term, high-energy diet induces obesity, cardiac steatosis, and hypertrophy and provides insights into the molecular mechanisms of hypertrophy and fatty heart to facilitate further research.

  15. Cell contact as an independent factor modulating cardiac myocyte hypertrophy and survival in long-term primary culture

    Science.gov (United States)

    Clark, W. A.; Decker, M. L.; Behnke-Barclay, M.; Janes, D. M.; Decker, R. S.

    1998-01-01

    Cardiac myocytes maintained in cell culture develop hypertrophy both in response to mechanical loading as well as to receptor-mediated signaling mechanisms. However, it has been shown that the hypertrophic response to these stimuli may be modulated through effects of intercellular contact achieved by maintaining cells at different plating densities. In this study, we show that the myocyte plating density affects not only the hypertrophic response and features of the differentiated phenotype of isolated adult myocytes, but also plays a significant role influencing myocyte survival in vitro. The native rod-shaped phenotype of freshly isolated adult myocytes persists in an environment which minimizes myocyte attachment and spreading on the substratum. However, these conditions are not optimal for long-term maintenance of cultured adult cardiac myocytes. Conditions which promote myocyte attachment and spreading on the substratum, on the other hand, also promote the re-establishment of new intercellular contacts between myocytes. These contacts appear to play a significant role in the development of spontaneous activity, which enhances the redevelopment of highly differentiated contractile, junctional, and sarcoplasmic reticulum structures in the cultured adult cardiomyocyte. Although it has previously been shown that adult cardiac myocytes are typically quiescent in culture, the addition of beta-adrenergic agonists stimulates beating and myocyte hypertrophy, and thereby serves to increase the level of intercellular contact as well. However, in densely-plated cultures with intrinsically high levels of intercellular contact, spontaneous contractile activity develops without the addition of beta-adrenergic agonists. In this study, we compare the function, morphology, and natural history of adult feline cardiomyocytes which have been maintained in cultures with different levels of intercellular contact, with and without the addition of beta-adrenergic agonists

  16. Pterostilbene reduces oxidative stress, prevents hypertrophy and preserves systolic function of right ventricle in cor pulmonale model.

    Science.gov (United States)

    Dos Santos Lacerda, Denise; Türck, Patrick; Gazzi de Lima-Seolin, Bruna; Colombo, Rafael; Duarte Ortiz, Vanessa; Poletto Bonetto, Jéssica Hellen; Campos-Carraro, Cristina; Bianchi, Sara Elis; Belló-Klein, Adriane; Linck Bassani, Valquiria; Sander da Rosa Araujo, Alex

    2017-10-01

    In cor pulmonale, the increased afterload imposed on the right ventricle (RV) generates a maladaptive response, impairing the contractile cardiac function. Oxidative mechanisms play an important role in the pathophysiology and progression of this disease. The administration of pterostilbene (PTS), a phytophenol with antioxidant potential, may represent a therapeutic option. In the present study, we evaluated the effect of PTS complexed with hydroxypropyl-β-cyclodextrin (HPβCD) on hypertrophy, contractile function and oxidative parameters in the RV of rats with pulmonary hypertension, induced by the administration of monocrotaline (MCT). The rats received daily doses of the PTS : HPβCD complex at 25, 50 or 100 mg·kg -1 , p.o., for 14 days. The diastolic function, E/A ratio, and systolic function, shortening fraction, fractional area change (FAC) and tricuspid annular plane systolic excursion (TAPSE) of the RV were determined by echocardiography. The PTS : HPβCD complex reduced the production of NADPH oxidase-dependent superoxide anions and oxidative stress in the RV of MCT-treated rats in a dose-dependent manner. At higher doses it prevented the reduction in FAC and TAPSE in MCT-treated animals. The PTS : HPβCD complex prevented the maladaptative remodelling and protected systolic function in the RV of rats with pulmonary hypertension. These cardioprotective mechanisms may be related, in part, to the antioxidant potential of PTS, favoured by the increased p.o. bioavailability promoted by the presence of HPβCD in the complex. © 2017 The British Pharmacological Society.

  17. Strategies for the prevention of sudden cardiac death during sports.

    Science.gov (United States)

    Corrado, Domenico; Drezner, Jonathan; Basso, Cristina; Pelliccia, Antonio; Thiene, Gaetano

    2011-04-01

    Sudden cardiac death of a young athlete is the most tragic event in sports and devastates the family, the sports medicine team, and the local community. Such a fatality represents the first manifestation of cardiac disease in up to 80% of young athletes who remain asymptomatic before sudden cardiac arrest occurs; this explains the limited power of screening modalities based solely on history and physical examination. The long-running Italian experience showed that electrocardiogram (ECG) screening definitively improves the sensitivity of pre-participation evaluation for heart diseases and substantially reduces the risk of death in the athletic field (primary prevention). However, some cardiac conditions, such as coronary artery diseases, present no abnormalities on 12-lead ECG. Moreover, cardiac arrest due to non-penetrating chest injury (commotio cordis) cannot be prevented by screening. This justifies the efforts for implementing programmes of early external defibrillation of unpredictable arrhythmic cardiac arrest. This article reviews the epidemiology of sudden cardiac arrest in the athlete in terms of incidence, sport-related risk, underlying causes, and the currently available prevention programmes such as pre-participation screening and early external defibrillation by using automated external defibrillators. The best strategy is to combine synergistically primary prevention of sudden cardiac death by pre-participation identification of athletes affected by at-risk cardiomyopathies and secondary prevention with back-up defibrillation of unpredictable sudden cardiac arrest on the athletic field.

  18. Overexpression of miR-223 Tips the Balance of Pro- and Anti-hypertrophic Signaling Cascades toward Physiologic Cardiac Hypertrophy*

    Science.gov (United States)

    Yang, Liwang; Li, Yutian; Wang, Xiaohong; Mu, Xingjiang; Qin, Dongze; Huang, Wei; Alshahrani, Saeed; Nieman, Michelle; Peng, Jiangtong; Essandoh, Kobina; Peng, Tianqing; Wang, Yigang; Lorenz, John; Soleimani, Manoocher; Zhao, Zhi-Qing; Fan, Guo-Chang

    2016-01-01

    MicroRNAs (miRNAs) have been extensively examined in pathological cardiac hypertrophy. However, few studies focused on profiling the miRNA alterations in physiological hypertrophic hearts. In this study we generated a transgenic mouse model with cardiac-specific overexpression of miR-223. Our results showed that elevation of miR-223 caused physiological cardiac hypertrophy with enhanced cardiac function but no fibrosis. Using the next generation RNA sequencing, we observed that most of dys-regulated genes (e.g. Atf3/5, Egr1/3, Sfrp2, Itgb1, Ndrg4, Akip1, Postn, Rxfp1, and Egln3) in miR-223-transgenic hearts were associated with cell growth, but they were not directly targeted by miR-223. Interestingly, these dys-regulated genes are known to regulate the Akt signaling pathway. We further identified that miR-223 directly interacted with 3′-UTRs of FBXW7 and Acvr2a, two negative regulators of the Akt signaling. However, we also validated that miR-223 directly inhibited the expression of IGF-1R and β1-integrin, two positive regulators of the Akt signaling. Lastly, Western blotting did reveal that Akt was activated in miR-223-overexpressing hearts. Adenovirus-mediated overexpression of miR-223 in neonatal rat cardiomyocytes induced cell hypertrophy, which was blocked by the addition of MK2206, a specific inhibitor of Akt. Taken together, these data represent the first piece of work showing that miR-223 tips the balance of promotion and inactivation of Akt signaling cascades toward activation of Akt, a key regulator of physiological cardiac hypertrophy. Thus, our study suggests that the ultimate phenotype outcome of a miRNA may be decided by the secondary net effects of the whole target network rather than by several primary direct targets in an organ/tissue. PMID:27226563

  19. MuRF1 mono-ubiquitinates TRα to inhibit T3-induced cardiac hypertrophy in vivo.

    Science.gov (United States)

    Wadosky, Kristine M; Berthiaume, Jessica M; Tang, Wei; Zungu, Makhosi; Portman, Michael A; Gerdes, A Martin; Willis, Monte S

    2016-04-01

    Thyroid hormone (TH) is recognized for its role in cellular metabolism and growth and participates in homeostasis of the heart. T3 activates pro-survival pathways including Akt and mTOR. Treatment with T3 after myocardial infarction is cardioprotective and promotes elements of physiological hypertrophic response after cardiac injury. Although T3 is known to benefit the heart, very little about its regulation at the molecular level has been described to date. The ubiquitin proteasome system (UPS) regulates nuclear hormone receptors such as estrogen, progesterone, androgen, and glucocorticoid receptors by both degradatory and non-degradatory mechanisms. However, how the UPS regulates T3-mediated activity is not well understood. In this study, we aim to determine the role of the muscle-specific ubiquitin ligase muscle ring finger-1 (MuRF1) in regulating T3-induced cardiomyocyte growth. An increase in MuRF1 expression inhibits T3-induced physiological cardiac hypertrophy, whereas a decrease in MuRF1 expression enhances T3's activity both in vitro and in cardiomyocytes in vivo MuRF1 interacts directly with TRα to inhibit its activity by posttranslational ubiquitination in a non-canonical manner. We then demonstrated that a nuclear localization apparatus that regulates/inhibits nuclear receptors by sequestering them within a subcompartment of the nucleus was necessary for MuRF1 to inhibit T3 activity. This work implicates a novel mechanism that enhances the beneficial T3 activity specifically within the heart, thereby offering a potential target to enhance cardiac T3 activity in an organ-specific manner. © 2016 Society for Endocrinology.

  20. Usefulness of Non-Anteroseptal Region Left Ventricular Hypertrophy Using Cardiac Magnetic Resonance to Predict Repeat Alcohol Septal Ablation for Refractory Obstructive Hypertrophic Cardiomyopathy.

    Science.gov (United States)

    Kitamura, Mitsunobu; Amano, Yasuo; Takayama, Morimasa; Shibuya, Junsuke; Matsuda, Junya; Sangen, Hideto; Nakamura, Shunichi; Takano, Hitoshi; Asai, Kuniya; Kumita, Shinichiro; Shimizu, Wataru

    2017-07-01

    We evaluated a cohort of patients treated with alcohol septal ablation (ASA) to identify predictive factors for repeat ASA. We compared 15 patients who underwent repeat ASA procedures (group R) with 69 patients not requiring repeat procedures (group S) in terms of clinical parameters and morphologic cardiac magnetic resonance. Group R showed higher number of hypertrophic segments (thickness ≥15 mm) in the basal left ventricular level (2.8 ± 1.7 vs 1.7 ± 0.8, p = 0.009) than group S. In the multivariate analysis, diuretics use (adjusted odds ratio 5.8, 95% confidential interval [CI] 1.04 to 32.2, p = 0.045) and the number of non-anteroseptal extended hypertrophy segments at the basal level were independent predictors of a repeat ASA procedure (adjusted odds ratio 3.64/segment, 95% CI 1.40 to 9.4, p = 0.008). One repeat ASA among 21 patients without non-anteroseptal hypertrophy and 1 repeat ASA among 29 patients without posteroseptal hypertrophy were observed; however, 7 of the 14 patients with ≥2 segments of non-anteroseptal hypertrophy received repeat ASA. In conclusion, cardiac magnetic resonance-based cross-sectional investigation elucidated non-anteroseptal hypertrophy (≥2 segments) to be a crucial predictor of repeat ASA. ASA is useful for patients with regional hypertrophy in the basal anteroseptal, but not posteroseptal region, and without heart failure requiring diuretics. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Cardiac myocyte follistatin-like 1 functions to attenuate hypertrophy following pressure overload

    NARCIS (Netherlands)

    Shimano, Masayuki; Ouchi, Noriyuki; Nakamura, Kazuto; van Wijk, Bram; Ohashi, Koji; Asaumi, Yasuhide; Higuchi, Akiko; Pimentel, David R.; Sam, Flora; Murohara, Toyoaki; van den Hoff, Maurice J. B.; Walsh, Kenneth

    2011-01-01

    Factors secreted by the heart, referred to as "cardiokines," have diverse actions in the maintenance of cardiac homeostasis and remodeling. Follistatin-like 1 (Fstl1) is a secreted glycoprotein expressed in the adult heart and is induced in response to injurious conditions that promote myocardial

  2. Cardiac remodelling: concentric versus eccentric hypertrophy in strength and endurance athletes.

    Science.gov (United States)

    Mihl, C; Dassen, W R M; Kuipers, H

    2008-04-01

    Cardiac remodelling is commonly defined as a physiological or pathological state that may occur after conditions such as myocardial infarction, pressure overload, idiopathic dilated cardiomyopathy or volume overload. When training excessively, the heart develops several myocardial adaptations causing a physiological state of cardiac remodelling. These morphological changes depend on the kind of training and are clinically characterised by modifications in cardiac size and shape due to increased load. Several studies have investigated morphological differences in the athlete's heart between athletes performing strength training and athletes performing endurance training. Endurance training is associated with an increased cardiac output and volume load on the left and right ventricles, causing the endurance-trained heart to generate a mild to moderate dilatation of the left ventricle combined with a mild to moderate increase in left ventricular wall thickness. Strength training is characterised by an elevation of both systolic and diastolic blood pressure. This pressure overload causes an increase in left ventricular wall thickness. This may or may not be accompanied by a slight raise in the left ventricular volume. However, the development of an endurancetrained heart and a strength-trained heart should not be considered an absolute concept. Both forms of training cause specific morphological changes in the heart, dependent on the type of sport. (Neth Heart J 2008;16:129-33.).

  3. Resveratrol prevents angiotensin II-induced hypertrophy of vascular smooth muscle cells through the transactivation of growth factor receptors.

    Science.gov (United States)

    Hossain, Ekhtear; Anand-Srivastava, Madhu B

    2017-08-01

    We previously showed that augmented levels of endogenous angiotensin II (AngII) contribute to vascular smooth muscle cell (VSMC) hypertrophy through the transactivation of growth factor receptors in spontaneously hypertensive rats. Resveratrol (RV), a polyphenolic component of red wine, has also been shown to attenuate AngII-evoked VSMC hypertrophy; however, the molecular mechanism mediating this response is obscure. The present study was therefore undertaken to examine whether RV could prevent AngII-induced VSMC hypertrophy through the transactivation of growth factor receptor and associated signaling pathways. AngII treatment of VSMC enhanced the protein synthesis that was attenuated towards control levels by RV pretreatment as well as by the inhibitors of NADPH oxidase, c-Src, and growth factor receptors. Furthermore, RV pretreatment also inhibited enhanced levels of superoxide anion, NADPH oxidase activity, increased expression of NADPH oxidase subunits, and phosphorylation of c-Src, EGF-R, PDGE-R, ERK1/2, and AKT1/2. In conclusion, these results indicate that RV attenuates AngII-induced VSMC hypertrophy through the inhibition of enhanced oxidative stress and activation of c-Src, growth factor receptors, and MAPK/AKT signaling. We suggest that RV could be used as a therapeutic agent in the treatment of vascular complications associated with hypertension and hypertrophy.

  4. Inhibition of FoxO transcriptional activity prevents muscle fiber atrophy during cachexia and induces hypertrophy

    Science.gov (United States)

    Reed, Sarah A.; Sandesara, Pooja B.; Senf, Sarah M.; Judge, Andrew R.

    2012-01-01

    Cachexia is characterized by inexorable muscle wasting that significantly affects patient prognosis and increases mortality. Therefore, understanding the molecular basis of this muscle wasting is of significant importance. Recent work showed that components of the forkhead box O (FoxO) pathway are increased in skeletal muscle during cachexia. In the current study, we tested the physiological significance of FoxO activation in the progression of muscle atrophy associated with cachexia. FoxO-DNA binding dependent transcription was blocked in the muscles of mice through injection of a dominant negative (DN) FoxO expression plasmid prior to inoculation with Lewis lung carcinoma cells or the induction of sepsis. Expression of DN FoxO inhibited the increased mRNA levels of atrogin-1, MuRF1, cathepsin L, and/or Bnip3 and inhibited muscle fiber atrophy during cancer cachexia and sepsis. Interestingly, during control conditions, expression of DN FoxO decreased myostatin expression, increased MyoD expression and satellite cell proliferation, and induced fiber hypertrophy, which required de novo protein synthesis. Collectively, these data show that FoxO-DNA binding-dependent transcription is necessary for normal muscle fiber atrophy during cancer cachexia and sepsis, and further suggest that basal levels of FoxO play an important role during normal conditions to depress satellite cell activation and limit muscle growth.—Reed, S. A., Sandesara, P. B., Senf, S. F., Judge, A. R. Inhibition of FoxO transcriptional activity prevents muscle fiber atrophy during cachexia and induces hypertrophy. PMID:22102632

  5. Ablation of plasma membrane Ca(2+)-ATPase isoform 4 prevents development of hypertrophy in a model of hypertrophic cardiomyopathy.

    Science.gov (United States)

    Prasad, Vikram; Lorenz, John N; Lasko, Valerie M; Nieman, Michelle L; Jiang, Min; Gao, Xu; Rubinstein, Jack; Wieczorek, David F; Shull, Gary E

    2014-12-01

    The mechanisms linking the expression of sarcomeric mutant proteins to the development of pathological hypertrophy in hypertrophic cardiomyopathy (HCM) remain poorly understood. We investigated the role of the plasma membrane Ca(2+)-ATPase PMCA4 in the HCM phenotype using a transgenic model that expresses mutant (Glu180Gly) α-tropomyosin (Tm180) in heart. Immunoblot analysis revealed that cardiac PMCA4 expression was upregulated early in Tm180 disease pathogenesis. This was accompanied by an increase in levels of the L-type Ca(2+)-channel, which is implicated in pathological hypertrophy. When Tm180 mice were crossed with a PMCA4-null line, loss of PMCA4 caused the abrogation of hypertrophy in Tm180/PMCA4-null double mutant mice. RT-PCR analysis of Tm180/PMCA4-null hearts revealed blunting of the fetal program and reversion of pro-fibrotic Col1a1 and Col3a1 gene expression to wild-type levels. This was accompanied by evidence of reduced L-type Ca(2+)-channel expression, and diminished calcineurin activity. Expression of the metabolic substrate transporters glucose transporter 4 and carnitine palmitoyltransferase 1b was preserved and Tm180-related changes in mRNA levels of various contractile stress-related proteins including the cardiac ankyrin protein CARP and the N2B isoform of titin were reversed in Tm180/PMCA4-null hearts. cGMP levels were increased and phosphorylation of vasodilator-stimulated phosphoprotein was elevated in Tm180/PMCA4-null hearts. These changes were associated with a sharp reduction in left ventricular end-diastolic pressure in Tm180/PMCA4-null hearts, which occurred despite persistence of Tm180-related impairment of relaxation dynamics. These results reveal a novel and specific role for PMCA4 in the Tm180 hypertrophic phenotype, with the "protective" effects of PMCA4 deficiency encompassing multiple determinants of HCM-related hypertrophy. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. The role of echocardiography in the evaluation of cardiac re-modelling and differentiation between physiological and pathological hypertrophy in teenagers engaged in competitive amateur sports.

    Science.gov (United States)

    Sulovic, Ljiljana S; Mahmutovic, Meho; Lazic, Snezana; Sulovic, Nenad

    2017-05-01

    Aims "Athlete's heart" is a cardiac adaptation to long-term intensive training. The aims of this study were to show the prevalence of left ventricular hypertrophy in teenagers who participate in sports, to define the different types of cardiac re-modelling, and to differentiate between physiological and pathological hypertrophy. Echocardiographic measurements were obtained by M-mode, two dimensional, and Doppler techniques of participants from sports and control groups. The echocardiographic examinations included 100 healthy teenagers taking part in dynamic sports such as football and basketball and 100 healthy teenagers taking part in static sports such as karate and judo. The control group (n=100) included healthy, sedentary teenagers. Sports participants had significantly higher left ventricular mass when compared with the control group, (p0.05). Respondents from both groups had E/A ratios (transmitral flow velocity ratio)>1, preserved diastolic function, and statistically they did not differ from the control group. Echocardiographic parameters show that physiological hypertrophy and cardiac re-modelling are present in teenagers who play sports. Unexpectedly, the prevalence of concentric and eccentric types of re-modelling is equally possible in the group of static sports participants.

  7. A Novel α-Calcitonin Gene-Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy and Heart Failure

    DEFF Research Database (Denmark)

    Aubdool, Aisah A; Thakore, Pratish; Argunhan, Fulye

    2017-01-01

    was investigated over 14 days. Blood pressure was measured by radio-telemetry. The ability of the αAnalogue to modulate heart failure was studied in an abdominal aortic constriction (AAC) model of murine cardiac hypertrophy and heart failure over 5 weeks. Extensive ex vivo analysis was performed via RNA analysis......, Western blot and histology. Results -The AngII-induced hypertension was attenuated by co-treatment with the αAnalogue (50nmol/kg/day, s.c., at a dose selected for lack of long term hypotensive effects at baseline). The αAnalogue protected against vascular, renal and cardiac dysfunction, characterised...

  8. Downregulation of miR-21 is involved in direct actions of ursolic acid on the heart: implications for cardiac fibrosis and hypertrophy.

    Science.gov (United States)

    Dong, Xingli; Liu, Shangkun; Zhang, Lingling; Yu, Siming; Huo, Linman; Qile, Muge; Liu, Lu; Yang, Baofeng; Yu, Jinling

    2015-08-01

    Myocardial fibrosis contributes to cardiac remodeling and loss of cardiac function in myocardial infarction and heart failure. This study used in vitro and in vivo models to examine the effects of ursolic acid (UA) on myocardial fibrosis and to explore its potential mechanism. Transverse aortic constriction (TAC) surgery was performed in mice to induce cardiac hypertrophy and fibrosis. UA was orally administered 1 week prior to TAC. Two weeks after TAC, myocardial pathology was detected using Masson's trichrome staining and transmission electron microscopy, and heart-to-body weight ratio was measured. For in vitro studies, cultured cardiac fibroblasts were treated with serum in the presence or absence of UA. The relative levels of miR-21 and p-ERK/ERK, collagen content and cell viability were measured. Ursolic acid attenuated pathological cardiac hypertrophy and myocardial fibrosis in vivo induced by TAC. Downregulation of miR-21 and p-ERK/ERK were observed in myocardial fibroblasts treated with UA in a dose-dependent manner compared with the control group both in vitro and in vivo. Our study demonstrates that UA can inhibit myocardial fibrosis both in vitro and in vivo, and the effects of UA on myocardial fibrosis may be due to the inhibition of miR-21/ERK signaling pathways. © 2015 John Wiley & Sons Ltd.

  9. Pathophysiology and meaning of washout rate in hypertrophic heart. Comparison between hypertensive cardiac hypertrophy and hypertrophic cardiomyopathy

    Energy Technology Data Exchange (ETDEWEB)

    Nitta, Yutaka (Kanazawa Univ. (Japan). School of Medicine)

    1989-02-01

    The present study was attempted to clarify clinically the pathogenesis of hypertensive cardiac hypertrophy (HT) and hypertrophic cardiomyopathy (HCM). The exercise thallium-201 (Tl-201) myocardial scintigraphy by bicycle ergometer was performed in three groups: control, HT and HCM. The scintigrams were evaluated by circumferential profile analysis. Furthermore, the change of Tl-201 dynamics of exercise Tl-201 scintigraphy with verapamil injection was compared with the change of coronary sinus flow after verapamil injection at cardiac catheterization. The analysis of exercise Tl-201 scintigraphy without verapamil injection showed that initial uptake was not different among the three groups, but washout rate at three hours after Tl-201 injection (WR{sub 3}) was different among the three groups. Although WR{sub 3} of HT was not different from that of control, WR{sub 3} of HCM was lower than that of control. Comparison of WR{sub 3} with and without verapamil was performed. Although WR{sub 3} with verapamil injection was equal to that without verapamil injection in control and HT, WR{sub 3} with verapamil injection decreased compared to that without verapamil injection in HCM. As an index at the time that circulation changes rapidly and on a large scale, washout rate at one hour after Tl-201 injection (WR{sub 1}) was calculated. WR{sub 1} without verapamil injection was not different in the three groups and did not differ from that with verapamil injection in each group. By intravenous administration of verapamil, coronary sinus flow (CSF) increased to the same extent in the three groups. And the increment of CSF was not different in the three groups. (J.P.N.).

  10. Transgenic knockdown of cardiac sodium/glucose cotransporter 1 (SGLT1) attenuates PRKAG2 cardiomyopathy, whereas transgenic overexpression of cardiac SGLT1 causes pathologic hypertrophy and dysfunction in mice.

    Science.gov (United States)

    Ramratnam, Mohun; Sharma, Ravi K; D'Auria, Stephen; Lee, So Jung; Wang, David; Huang, Xue Yin N; Ahmad, Ferhaan

    2014-08-04

    The expression of a novel cardiac glucose transporter, SGLT1, is increased in glycogen storage cardiomyopathy secondary to mutations in PRKAG2. We sought to determine the role of SGLT1 in the pathogenesis of PRKAG2 cardiomyopathy and its role in cardiac structure and function. Transgenic mice with cardiomyocyte-specific overexpression of human T400N mutant PRKAG2 cDNA (TG(T400N)) and transgenic mice with cardiomyocyte-specific RNA interference knockdown of SGLT1 (TG(SGLT1-DOWN)) were crossed to produce double-transgenic mice (TG(T400N)/TG(SGLT1-DOWN)). Tet-off transgenic mice conditionally overexpressing cardiac SGLT1 in the absence of doxycycline were also constructed (TG(SGLT-ON)). Relative to TG(T400N) mice, TG(T400N)/TG(SGLT1-DOWN) mice exhibited decreases in cardiac SGLT1 expression (63% decrease, Pmice had less left ventricular dilation at age 12 weeks compared to TG(T400N) mice. Relative to wildtype (WT) mice, TG(SGLT1-ON) mice exhibited increases in heart/body weight ratio, glycogen content, and markers of cardiac hypertrophy at ages 10 and 20 weeks. TG(SGLT1-ON) mice had increased myocyte size and interstitial fibrosis, and progressive left ventricular dysfunction. When SGLT1 was suppressed after 10 weeks of overexpression (TG(SGLT1-ON/OFF)), there was a reduction in cardiac hypertrophy and improvement in left ventricular failure. Cardiac knockdown of SGLT1 in a murine model of PRKAG2 cardiomyopathy attenuates the disease phenotype, implicating SGLT1 in the pathogenesis. Overexpression of SGLT1 causes pathologic cardiac hypertrophy and left ventricular failure that is reversible. This is the first report of cardiomyocyte-specific transgenic knockdown of a target gene. © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  11. Cardiac MRI assessed left ventricular hypertrophy in differentiating hypertensive heart disease from hypertrophic cardiomyopathy attributable to a sarcomeric gene mutation

    Energy Technology Data Exchange (ETDEWEB)

    Sipola, Petri [Kuopio University Hospital, Department of Clinical Radiology, Kuopio (Finland); University of Eastern Finland, Institute of Clinical Medicine, Faculty of Health Sciences, Kuopio (Finland); Magga, Jarkko; Peuhkurinen, Keijo [Kuopio University Hospital, Department of Medicine, Kuopio (Finland); Husso, Minna [Kuopio University Hospital, Department of Clinical Radiology, Kuopio (Finland); Jaeaeskelaeinen, Pertti; Kuusisto, Johanna [Kuopio University Hospital, Department of Medicine, Kuopio (Finland); Kuopio University Hospital, Heart Center, P.O. Box 1777, Kuopio (Finland)

    2011-07-15

    To evaluate the value of cardiac magnetic resonance imaging (CMRI)-assessed left ventricular hypertrophy (LVH) in differentiating between hypertensive heart disease and hypertrophic cardiomyopathy (HCM). 95 unselected subjects with mild-to-moderate hypertension, 24 patients with HCM attributable to the D175N mutation of the {alpha}-tropomyosin gene and 17 control subjects were studied by cine CMRI. Left ventricular (LV) quantitative and qualitative characteristics were evaluated. LV maximal end-diastolic wall thickness, wall thickness-to-LV volume ratio, end-diastolic septum thickness and septum-to-lateral wall thickness ratio were useful measures for differentiating between LVH due to hypertension and HCM. The most accurate measure for identifying patients with HCM was the LV maximal wall thickness {>=}17 mm, with a sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of 90%, 93%, 86%, 95% and 91%, respectively. LV maximal wall thickness in the anterior wall, or regional bulging in left ventricular wall was found only in patients with HCM. LV mass index was not discriminant between patients with HCM and those with LVH due to hypertension. LV maximal thickness measured by CMRI is the best anatomical parameter in differentiating between LVH due to mild-to-moderate hypertension and HCM attributable to a sarcomeric mutation. CMRI assessment of location and quality of LVH is also of value in differential diagnosis. (orig.)

  12. Genetically Modified Mouse Models Used for Studying the Role of the AT2 Receptor in Cardiac Hypertrophy and Heart Failure

    Directory of Open Access Journals (Sweden)

    Maria D. Avila

    2011-01-01

    Full Text Available The actions of Angiotensin II have been implicated in many cardiovascular conditions. It is widely accepted that the cardiovascular effects of Angiotensin II are mediated by different subtypes of receptors: AT1 and AT2. These membrane-bound receptors share a part of their nucleic acid but seem to have different distribution and pathophysiological actions. AT1 mediates most of the Angiotensin II actions since it is ubiquitously expressed in the cardiovascular system of the normal adult. Moreover AT2 is highly expressed in the developing fetus but its expression in the cardiovascular system is low and declines after birth. However the expression of AT2 appears to be modulated by pathological states such as hypertension, myocardial infarction or any pathology associated to tissue remodeling or inflammation. The specific role of this receptor is still unclear and different studies involving in vivo and in vitro experiments have shown conflicting data. It is essential to clarify the role of the AT2 receptor in the different pathological states as it is a potential site for an effective therapeutic regimen that targets the Angiotensin II system. We will review the different genetically modified mouse models used to study the AT2 receptor and its association with cardiac hypertrophy and heart failure.

  13. The Importance of Identifying Early Changes in Cardiac Structure and Function for the Prevention of Cognitive Impairment and Dementia.

    Science.gov (United States)

    Edwards, Jodi D

    2017-01-01

    Multiple cardiac pathologies have been shown to contribute to progressive cognitive decline and dementia in elderly populations, including left ventricular hypertrophy (LVH), a marker of prolonged exposure to hypertension. Although associations between chronic hypertension and cognitive function are thought to be mediated primarily by these end organ effects, there is increasing evidence that early changes in cardiac structure and function, such as LVH, may independently contribute to cognitive decline and impairment. In the current issue of the Journal of Alzheimer's Disease, Mahinrad and colleagues report important new findings on the association between LVH and cognitive function that are incremental to cardiovascular risk and co-morbidity, including hypertension. Emerging evidence that early changes in cardiac structure and function may independently contribute to cognitive decline in elderly populations has resulted in an increased interest in these preclinical substrates as potential treatment targets for the prevention of cognitive decline and in their putative contributions to the pathogenesis of dementia.

  14. Effects of taurine on myocardial cGMP/cAMP ratio, antioxidant ability, and ultrastructure in cardiac hypertrophy rats induced by isoproterenol.

    Science.gov (United States)

    Yang, Qunhui; Yang, Jiancheng; Wu, Gaofeng; Feng, Ying; Lv, Qiufeng; Lin, Shumei; Hu, Jianmin

    2013-01-01

    Taurine is the most abundant free amino acid in the human body and accounts for more than 50% of the total amino acid pool in the mammalian heart. To investigate the preventive effects of taurine on cardiac hypertrophy in rats, myocardial injury was established by hypodermic injection of isoprenaline (ISO) (10 mg/kg d) for 7 days. The preventive effects of taurine (100 mg/kg d, 200 mg/kg d, and 300 mg/kg d, i.p) on heart coefficient; ultrastructure of cardiac muscle; the levels of creatine kinase heart isoenzyme (CK-MB), cAMP, and cGMP; and antioxidant ability were investigated. The results showed that taurine could significantly prevent the increase of heart coefficient induced by ISO. Compared with the model group, 100 mg/kg and 200 mg/kg taurine significantly decrease the levels of cAMP and cGMP, while 300 mg/kg taurine could significantly decrease the levels of cAMP in myocardium, and all the three concentrations of taurine could significantly increase the ratio of cGMP/cAMP. The level of serum CK-MB was significantly increased by ISO; 200 mg/kg taurine could significantly decrease it, but 100 mg/kg and 300 mg/kg taurine had no significant effect. As for the antioxidant ability, ISO administration could significantly increase the myocardial level of MDA but had no significant effects on the myocardial levels of SOD, GSH, GSH-Px, and T-AOC. However, taurine administration could significantly decrease the myocardial level of MDA and increase the levels of GSH and T-AOC compared with the model group. The serum levels of SOD, GSH-Px, GSH, and T-AOC were significantly reduced by ISO administration, but the level of MDA showed no significant changes compared with the control group. Taurine administration could significantly increase the serum levels of SOD, GSH-Px, GSH, and T-AOC and decrease the level of MDA compared with the model group. All the results indicated that 200 mg/kg taurine had better effects. The ultrastructure of cardiomyocytes showed that taurine

  15. Inhibition of NF-κB activity in the hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by modulating cytokines and attenuating oxidative stress

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Xiao-Jing [Department of Physiology and Pathophysiology, Xi' an Jiaotong University School of Basic Medical Sciences, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China); Zhang, Dong-Mei [Department of Physiology, Dalian Medical University, Dalian 116044 (China); Jia, Lin-Lin; Qi, Jie; Song, Xin-Ai; Tan, Hong [Department of Physiology and Pathophysiology, Xi' an Jiaotong University School of Basic Medical Sciences, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China); Cui, Wei [Department of Endocrinology and Metabolism, First Affiliated Hospital of Xi' an Jiaotong University, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China); Chen, Wensheng [Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi' an 710032 (China); Zhu, Guo-Qing [Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029 (China); Qin, Da-Nian, E-mail: dnqin@stu.edu.cn [Department of Physiology, Shantou University Medical College, Shantou 515041 (China); Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn [Department of Physiology and Pathophysiology, Xi' an Jiaotong University School of Basic Medical Sciences, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China)

    2015-05-01

    We hypothesized that chronic inhibition of NF-κB activity in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), attenuating nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase in the PVN of young spontaneously hypertensive rats (SHR). Young normotensive Wistar–Kyoto (WKY) and SHR rats received bilateral PVN infusions with NF–κB inhibitor pyrrolidine dithiocarbamate (PDTC) or vehicle for 4 weeks. SHR rats had higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, cardiomyocyte diameters of the left cardiac ventricle, and mRNA expressions of cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC). These SHR rats had higher PVN levels of proinflammatory cytokines (PICs), reactive oxygen species (ROS), the chemokine monocyte chemoattractant protein-1 (MCP-1), NAD(P)H oxidase activity, mRNA expression of NOX-2 and NOX-4, and lower PVN IL-10, and higher plasma levels of PICs and NE, and lower plasma IL-10. PVN infusion of NF-κB inhibitor PDTC attenuated all these changes. These findings suggest that NF-κB activation in the PVN increases sympathoexcitation and hypertensive response, which are associated with the increases of PICs and oxidative stress in the PVN; PVN inhibition of NF-κB activity attenuates PICs and oxidative stress in the PVN, thereby attenuates hypertension and cardiac hypertrophy. - Highlights: • Spontaneously hypertensive rats exhibit neurohormonal excitation in the PVN. • PVN inhibition of NF-κB attenuates hypertension-induced cardiac hypertrophy. • PVN inhibition of NF-κB attenuates hypertension-induced neurohormonal excitation. • PVN inhibition of NF-κB attenuates hypertension-induced imbalance of cytokines

  16. Prediction and Prevention of Sudden Cardiac Death.

    Science.gov (United States)

    Morin, Daniel P; Homoud, Munther K; Estes, N A Mark

    2017-12-01

    Sudden death is a major problem, with significant impact on public health. Many conditions predispose to sudden cardiac death and sudden cardiac arrest (SCA), foremost among them coronary artery disease, and an effective therapy exists in the form of the implantable cardioverter defibrillator. Risk stratification for SCA remains imperfect, especially for patients with nonischemic cardiomyopathy. Ongoing trials may make it easier to identify those at high risk, and potentially those at very low risk, in the future. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Cardiac rehabilitation: an effective secondary prevention intervention.

    Science.gov (United States)

    Milligan, Fiona

    A combination of quantitative and qualitative research was used to determine the effectiveness of a cardiac rehabilitation (CR) programme in a cohort of patients referred to the service at a London hospital. Quantitative data analysis provided evidence of effectiveness of participation in CR in reduced hospital readmission rates and use of recognised pharmacological management strategies. Self-reported physical activity levels and quality of life (QOL) in individuals who participated in the cardiac rehabilitation programme were qualitatively measured with questionnaires. Results provided evidence of benefit in continued participation in exercise. However, there was no evidence of benefit to QOL status post participation at 1 year. A p-value of 0.001 provided significant statistical evidence supporting the hypothesis of benefit in continued participation in exercise in participants following attendance at a cardiac rehabilitation programme. QOL status; a statistically significant p-value of 0.001 rejected the hypothesis (H1) of benefit. This would imply that participation CR programmes does not appear to provide sustained benefits in QOL. A number of moderating variables were suggested as explaining the finding such as homogeneity of respondents, age, mood bias and the timeframe of 1 year between participation in rehabilitation and self-reporting. CR appears to be an effective but time-limited intervention in relation to improvements in QOL. Collaborative working partnerships between specialist interventions, such as CR with chronic disease management strategies may provide greater sustainability of benefits gained from participation in cardiac rehabilitation programmes.

  18. Pressure overload-induced mild cardiac hypertrophy reduces leftventricular transmural differences in mitochondrial respiratory chainactivity and increases oxidative stress

    Directory of Open Access Journals (Sweden)

    Michel eKINDO

    2012-08-01

    Full Text Available Objective: Increased mechanical stress and contractility characterizes normal left ventricular subendocardium (Endo but whether Endo mitochondrial respiratory chain complex activities is reduced as compared to subepicardium (Epi and whether pressure overload-induced left ventricular hypertrophy (LVH might modulate transmural gradients through increased reactive oxygen species (ROS production is unknown. Methods: LVH was induced by 6 weeks abdominal aortic banding and cardiac structure and function were determined with echocardiography and catheterization in sham-operated and LVH rats (n=10 for each group. Mitochondrial respiration rates, coupling, content and ROS production were measured in LV Endo and Epi, using saponin-permeabilised fibres, Amplex Red fluorescence and citrate synthase activity.Results: In sham, a transmural respiratory gradient was observed with decreases in endo maximal oxidative capacity (-36.7%, P<0.01 and complex IV activity (-57.4%, P<0.05. Mitochondrial hydrogen peroxide (H2O2 production was similar in both LV layers.Aortic banding induced mild LVH (+31.7% LV mass, associated with normal LV fractional shortening and end diastolic pressure. LVH reduced maximal oxidative capacity (-23.6 and -33.3%, increased mitochondrial H2O2 production (+86.9 and +73.1%, free radical leak (+27.2% and +36.3% and citrate synthase activity (+27.2% and +36.3% in Endo and Epi, respectively.Transmural mitochondrial respiratory chain complex IV activity was reduced in LVH (-57.4 vs –12.2%; P=0.02. Conclusions: Endo mitochondrial respiratory chain complexes activities are reduced compared to LV Epi. Mild LVH impairs mitochondrial oxidative capacity, increases oxidative stress and reduces transmural complex IV activity. Further studies will be helpful to determine whether reduced LV transmural gradient in mitochondrial respiration might be a new marker of a transition from uncomplicated toward complicated LVH.

  19. Left ventricular mass and hypertrophy by echocardiography and cardiac magnetic resonance: the multi-ethnic study of atherosclerosis.

    Science.gov (United States)

    Armstrong, Anderson C; Gjesdal, Ola; Almeida, André; Nacif, Marcelo; Wu, Colin; Bluemke, David A; Brumback, Lyndia; Lima, João A C

    2014-01-01

    Left ventricular mass (LVM) and hypertrophy (LVH) are important parameters, but their use is surrounded by controversies. We compare LVM by echocardiography and cardiac magnetic resonance (CMR), investigating reproducibility aspects and the effect of echocardiography image quality. We also compare indexing methods within and between imaging modalities for classification of LVH and cardiovascular risk. Multi-Ethnic Study of Atherosclerosis enrolled 880 participants in Baltimore city, 146 had echocardiograms and CMR on the same day. LVM was then assessed using standard techniques. Echocardiography image quality was rated (good/limited) according to the parasternal view. LVH was defined after indexing LVM to body surface area, height(1.7) , height(2.7) , or by the predicted LVM from a reference group. Participants were classified for cardiovascular risk according to Framingham score. Pearson's correlation, Bland-Altman plots, percent agreement, and kappa coefficient assessed agreement within and between modalities. Left ventricular mass by echocardiography (140 ± 40 g) and by CMR were correlated (r = 0.8, P echocardiography image quality. The reproducibility profile had strong correlations and agreement for both modalities. Image quality groups had similar characteristics; those with good images compared to CMR slightly superiorly. The prevalence of LVH tended to be higher with higher cardiovascular risk. The agreement for LVH between imaging modalities ranged from 77% to 98% and the kappa coefficient from 0.10 to 0.76. Echocardiography has a reliable performance for LVM assessment and classification of LVH, with limited influence of image quality. Echocardiography and CMR differ in the assessment of LVH, and additional differences rise from the indexing methods. © 2013. This article is a U.S. Government work and is in the public domain in the USA.

  20. Sitagliptin reduces cardiac apoptosis, hypertrophy and fibrosis primarily by insulin-dependent mechanisms in experimental type-II diabetes. Potential roles of GLP-1 isoforms.

    Directory of Open Access Journals (Sweden)

    Belén Picatoste

    Full Text Available BACKGROUND: Myocardial fibrosis is a key process in diabetic cardiomyopathy. However, their underlying mechanisms have not been elucidated, leading to a lack of therapy. The glucagon-like peptide-1 (GLP-1 enhancer, sitagliptin, reduces hyperglycemia but may also trigger direct effects on the heart. METHODS: Goto-Kakizaki (GK rats developed type-II diabetes and received sitagliptin, an anti-hyperglycemic drug (metformin or vehicle (n=10, each. After cardiac structure and function assessment, plasma and left ventricles were isolated for biochemical studies. Cultured cardiomyocytes and fibroblasts were used for in vitro assays. RESULTS: Untreated GK rats exhibited hyperglycemia, hyperlipidemia, plasma GLP-1 decrease, and cardiac cell-death, hypertrophy, fibrosis and prolonged deceleration time. Moreover, cardiac pro-apoptotic/necrotic, hypertrophic and fibrotic factors were up-regulated. Importantly, both sitagliptin and metformin lessened all these parameters. In cultured cardiomyocytes and cardiac fibroblasts, high-concentration of palmitate or glucose induced cell-death, hypertrophy and fibrosis. Interestingly, GLP-1 and its insulinotropic-inactive metabolite, GLP-1(9-36, alleviated these responses. In addition, despite a specific GLP-1 receptor was only detected in cardiomyocytes, GLP-1 isoforms attenuated the pro-fibrotic expression in cardiomyocytes and fibroblasts. In addition, GLP-1 receptor signalling may be linked to PPARδ activation, and metformin may also exhibit anti-apoptotic/necrotic and anti-fibrotic direct effects in cardiac cells. CONCLUSIONS: Sitagliptin, via GLP-1 stabilization, promoted cardioprotection in type-II diabetic hearts primarily by limiting hyperglycemia e hyperlipidemia. However, GLP-1 and GLP-1(9-36 promoted survival and anti-hypertrophic/fibrotic effects on cultured cardiac cells, suggesting cell-autonomous cardioprotective actions.

  1. Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Zhang, Dong-Mei [Department of Physiology, Dalian Medical University, Dalian 116044 (China); Yu, Xiao-Jing; Yang, Qing; Qi, Jie; Su, Qing [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Suo, Yu-Ping [Department of Obstetrics and Gynecology, Shanxi Provincial People' s Hospital, Taiyuan 030012 (China); Yue, Li-Ying [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Zhu, Guo-Qing [Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029 (China); Qin, Da-Nian, E-mail: dnqin@stu.edu.cn [Department of Physiology, Shantou University Medical College, Shantou 515041 (China)

    2014-02-01

    The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5 μg/h) or vehicle for 4 weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiac atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy. - Highlights: • Chronic ANG II infusion results in sympathetic hyperactivity and cardiac hypertrophy. • PVN inhibition of ACE

  2. Inhibition of TNF-α in hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by inhibiting neurohormonal excitation in spontaneously hypertensive rats

    Energy Technology Data Exchange (ETDEWEB)

    Song, Xin-Ai; Jia, Lin-Lin [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Cui, Wei [Department of Endocrinology and Metabolism, First Affiliated Hospital of Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Zhang, Meng [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Chen, Wensheng [Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi' an 710032 (China); Yuan, Zu-Yi [Department of Cardiovascular Medicine, First Affiliated Hospital of Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Guo, Jing [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Li, Hui-Hua [Key Laboratory of Remodeling-related Cardiovascular Diseases, Department of Pathology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069 (China); Zhu, Guo-Qing [Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029 (China); Liu, Hao, E-mail: haoliu75@163.com [Department of Neurosurgery, First Affiliated Hospital of Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China)

    2014-11-15

    We hypothesized that chronic inhibition of tumor necrosis factor-alpha (TNF-α) in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), decreasing nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase activities, as well as restoring the neurotransmitters balance in the PVN of spontaneously hypertensive rats (SHR). Adult normotensive Wistar–Kyoto (WKY) and SHR rats received bilateral PVN infusion of a TNF-α blocker (pentoxifylline or etanercept) or vehicle for 4 weeks. SHR rats showed higher mean arterial pressure and cardiac hypertrophy compared with WKY rats, as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC) mRNA expressions. Compared with WKY rats, SHR rats had higher PVN levels of tyrosine hydroxylase, PICs, the chemokine monocyte chemoattractant protein-1 (MCP-1), NF-κB p65 activity, mRNA expressions of NOX-2 and NOX-4, and lower PVN levels of IL-10 and 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma norepinephrine. PVN infusion of pentoxifylline or etanercept attenuated all these changes in SHR rats. These findings suggest that SHR rats have an imbalance between excitatory and inhibitory neurotransmitters, as well as an imbalance between pro- and anti-inflammatory cytokines in the PVN; and chronic inhibition of TNF-α in the PVN delays the progression of hypertension by restoring the balances of neurotransmitters and cytokines in the PVN, and attenuating PVN NF-κB p65 activity and oxidative stress, thereby attenuating hypertension-induced sympathetic hyperactivity and cardiac hypertrophy. - Highlights: • Spontaneously hypertensive rats exhibit neurohormonal excitation in the PVN. • PVN inhibition of

  3. Astragaloside IV protects against isoproterenol-induced cardiac hypertrophy by regulating NF-κB/PGC-1α signaling mediated energy biosynthesis.

    Directory of Open Access Journals (Sweden)

    Suping Zhang

    Full Text Available We previously reported that Astragaloside IV (ASIV, a major active constituent of Astragalus membranaceus (Fisch Bge protects against cardiac hypertrophy in rats induced by isoproterenol (Iso, however the mechanism underlying the protection remains unknown. Dysfunction of cardiac energy biosynthesis contributes to the hypertrophy and Nuclear Factor κB (NF-κB/Peroxisome Proliferator-Activated Receptor-γ Coactivator 1α (PGC-1α signaling gets involved in the dysfunction. The present study was designed to investigate the mechanism by which ASIV improves the cardiac hypertrophy with focuses on the NF-κB/PGC-1α signaling mediated energy biosynthesis. Sprague-Dawley (SD rats or Neonatal Rat Ventricular Myocytes (NRVMs were treated with Iso alone or in combination with ASIV. The results showed that combination with ASIV significantly attenuated the pathological changes, reduced the ratios of heart weight/body weight and Left ventricular weight/body weight, improved the cardiac hemodynamics, down-regulated mRNA expression of Atrial Natriuretic Peptide (ANP and Brain Natriuretic Peptide (BNP, increased the ratio of ATP/AMP, and decreased the content of Free Fat Acid (FFA in heart tissue of rats compared with Iso alone. In addition, pretreatment with ASIV significantly decreased the surface area and protein content, down-regulated mRNA expression of ANP and BNP, increased the ratio of ATP/AMP, and decreased the content of FFA in NRVMs compared with Iso alone. Furthermore, ASIV increased the protein expression of ATP5D, subunit of ATP synthase and PGC-1α, inhibited translocation of p65, subunit of NF-κB into nuclear fraction in both rats and NRVMs compared with Iso alone. Parthenolide (Par, the specific inhibitor of p65, exerted similar effects as ASIV in NRVMs. Knockdown of p65 with siRNA decreased the surface areas and increased PGC-1α expression of NRVMs compared with Iso alone. The results suggested that ASIV protects against Iso

  4. Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines

    International Nuclear Information System (INIS)

    Kang, Yu-Ming; Zhang, Dong-Mei; Yu, Xiao-Jing; Yang, Qing; Qi, Jie; Su, Qing; Suo, Yu-Ping; Yue, Li-Ying; Zhu, Guo-Qing; Qin, Da-Nian

    2014-01-01

    The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5 μg/h) or vehicle for 4 weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiac atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy. - Highlights: • Chronic ANG II infusion results in sympathetic hyperactivity and cardiac hypertrophy. • PVN inhibition of ACE

  5. Periodontitis and myocardial hypertrophy.

    Science.gov (United States)

    Suzuki, Jun-Ichi; Sato, Hiroki; Kaneko, Makoto; Yoshida, Asuka; Aoyama, Norio; Akimoto, Shouta; Wakayama, Kouji; Kumagai, Hidetoshi; Ikeda, Yuichi; Akazawa, Hiroshi; Izumi, Yuichi; Isobe, Mitsuaki; Komuro, Issei

    2017-04-01

    There is a deep relationship between cardiovascular disease and periodontitis. It has been reported that myocardial hypertrophy may be affected by periodontitis in clinical settings. Although these clinical observations had some study limitations, they strongly suggest a direct association between severity of periodontitis and left ventricular hypertrophy. However, the detailed mechanisms between myocardial hypertrophy and periodontitis have not yet been elucidated. Recently, we demonstrated that periodontal bacteria infection is closely related to myocardial hypertrophy. In murine transverse aortic constriction models, a periodontal pathogen, Aggregatibacter actinomycetemcomitans markedly enhanced cardiac hypertrophy with matrix metalloproteinase-2 activation, while another pathogen Porphyromonas gingivalis (P.g.) did not accelerate these pathological changes. In the isoproterenol-induced myocardial hypertrophy model, P.g. induced myocardial hypertrophy through Toll-like receptor-2 signaling. From our results and other reports, regulation of chronic inflammation induced by periodontitis may have a key role in the treatment of myocardial hypertrophy. In this article, we review the pathophysiological mechanism between myocardial hypertrophy and periodontitis.

  6. Melatonin prevents fibrosis but not hypertrophy development in the left ventricle of NG-nitro-L-arginine-methyl ester hypertensive rats

    Czech Academy of Sciences Publication Activity Database

    Paulis, L.; Pecháňová, Olga; Zicha, Josef; Krajčírovičová, K.; Barta, A.; Pelouch, V.; Adamcová, M.; Šimko, F.

    2009-01-01

    Roč. 27, Suppl.6 (2009), S11-S16 ISSN 0263-6352 R&D Projects: GA ČR(CZ) GA305/08/0139 Institutional research plan: CEZ:AV0Z50110509 Keywords : hypertension * cardiac hypertrophy * collagen Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 4.988, year: 2009

  7. Exercise-induced arterial hypertension - an independent factor for hypertrophy and a ticking clock for cardiac fatigue or atrial fibrillation in athletes? [v1; ref status: indexed, http://f1000r.es/3b4

    Directory of Open Access Journals (Sweden)

    Roman Leischik

    2014-05-01

    Full Text Available Background: Exercise-induced arterial hypertension (EIAH leads to myocardial hypertrophy and is associated with a poor prognosis. EIAH might be related to the “cardiac fatigue” caused by endurance training. The goal of this study was to examine whether there is any relationship between EIAH and left ventricular hypertrophy in Ironman-triathletes. Methods: We used echocardiography and spiroergometry to determine the left ventricular mass (LVM, the aerobic/anaerobic thresholds and the steady-state blood pressure of 51 healthy male triathletes. The main inclusion criterion was the participation in at least one middle or long distance triathlon. Results: When comparing triathletes with LVM 220g there was a significant difference between blood pressure values (BP at the anaerobic threshold (185.2± 21.5 mmHg vs. 198.8 ±22.3 mmHg, p=0.037. The spiroergometric results were: maximum oxygen uptake (relative VO2max 57.3 ±7.5ml/min/kg vs. 59.8±9.5ml/min/kg (p=ns. Cut-point analysis for the relationship of BP >170 mmHg at the aerobic threshold and the probability of LVM >220g showed a sensitivity of 95.8%, a specificity of 33.3%, with a positive predictive value of 56.8 %, a good negative predictive value of 90%. The probability of LVM >220g increased with higher BP during exercise (OR: 1.027, 95% CI 1.002-1.052, p= 0.034 or with higher training volume (OR: 1.23, 95% CI 1.04 -1.47, p = 0.019. Echocardiography showed predominantly concentric remodelling, followed by concentric hypertrophy. Conclusion: Significant left ventricular hypertrophy with LVM >220g is associated with higher arterial blood pressure at the aerobic or anaerobic threshold. The endurance athletes with EIAH may require a therapeutic intervention to at least prevent extensive stiffening of the heart muscle and exercise-induced cardiac fatigue.

  8. HSF1 and NF-κB p65 participate in the process of exercise preconditioning attenuating pressure overload-induced pathological cardiac hypertrophy

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Tongyi [Department of Cardiothoracic Surgery, No. 401 Hospital of PLA, Qingdao (China); Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai (China); Zhang, Ben [Centre of Cardiovascular Surgery, Guangzhou General Hospital of Guangzhou Military Region, Guangzhou (China); Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai (China); Yang, Fan; Cai, Chengliang; Wang, Guokun [Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai (China); Han, Qingqi, E-mail: handoctor@gmail.com [Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai (China); Zou, Liangjian, E-mail: zouliangjiansh@gmail.com [Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai (China)

    2015-05-08

    Pathological cardiac hypertrophy, often accompanied by hypertension, aortic stenosis and valvular defects, is typically associated with myocyte remodeling and cardiac dysfunction. Exercise preconditioning (EP) has been proven to enhance the tolerance of the myocardium to cardiac ischemia-reperfusion injury. However, the effects of EP in pathological cardiac hypertrophy are rarely reported. 10-wk-old male Sprague–Dawley rats (n = 80) were randomly divided into four groups: sham, TAC, EP + sham and EP + TAC. Two EP groups were subjected to 4 weeks of treadmill training, and the EP + TAC and TAC groups were followed by TAC operations. The sham and EP + sham groups underwent the same operation without aortic constriction. Eight weeks after the surgery, we evaluated the effects of EP by echocardiography, morphology, and histology and observed the expressions of the associated proteins. Compared with the respective control groups, hypertrophy-related indicators were significantly increased in the TAC and EP + TAC groups (p < 0.05). However, between the TAC and EP + TAC groups, all of these changes were effectively inhibited by EP treatment (p < 0.05). Furthermore, EP treatment upregulated the expression of HSF1 and HSP70, increased the HSF1 levels in the nuclear fraction, inhibited the expression of the NF-κB p65 subunit, decreased the NF-κB p65 subunit levels in the nuclear fraction, and reduced the IL2 levels in the myocardia of rats. EP could effectively reduce the cardiac hypertrophic responses induced by TAC and may play a protective role by upregulating the expressions of HSF1 and HSP70, activating HSF1 and then inhibiting the expression of NF-κB p65 and nuclear translocation. - Highlights: • EP could effectively reduce the cardiac hypertrophic responses induced by TAC. • EP may play a protective role by upregulating the expressions of HSF1 and HSP70 and then activating HSF1. • EP may play a protective role by inhibiting the expression

  9. Inhibition of platelet-derived growth factor signaling prevents muscle fiber growth during skeletal muscle hypertrophy.

    Science.gov (United States)

    Sugg, Kristoffer B; Korn, Michael A; Sarver, Dylan C; Markworth, James F; Mendias, Christopher L

    2017-03-01

    The platelet-derived growth factor receptors alpha and beta (PDGFRα and PDGFRβ) mark fibroadipogenic progenitor cells/fibroblasts and pericytes in skeletal muscle, respectively. While the role that these cells play in muscle growth and development has been evaluated, it was not known whether the PDGF receptors activate signaling pathways that control transcriptional and functional changes during skeletal muscle hypertrophy. To evaluate this, we inhibited PDGFR signaling in mice subjected to a synergist ablation muscle growth procedure, and performed analyses 3 and 10 days after induction of hypertrophy. The results from this study indicate that PDGF signaling is required for fiber hypertrophy, extracellular matrix production, and angiogenesis that occur during muscle growth. © 2017 Federation of European Biochemical Societies.

  10. Differential diagnosis of left ventricular hypertrophy: usefulness of multimodality imaging and tissue characterization with cardiac magnetic resonance.

    Science.gov (United States)

    Izgi, Cemil; Vassiliou, Vassilis; Baksi, A John; Prasad, Sanjay K

    2016-11-01

    Differential diagnosis of asymmetrical left ventricular hypertrophy may be challenging, particularly in patients with history of hypertension. A middle-aged man underwent an echocardiographic examination during workup for hypertension, which unexpectedly showed significant asymmetrical septal hypertrophy and raised suspicion for hypertrophic cardiomyopathy. Cardiovascular magnetic resonance confirmed the asymmetrical hypertrophy. No myocardial late gadolinium contrast enhancement was seen. However, precontrast T1 mapping revealed a low native myocardial T1 value. This was highly suggestive of Anderson-Fabry disease, which was subsequently proved with very low alpha galactosidase enzyme levels and mutation analysis. The case illustrates clinical usefulness of multimodality imaging and the novel tissue characterization techniques for assessment of left ventricular hypertrophy. © 2016, Wiley Periodicals, Inc.

  11. Garlic extracts prevent oxidative stress, hypertrophy and apoptosis in cardiomyocytes: a role for nitric oxide and hydrogen sulfide

    Science.gov (United States)

    2012-01-01

    Background In ancient times, plants were recognized for their medicinal properties. Later, the arrival of synthetic drugs pushed it to the backstage. However, from being merely used for food, plants are now been widely explored for their therapeutic value. The current study explores the potential of skin and flesh extracts from a hard-necked Rocambole variety of purple garlic in preventing cardiomyocyte hypertrophy and cell death. Methods Norepinephrine (NE) was used to induce hypertrophy in adult rat cardiomyocytes pretreated with garlic skin and flesh extracts. Cell death was measured as ratio of rod to round shaped cardiomyocytes. Fluorescent probes were used to measure apoptosis and oxidative stress in cardiomyocytes treated with and without extracts and NE. Pharmacological blockade of nitric oxide (NO) and hydrogen sulfide (H2S) were used to elucidate the mechanism of action of garlic extracts. Garlic extract samples were also tested for alliin and allicin concentrations. Results Exposure of cardiomyocytes to NE induced an increase in cell size and cell death; this increase was significantly prevented upon treatment with garlic skin and flesh extracts. Norepinephrine increased apoptosis and oxidative stress in cardiomyocytes which was prevented upon pretreatment with skin and flesh extracts; NO, and H2S blockers significantly inhibited this beneficial effect. Allicin and alliin concentration were significantly higher in garlic flesh extract when compared to the skin extract. Conclusion These results suggest that both skin and flesh garlic extracts are effective in preventing NE induced cardiomyocyte hypertrophy and cell death. Reduction in oxidative stress may also play an important role in the anti-hypertrophic and anti-apoptotic properties of garlic extracts. These beneficial effects may in part be mediated by NO and H2S. PMID:22931510

  12. Myocardial Rac1 exhibits partial involvement in thyroxin-induced cardiomyocyte hypertrophy and its inhibition is not sufficient to improve cardiac dysfunction or contractile abnormalities in mouse papillary muscles.

    Science.gov (United States)

    Elnakish, Mohammad T; Moldovan, Leni; Khan, Mahmood; Hassanain, Hamdy H; Janssen, Paul M L

    2013-06-01

    : Development of cardiac hypertrophy after thyroxin (T4) treatment is well recognized. Recently, we observed that T4-induced cardiac hypertrophy is associated with increased cardiac Rac1 expression and activity. Whether this Rac1 increase has a role in inducing this cardiac phenotype is, however, still unknown. Here, we showed that T4 treatment (500 µg/kg/d) for 2 weeks resulted in increased myocardial Rac1 activity with subsequent hypertension, cardiac hypertrophy, and left ventricular systolic dysfunction in vivo. Isolated right ventricular papillary muscles of T4-treated mice maintained their peak isometric active developed tension but exhibited significant decreases in their corresponding time to peak and in relaxation times. Positive inotropic responses to increasing pacing rate and β-adrenergic stimulation were also depressed in these muscles. Pravastatin (10 mg/kg/d), a Rac1 inhibitor, significantly decreased myocardial Rac1 activity, hypertension, and cardiomyocyte size in T4-treated mice but could not attenuate gross heart weight or functional cardiac changes in these mice. Our data showed that T4 could activate different signaling pathways with distinct cardiovascular outcomes. We also provide the first mechanistic evidence for the partial involvement of Rac1 activation in T4-induced cardiomyocyte hypertrophy and reveal a putative role for Rac1 in the development of T4-induced hypertension.

  13. Aerobic exercise protects against pressure overload-induced cardiac dysfunction and hypertrophy via β3-AR-nNOS-NO activation.

    Science.gov (United States)

    Wang, Bin; Xu, Ming; Li, Wenju; Li, Xiaoli; Zheng, Qiangsun; Niu, Xiaolin

    2017-01-01

    Aerobic exercise confers sustainable protection against cardiac hypertrophy and heart failure (HF). Nitric oxide synthase (NOS) and nitric oxide (NO) are known to play an important role in exercise-mediated cardioprotection, but the mechanism of NOS/NO stimulation during exercise remains unclear. The aim of this study is to determine the role of β3-adrenergic receptors (β3-ARs), NOS activation, and NO metabolites (nitrite and nitrosothiols) in the sustained cardioprotective effects of aerobic exercise. An HF model was constructed by transverse aortic constriction (TAC). Animals were treated with either moderate aerobic exercise by swimming for 9 weeks and/or the β3-AR-specific inhibitor SR59230A at 0.1 mg/kg/hour one day after TAC operation. Myocardial fibrosis, myocyte size, plasma catecholamine (CA) level, cardiac function and geometry were assessed using Masson's trichrome staining, FITC-labeled wheat germ agglutinin staining, enzyme-linked immuno sorbent assay (ELISA) and echocardiography, respectively. Western blot analysis was performed to elucidate the expression of target proteins. The concentration of myocardial NO production was evaluated using the nitrate reductase method. Myocardial oxidative stress was assessed by detecting the concentration of myocardial super oxidative dismutase (SOD), malonyldialdehyde (MDA), and reactive oxygen species (ROS). Aerobic exercise training improved dilated left ventricular function and partially attenuated the degree of cardiac hypertrophy and fibrosis in TAC mice. Moreover, the increased expression of β3-AR, activation of neuronal NOS (nNOS), and production of NO were detected after aerobic exercise training in TAC mice. However, selective inhibition of β3-AR by SR59230A abolished the upregulation and activation of nNOS induced NO production. Furthermore, aerobic exercise training decreased the myocardial ROS and MDA contents and increased myocardial levels of SOD; both effects were partially attenuated by SR59230

  14. Aerobic exercise protects against pressure overload-induced cardiac dysfunction and hypertrophy via β3-AR-nNOS-NO activation

    Science.gov (United States)

    Li, Wenju; Li, Xiaoli; Zheng, Qiangsun; Niu, Xiaolin

    2017-01-01

    Aerobic exercise confers sustainable protection against cardiac hypertrophy and heart failure (HF). Nitric oxide synthase (NOS) and nitric oxide (NO) are known to play an important role in exercise-mediated cardioprotection, but the mechanism of NOS/NO stimulation during exercise remains unclear. The aim of this study is to determine the role of β3-adrenergic receptors (β3-ARs), NOS activation, and NO metabolites (nitrite and nitrosothiols) in the sustained cardioprotective effects of aerobic exercise. An HF model was constructed by transverse aortic constriction (TAC). Animals were treated with either moderate aerobic exercise by swimming for 9 weeks and/or the β3-AR-specific inhibitor SR59230A at 0.1 mg/kg/hour one day after TAC operation. Myocardial fibrosis, myocyte size, plasma catecholamine (CA) level, cardiac function and geometry were assessed using Masson’s trichrome staining, FITC-labeled wheat germ agglutinin staining, enzyme-linked immuno sorbent assay (ELISA) and echocardiography, respectively. Western blot analysis was performed to elucidate the expression of target proteins. The concentration of myocardial NO production was evaluated using the nitrate reductase method. Myocardial oxidative stress was assessed by detecting the concentration of myocardial super oxidative dismutase (SOD), malonyldialdehyde (MDA), and reactive oxygen species (ROS). Aerobic exercise training improved dilated left ventricular function and partially attenuated the degree of cardiac hypertrophy and fibrosis in TAC mice. Moreover, the increased expression of β3-AR, activation of neuronal NOS (nNOS), and production of NO were detected after aerobic exercise training in TAC mice. However, selective inhibition of β3-AR by SR59230A abolished the upregulation and activation of nNOS induced NO production. Furthermore, aerobic exercise training decreased the myocardial ROS and MDA contents and increased myocardial levels of SOD; both effects were partially attenuated by SR

  15. Preventive role of Withania somnifera on hyperlipidemia and cardiac ...

    African Journals Online (AJOL)

    Original Research Article. Preventive role of Withania somnifera on hyperlipidemia and cardiac oxidative stress in streptozotocin induced type. 2 diabetic rats. Tarique .... reaction of thiobarbituric acid (TBA) with ... Table 1: Levels of blood glucose, lipid peroxidation (LPO) and reduced glutathione (GSH) contents in normal.

  16. QT corrected for heart rate and qtc dispersion in Gujarati type 2 diabetics predominantly using preventive pharmacotherapy and with very low electrocardiogram left ventricular hypertrophy

    Directory of Open Access Journals (Sweden)

    Jayesh Dalpatbhai Solanki

    2017-01-01

    Full Text Available Background: There is a rising trend in the incidence of type 2 diabetes mellitus, and hyperglycaemia is known to cause cardiac dysautonomia, which may lead to life-threatening arrhythmias. It can be screened by simple electrocardiogram (ECG-based QTc (QT corrected for heart rate and QTd (QTc dispersion indicating cardiac repolarisation abnormality. We studied QTc and QTd intervals in treated type 2 diabetics (T2D, testing the effect of age, gender, duration and control of disease. Materials and Methods: We conducted a cross-sectional study in a tertiary care teaching hospital of Gujarat, India, on 199 T2D (67 males and 132 females. Standard 12-lead ECG was recorded to derive QTc by Bazett's formula, QTd and ECG left ventricular hypertrophy (LVH. QTc> 0.43 s in male and> 0.45 s in female, QTd> 80 msec were considered abnormal. Results: T2D (mean age 56 years, duration 6 years, coexisting hypertension 69%, glycaemic control 32% and use of β-blockers 56% had QTc and QTd abnormality prevalence 15% and 20% respectively with ECG LVH prevailing in 3%. Male gender, poor glycaemic control and increased duration had negative impact on QT parameters with statistical significance only for first two and not for all results. Conclusion: Our study showed low-to-moderate prevalence of prolonged QTc and QTd, qualitatively more than quantitatively, in T2D with very low LVH and high prevalence of preventive pharmacotherapy, associated with male gender and glycaemic control. It underscores high risk of repolarisation abnormality, though moderate, that can be further primarily prevented by early screening and strict disease control.

  17. Regulation of cardiac remodeling by cardiac Na/K-ATPase isoforms

    Directory of Open Access Journals (Sweden)

    Lijun Catherine Liu

    2016-09-01

    Full Text Available Cardiac remodeling occurs after cardiac pressure/volume overload or myocardial injury during the development of heart failure and is a determinant of heart failure. Preventing or reversing remodeling is a goal of heart failure therapy. Human cardiomyocyte Na+/K+-ATPase has multiple α isoforms (1-3. The expression of the α subunit of the Na+/K+-ATPase is often altered in hypertrophic and failing hearts. The mechanisms are unclear. There are limited data from human cardiomyocytes. Abundant evidences from rodents show that Na+/K+-ATPase regulates cardiac contractility, cell signaling, hypertrophy and fibrosis. The α1 isoform of the Na+/K+-ATPase is the ubiquitous isoform and possesses both pumping and signaling functions. The α2 isoform of the Na+/K+-ATPase regulates intracellular Ca2+ signaling, contractility and pathological hypertrophy. The α3 isoform of the Na+/K+-ATPase may also be a target for cardiac hypertrophy. Restoration of cardiac Na+/K+-ATPase expression may be an effective approach for prevention of cardiac remodeling. In this article, we will overview: (1 the distribution and function of isoform specific Na+/K+-ATPase in the cardiomyocytes. (2 the role of cardiac Na+/K+-ATPase in the regulation of cell signaling, contractility, cardiac hypertrophy and fibrosis in vitro and in vivo. Selective targeting of cardiac Na+/K+-ATPase isoform may offer a new target for the prevention of cardiac remodeling.

  18. Left Ventricular Outflow Tract Obstruction in Hypertrophic Cardiomyopathy Patients Without Severe Septal Hypertrophy: Implications of Mitral Valve and Papillary Muscle Abnormalities Assessed Using Cardiac Magnetic Resonance and Echocardiography.

    Science.gov (United States)

    Patel, Parag; Dhillon, Ashwat; Popovic, Zoran B; Smedira, Nicholas G; Rizzo, Jessica; Thamilarasan, Maran; Agler, Deborah; Lytle, Bruce W; Lever, Harry M; Desai, Milind Y

    2015-07-01

    In patients with hypertrophic cardiomyopathy and left ventricular outflow tract (LVOT) obstruction, but without basal septal hypertrophy, we sought to identify mitral valve (MV) and papillary muscle (PM) abnormalities that predisposed to LVOT obstruction, using echo and cardiac magnetic resonance. We studied 121 patients with hypertrophic cardiomyopathy hypertrophic cardiomyopathy (age, 49±17 years; 60% men; 57% on β-blockers) with a basal septal thickness of ≤1.8 cm who underwent echocardiography (rest+stress) and cine cardiac magnetic resonance. Echo measurements included maximal LVOT gradient (rest/provocable), MV leaflet length (parasternal long, 4 and 3-chamber views), and abnormal chordal attachment to mid/base of anterior MV. Cine cardiac magnetic resonance measurements included basal septal thickness, number/area of PM heads, and bifid PM mobility (in systole and diastole). Mean basal septal thickness, LVOT gradient, and LV ejection fraction were 1.5±0.3 cm, 72±54 mm Hg, and 61±6%, respectively. The number of anterolateral and posteromedial PM heads was 2.7±0.7 and 2.6±0.7, respectively. Anterolateral and posteromedial PM areas were 19.9±7 cm(2) and 17.1±6 cm(2), respectively. PM mobility was 11±6°. On multivariable analysis, predictors of maximal LVOT gradient were basal septal thickness, bifid PM mobility, anterior mitral leaflet length, and abnormal chordal attachment to base of anterior mitral leaflet. Forty-five patients underwent surgery to relieve LVOT obstruction, of which 52% needed an additional nonmyectomy (MV repair/replacement or PM reorientation) approach. In hypertrophic cardiomyopathy patients without significant LV hypertrophy, in addition to basal septal thickness, anterior MV length, abnormal chordal attachment, and bifid PM mobility are associated with LVOT obstruction. In such patients, additional procedures on MV and PM (±myectomy) could be considered. © 2015 American Heart Association, Inc.

  19. Beneficial effect of isradipine on the development of left ventricular hypertrophy in mild hypertension

    DEFF Research Database (Denmark)

    Mehlsen, J; Fornitz, Gitte Gleerup; Haedersdal, C

    1993-01-01

    The objective of this study was to analyze the long-term hemodynamic effects of the calcium antagonist isradipine in mild hypertension compared with those of the beta 1-selective adrenoceptor antagonist atenolol, focusing in particular on the development of cardiac hypertrophy. Ten male patients...... with isradipine (254 +/- 55 g). The results indicate that antihypertensive treatment with isradipine as monotherapy may prevent the development of left ventricular hypertrophy whereas treatment with atenolol as monotherapy does not appear to offer this possibility....

  20. Tempol improves lipid profile and prevents left ventricular hypertrophy in LDL receptor gene knockout (LDLr-/-) mice on a high-fat diet.

    Science.gov (United States)

    Viana Gonçalves, Igor Cândido; Cerdeira, Cláudio Daniel; Poletti Camara, Eduardo; Dias Garcia, José Antônio; Ribeiro Pereira Lima Brigagão, Maísa; Bessa Veloso Silva, Roberta; Bitencourt Dos Santos, Gérsika

    2017-09-01

    Dyslipidemia is associated with increased risk of cardiovascular disease and atherosclerosis, and hence with high morbidity and mortality. This study investigated the effects of the nitroxide 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (Tempol) on lipid profile and cardiac morphology in low-density lipoprotein (LDL) receptor gene knockout (LDLr-/-) mice. Male LDLr-/- mice (three months old, approximately 22 g weight) were divided into the following groups: controls, including (1) standard chow (SC, n=8) and (2) high-fat diet (HFD, n=8); and treatment, including (3) standard chow + Tempol (SC+T, n=8) (30 mg/kg administered by gavage, once daily) and (4) high-fat diet + Tempol (HFD+T, n=8) (30 mg/kg). After 30 days of the diet/treatment, whole blood was collected for analysis of biochemical parameters (total cholesterol, triglycerides [TG], high-density lipoprotein [HDL], LDL, and very low-density lipoprotein [VLDL]). The heart was removed through thoracotomy and histological analysis of the left ventricle was performed. A significant increase in TG, LDL, and VLDL and marked left ventricular hypertrophy (LVH) were demonstrated in the HFD group relative to the SC group (pTempol treatment (HFD+T group) significantly (pTempol showed potential for the prevention of events related to serious diseases of the cardiovascular system. Copyright © 2017 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

  1. Increased CD36 expression in middle-aged mice contributes to obesity-related cardiac hypertrophy in the absence of cardiac dysfunction

    NARCIS (Netherlands)

    Sung, Miranda M. Y.; Koonen, Debby P. Y.; Soltys, Carrie-Lynn M.; Jacobs, Rene L.; Febbraio, Maria; Dyck, Jason R. B.

    As aging is a significant risk factor for the development of left ventricular hypertrophy and cardiovascular disease, we hypothesized that hearts from middle-aged mice may be more sensitive to the effects of a high fat (HF) diet than hearts from young mice. To investigate this, young (10-12 week

  2. High-Intensity Exercise Reduces Cardiac Fibrosis and Hypertrophy but Does Not Restore the Nitroso-Redox Imbalance in Diabetic Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Ulises Novoa

    2017-01-01

    Full Text Available Diabetic cardiomyopathy refers to the manifestations in the heart as a result of altered glucose homeostasis, reflected as fibrosis, cellular hypertrophy, increased oxidative stress, and apoptosis, leading to ventricular dysfunction. Since physical exercise has been indicated as cardioprotective, we tested the hypothesis that high-intensity exercise training could reverse the cardiac maladaptations produced by diabetes. For this, diabetes was induced in rats by a single dose of alloxan. Diabetic rats were randomly assigned to a sedentary group or submitted to a program of exercise on a treadmill for 4 weeks at 80% of maximal performance. Another group of normoglycemic rats was used as control. Diabetic rat hearts presented cardiomyocyte hypertrophy and interstitial fibrosis. Chronic exercise reduced both parameters but increased apoptosis. Diabetes increased the myocardial levels of the mRNA and proteins of NADPH oxidases NOX2 and NOX4. These altered levels were not reduced by exercise. Diabetes also increased the level of uncoupled endothelial nitric oxide synthase (eNOS that was not reversed by exercise. Finally, diabetic rats showed a lower degree of phosphorylated phospholamban and reduced levels of SERCA2 that were not restored by high-intensity exercise. These results suggest that high-intensity chronic exercise was able to reverse remodeling in the diabetic heart but was unable to restore the nitroso-redox imbalance imposed by diabetes.

  3. Pterosin B prevents chondrocyte hypertrophy and osteoarthritis in mice by inhibiting Sik3

    Science.gov (United States)

    Yahara, Yasuhito; Takemori, Hiroshi; Okada, Minoru; Kosai, Azuma; Yamashita, Akihiro; Kobayashi, Tomohito; Fujita, Kaori; Itoh, Yumi; Nakamura, Masahiro; Fuchino, Hiroyuki; Kawahara, Nobuo; Fukui, Naoshi; Watanabe, Akira; Kimura, Tomoatsu; Tsumaki, Noriyuki

    2016-01-01

    Osteoarthritis is a common debilitating joint disorder. Risk factors for osteoarthritis include age, which is associated with thinning of articular cartilage. Here we generate chondrocyte-specific salt-inducible kinase 3 (Sik3) conditional knockout mice that are resistant to osteoarthritis with thickened articular cartilage owing to a larger chondrocyte population. We also identify an edible Pteridium aquilinum compound, pterosin B, as a Sik3 pathway inhibitor. We show that either Sik3 deletion or intraarticular injection of mice with pterosin B inhibits chondrocyte hypertrophy and protects cartilage from osteoarthritis. Collectively, our results suggest Sik3 regulates the homeostasis of articular cartilage and is a target for the treatment of osteoarthritis, with pterosin B as a candidate therapeutic. PMID:27009967

  4. Omentin functions to attenuate cardiac hypertrophic response.

    Science.gov (United States)

    Matsuo, Kazuhiro; Shibata, Rei; Ohashi, Koji; Kambara, Takahiro; Uemura, Yusuke; Hiramatsu-Ito, Mizuho; Enomoto, Takashi; Yuasa, Daisuke; Joki, Yusuke; Ito, Masanori; Hayakawa, Satoko; Ogawa, Hayato; Kihara, Shinji; Murohara, Toyoaki; Ouchi, Noriyuki

    2015-02-01

    Cardiac hypertrophy occurs in many obesity-related conditions. Omentin is an adipose-derived plasma protein that is downregulated under obese conditions. Here, we investigated whether omentin modulates cardiac hypertrophic responses in vivo and in vitro. Systemic administration of an adenoviral vector expressing human omentin (Ad-OMT) to wild-type (WT) mice led to the attenuation of cardiac hypertrophy, fibrosis and ERK phosphorylation induced by transverse aortic constriction (TAC) or angiotensin II infusion. In cultured cardiomyocytes, stimulation with phenylephrine (PE) led to an increase in myocyte size, which was prevented by pretreatment with human omentin protein. Pretreatment of cardiomyocytes with omentin protein also reduced ERK phosphorylation in response to PE stimulation. Ad-OMT enhanced phosphorylation of AMP-activated protein kinase (AMPK) in the heart of WT mice after TAC operation. Blockade of AMPK activation by transduction with dominant-negative mutant forms of AMPK reversed the inhibitory effect of omentin on myocyte hypertrophy and ERK phosphorylation following PE stimulation. Moreover, fat-specific transgenic mice expressing human omentin showed reduced cardiac hypertrophy and ERK phosphorylation following TAC surgery compared to littermate controls. These data suggest that omentin functions to attenuate the pathological process of myocardial hypertrophy via the activation of AMPK in the heart, suggesting that omentin may represent a target molecule for the treatment of cardiac hypertrophy. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Markers of collagen synthesis is related to blood pressure and vascular hypertrophy: a LIFE substudy

    DEFF Research Database (Denmark)

    Olsen, M H; Christensen, M K; Wachtell, K

    2005-01-01

    Cardiac fibrosis and high levels of circulating collagen markers has been associated with left ventricular (LV) hypertrophy. However, the relationship to vascular hypertrophy and blood pressure (BP) load is unclear. In 204 patients with essential hypertension and electrocardiographic LV hypertrophy...

  6. Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy

    NARCIS (Netherlands)

    Schroen, Blanche; Leenders, Joost J.; van Erk, Arie; Bertrand, Anne T.; van Loon, Mirjam; van Leeuwen, Rick E.; Kubben, Nard; Duisters, Rudy F.; Schellings, Mark W.; Janssen, Ben J.; Debets, Jacques J.; Schwake, Michael; Høydal, Morten A.; Heymans, Stephane; Saftig, Paul; Pinto, Yigal M.

    2007-01-01

    The intercalated disc (ID) of cardiac myocytes is emerging as a crucial structure in the heart. Loss of ID proteins like N-cadherin causes lethal cardiac abnormalities, and mutations in ID proteins cause human cardiomyopathy. A comprehensive screen for novel mechanisms in failing hearts demonstrated

  7. Effects of the cyclo-oxygenase inhibitor, fenbufen, on clenbuterol-induced hypertrophy of cardiac and skeletal muscle of rats.

    Science.gov (United States)

    Palmer, R. M.; Delday, M. I.; McMillan, D. N.; Noble, B. S.; Bain, P.; Maltin, C. A.

    1990-01-01

    1. When rats were fed with clenbuterol for 7 days skeletal muscle mass increased by 21% in the tonic soleus and phasic plantaris muscles and a 16% hypertrophy of the heart was also induced. Fenbufen, fed to rats for the same period, blocked the hypertrophy of the heart but not that of the skeletal muscles. 2. When feeding of fenbufen commenced 3 days before the administration of clenbuterol, plasma prosta-glandin F2 alpha (PGF2 alpha) was reduced by 79%; there was again no effect of fenbufen on clenbuterol-induced increases in the RNA or protein content of plantaris, nor in the increased area of fast or slow twitch fibres in the soleus. In the heart the clenbuterol-induced increases in the RNA (+21%) and protein content (+20%) were totally inhibited. 3. The effects of clenbuterol on heart muscle appear to be mediated by a cyclo-oxygenase metabolite of arachidonic acid whilst the effects on skeletal muscle are not. PMID:1707704

  8. Inhibition of FoxO transcriptional activity prevents muscle fiber atrophy during cachexia and induces hypertrophy.

    Science.gov (United States)

    Reed, Sarah A; Sandesara, Pooja B; Senf, Sarah M; Judge, Andrew R

    2012-03-01

    Cachexia is characterized by inexorable muscle wasting that significantly affects patient prognosis and increases mortality. Therefore, understanding the molecular basis of this muscle wasting is of significant importance. Recent work showed that components of the forkhead box O (FoxO) pathway are increased in skeletal muscle during cachexia. In the current study, we tested the physiological significance of FoxO activation in the progression of muscle atrophy associated with cachexia. FoxO-DNA binding dependent transcription was blocked in the muscles of mice through injection of a dominant negative (DN) FoxO expression plasmid prior to inoculation with Lewis lung carcinoma cells or the induction of sepsis. Expression of DN FoxO inhibited the increased mRNA levels of atrogin-1, MuRF1, cathepsin L, and/or Bnip3 and inhibited muscle fiber atrophy during cancer cachexia and sepsis. Interestingly, during control conditions, expression of DN FoxO decreased myostatin expression, increased MyoD expression and satellite cell proliferation, and induced fiber hypertrophy, which required de novo protein synthesis. Collectively, these data show that FoxO-DNA binding-dependent transcription is necessary for normal muscle fiber atrophy during cancer cachexia and sepsis, and further suggest that basal levels of FoxO play an important role during normal conditions to depress satellite cell activation and limit muscle growth.

  9. Supplementation of creatine and ribose prevents apoptosis and right ventricle hypertrophy in hypoxic hearts.

    Science.gov (United States)

    Caretti, Anna; Bianciardi, Paola; Marini, Marina; Abruzzo, Provvidenza M; Bolotta, Alessandra; Terruzzi, Carlo; Lucchina, Franco; Samaja, Michele

    2013-01-01

    The simultaneous supplementation of creatine and D-ribose has been shown to reduce apoptosis in vitro in non-irreversibly injured cultured ischemic cardiomyocytes through down-regulation of the signaling mechanisms governing adenosine monophosphate-activated protein kinase (AMPK) and protein kinase B (Akt). Here, we test the hypothesis that an analogous mechanism exists in vivo when the challenge is chronic exposure to hypoxia. Five week-old mice were exposed to an atmosphere containing 10% O2 for 10 days. Mice were gavaged daily with vehicle, creatine, D-ribose or creatine + D-ribose. After sacrifice, myocardial and pulmonary tissue were harvested for structural and biochemical analyses. Hypoxia induced right ventricle hypertrophy and left ventricle apoptosis. Both phenotypes were slightly reduced by either creatine or D-ribose, whereas the simultaneous administration of creatine + D-ribose almost completely reversed the effects of hypoxia. Furthermore, creatine + D-ribose diminished the hypoxia-induced increases in the activity of AMPK, Akt and JNK, but not of ERK. Finally, the hypoxia-induced pulmonary overexpression of endothelin-1 mRNA was markedly reduced by creatine + D-ribose. The simultaneous administration of creatine + D-ribose confers additional cardiovascular protection with respect to that observed with either creatine or D-ribose. The mechanism stems from the AMPK and Akt signaling pathways. These findings may form the basis of a paradigm to re-energize non-irreversibly damaged cardiomyocytes, counteracting injury by triggering specific signaling pathways.

  10. Reversal of left ventricular hypertrophy by propranolol in ...

    African Journals Online (AJOL)

    Background: Hypertension contributes significantly to the development of left ventricular hypertrophy. Left ventricular hypertrophy is associated with increased incidence of sudden cardiac death. Recognition and management of hypertension is, therefore, imperative. Objective: To establish whether propranolol can reverse ...

  11. Degree and distribution of left ventricular hypertrophy as a determining factor for elevated natriuretic peptide levels in patients with hypertrophic cardiomyopathy: insights from cardiac magnetic resonance imaging.

    Science.gov (United States)

    Park, Jeong Rang; Choi, Jin-Oh; Han, Hye Jin; Chang, Sung-A; Park, Sung-Ji; Lee, Sang-Chol; Choe, Yeon Hyeon; Park, Seung Woo; Oh, Jae K

    2012-04-01

    Whether the left ventricular (LV) mass index (LVMI) and LV volumetric parameters are associated independently with natriuretic peptide levels is unclear in hypertrophic cardiomyopathy (HCM). Therefore, we investigated which parameters have an independent relationship with N-terminal pro-B type natriuretic peptide (NT-proBNP) levels in HCM patients using echocardiography and cardiac magnetic resonance imaging (CMR). A total of 103 patients with HCM (82 men, age 53 ± 12 years) were evaluated. Echocardiographic evaluations included left atrial volume index (LAVI) and early diastolic mitral inflow E velocity to early annular Ea velocity ratio (E/Ea). LVMI, maximal wall thickness and LV volumetric parameters were measured using CMR. The median value of NT-proBNP level was 387.0 pg/ml. The mean NT-proBNP level in patients with non-apical HCM (n = 69; 36 patients with asymmetric septal hypertrophy, 11 with diffuse, and 22 with mixed type) was significantly higher than in those with apical HCM (n = 34, P < 0.001). NT-proBNP level was negatively correlated with LV end-diastolic volume (LVEDV) (r = -0.263, P = 0.007) and positively with LVMI (r = 0.225, P = 0.022) and maximal wall thickness (r = 0.495, P < 0.001). Among the echocardiographic variables, LAVI (r = 0.492, P < 0.001) and E/Ea (r = 0.432, P < 0.001) were correlated with NT-proBNP. On multivariable analysis, non-apical HCM, increased maximal wall thickness and LAVI were independently related with NT-proBNP. Severity of LV hypertrophy and diastolic parameters might be important in the elevation of NT-proBNP level in HCM. Therefore, further evaluation of these parameters in HCM might be warranted.

  12. Regression of electrocardiographic left ventricular hypertrophy during antihypertensive therapy and reduction in sudden cardiac death: the LIFE Study

    DEFF Research Database (Denmark)

    Wachtell, Kristian; Okin, Peter M; Olsen, Michael H

    2007-01-01

    in Hypertension (LIFE) study included 9193 patients 55 to 80 years of age with essential hypertension and ECG LV hypertrophy by gender-adjusted Cornell product (CP) (RaVL+SV(3) [+6 mm in women]). QRS duration>2440 mm x ms) and/or Sokolow-Lyon voltage (SLV) (SV1+RV(5/6)>38 mm). During follow-up (mean, 4.8 years......-lower SLV (10.5 mm) with a 26% lower risk (HR, 0.74; 95% CI, 0.65 to 0.84). After adjustment for time-varying systolic and diastolic blood pressures, treatment allocation, age, gender, baseline Framingham risk score, ECG strain, heart rate, urine albumin/creatinine ratio, smoking, diabetes, congestive heart...

  13. Prediction and Prevention of Acute Kidney Injury after Cardiac Surgery

    Directory of Open Access Journals (Sweden)

    Su Rin Shin

    2016-01-01

    Full Text Available The incidence of acute kidney injury after cardiac surgery (CS-AKI ranges from 33% to 94% and is associated with a high incidence of morbidity and mortality. The etiology is suggested to be multifactorial and related to almost all aspects of perioperative management. Numerous studies have reported the risk factors and risk scores and novel biomarkers of AKI have been investigated to facilitate the subclinical diagnosis of AKI. Based on the known independent risk factors, many preventive interventions to reduce the risk of CS-AKI have been tested. However, any single preventive intervention did not show a definite and persistent benefit to reduce the incidence of CS-AKI. Goal-directed therapy has been considered to be a preventive strategy with a substantial level of efficacy. Many pharmacologic agents were tested for any benefit to treat or prevent CS-AKI but the results were conflicting and evidences are still lacking. The present review will summarize the current updated evidences about the risk factors and preventive strategies for CS-AKI.

  14. Evaluation of docosahexaenoic acid in a dog model of hypertension induced left ventricular hypertrophy.

    Science.gov (United States)

    Stanley, William C; Cox, James W; Asemu, Girma; O'Connell, Kelly A; Dabkowski, Erinne R; Xu, Wenhong; Ribeiro, Rogerio F; Shekar, Kadambari C; Hoag, Stephen W; Rastogi, Sharad; Sabbah, Hani N; Daneault, Caroline; des Rosiers, Christine

    2013-12-01

    Marine n-3 polyunsaturated fatty acids alter cardiac phospholipids and prevent cardiac pathology in rodents subjected to pressure overload. This approach has not been evaluated in humans or large animals with hypertension-induced pathological hypertrophy. We evaluated docosahexaenoic acid (DHA) in old female dogs with hypertension caused by 16 weeks of aldosterone infusion. Aldosterone-induced hypertension resulted in concentric left ventricular (LV) hypertrophy and impaired diastolic function in placebo-treated dogs. DHA supplementation increased DHA and depleted arachidonic acid in cardiac phospholipids, but did not improve LV parameters compared to placebo. Surprisingly, DHA significantly increased serum aldosterone concentration and blood pressure compared to placebo. Cardiac mitochondrial yield was decreased in placebo-treated hypertensive dogs compared to normal animals, which was prevented by DHA. Extensive analysis of mitochondrial function found no differences between DHA and placebo groups. In conclusion, DHA did not favorably impact mitochondrial or LV function in aldosterone hypertensive dogs.

  15. Enalaprilato na prevenção da hipertrofia ventricular esquerda induzida pelo isoproterenol Enalaprilat prevents the left ventricular hypertrophy induced by isoproterenol

    Directory of Open Access Journals (Sweden)

    Eduardo A. S. Costa

    1997-07-01

    Full Text Available OBJETIVO: Avaliar se o enalaprilato, droga inibidora da enzima de conversão da angiotensina I, previne a hipertrofia ventricular esquerda (HVE induzida pelo isoproterenol. MÉTODOS: Foram divididos em 4 grupos, 72 ratos Wistar-EPM: CON controle; ENA, tratados com enalaprilato (1mg/kg via subcutânea (sc por 8 dias; ISO, tratados com isoproterenol (0,3mg/kg via sc/8 dias e ENA+ISO, tratados simultaneamente com ambas as drogas. Em 10 animais de cada grupo foram determinadas a freqüência cardíaca (FC e a pressão arterial (PA e verificado o peso de ventrículo esquerdo (VE. Em 8 animais de cada grupo, fragmento do VE foi corado com hematoxilina-eosina e picro-sírius e preparado para estudo morfométrico e ultra-estrutural, respectivamente, com microscópio de luz e eletrônico. RESULTADOS: Nos grupos estudados (CON, ENA, ISO e ISO+ENA não ocorreram variações na PA. Os grupos ISO e ISO+ENA exibiram aumentos significantes na FC. O grupo ISO apresentou aumento significativo do peso do VE (PU= 0,821g e PS= 0,204g, quando comparado ao grupo CON. O grupo ENA não exibiu modificação de peso do VE quando comparado ao grupo CON (PU= 0,590g e PS= 0,139g. No grupo ENA+ISO (PU= 0,737g e PS= 0,177g constatou-se diferença de peso ao ser comparado aos grupos ISO e CON. A análise morfométrica e ultra-estrutural mostraram que o ISO induziu hipertrofia dos cardiomiócitos e aumento do tecido conjuntivo com depósito de fibras colágenas do tipo I. O enalaprilato associado com isoproterenol atenuou importantemente aquela manifestação. CONCLUSÃO: O enalaprilato inibiu a ação do isoproterenol sobre os cardiomiócitos, evitando parcialmente, na dose utilizada, a HVE e diminuindo também a quantidade de fibras colágenas.PURPOSE: To evaluate whether the enalaprilat, angiotensin I enzyme conversion inhibitor, could prevent the left ventricular hypertrophy (LVH induced by isoproterenol. METHODS: Seventy two adult Wistar-EPM rats were divided into four

  16. The effects of candesartan on left ventricular hypertrophy and function in nonobstructive hypertrophic cardiomyopathy: a pilot, randomized study.

    Science.gov (United States)

    Penicka, Martin; Gregor, Pavel; Kerekes, Roman; Marek, Dan; Curila, Karol; Krupicka, Jiri

    2009-01-01

    Hypertrophic cardiomyopathy is caused by mutations in the genes that encode sarcomeric proteins and is primarily characterized by unexplained left ventricular hypertrophy, impaired cardiac function, reduced exercise tolerance, and a relatively high incidence of sudden cardiac death, especially in the young. The extent of left ventricular hypertrophy is one of the major determinants of disease prognosis. Angiotensin II has trophic effects on the heart and plays an important role in the development of myocardial hypertrophy. Here in a double-blind, placebo-controlled, randomized study, we show that the long-term administration of the angiotensin II type 1 receptor antagonist candesartan in patients with hypertrophic cardiomyopathy was associated with the significant regression of left ventricular hypertrophy, improvement of left ventricular function, and exercise tolerance. The magnitude of the treatment effect was dependent on specific sarcomeric protein gene mutations that had the greatest responses on the carriers of ss-myosin heavy chain and cardiac myosin binding protein C gene mutations. These data indicate that modulating the role of angiotensin II in the development of hypertrophy is specific with respect to both the affected sarcomeric protein gene and the affected codon within that gene. Thus, angiotensin II type 1 receptor blockade has the potential to attenuate myocardial hypertrophy and may, therefore, provide a new treatment option to prevent sudden cardiac death in patients with hypertrophic cardiomyopathy.

  17. Sarcospan Regulates Cardiac Isoproterenol Response and Prevents Duchenne Muscular Dystrophy-Associated Cardiomyopathy.

    Science.gov (United States)

    Parvatiyar, Michelle S; Marshall, Jamie L; Nguyen, Reginald T; Jordan, Maria C; Richardson, Vanitra A; Roos, Kenneth P; Crosbie-Watson, Rachelle H

    2015-12-23

    Duchenne muscular dystrophy is a fatal cardiac and skeletal muscle disease resulting from mutations in the dystrophin gene. We have previously demonstrated that a dystrophin-associated protein, sarcospan (SSPN), ameliorated Duchenne muscular dystrophy skeletal muscle degeneration by activating compensatory pathways that regulate muscle cell adhesion (laminin-binding) to the extracellular matrix. Conversely, loss of SSPN destabilized skeletal muscle adhesion, hampered muscle regeneration, and reduced force properties. Given the importance of SSPN to skeletal muscle, we investigated the consequences of SSPN ablation in cardiac muscle and determined whether overexpression of SSPN into mdx mice ameliorates cardiac disease symptoms associated with Duchenne muscular dystrophy cardiomyopathy. SSPN-null mice exhibited cardiac enlargement, exacerbated cardiomyocyte hypertrophy, and increased fibrosis in response to β-adrenergic challenge (isoproterenol; 0.8 mg/day per 2 weeks). Biochemical analysis of SSPN-null cardiac muscle revealed reduced sarcolemma localization of many proteins with a known role in cardiomyopathy pathogenesis: dystrophin, the sarcoglycans (α-, δ-, and γ-subunits), and β1D integrin. Transgenic overexpression of SSPN in Duchenne muscular dystrophy mice (mdx(TG)) improved cardiomyofiber cell adhesion, sarcolemma integrity, cardiac functional parameters, as well as increased expression of compensatory transmembrane proteins that mediate attachment to the extracellular matrix. SSPN regulates sarcolemmal expression of laminin-binding complexes that are critical to cardiac muscle function and protects against transient and chronic injury, including inherited cardiomyopathy. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  18. Role of ubiquitin-proteasome system (UPS) in left ventricular hypertrophy (LVH).

    Science.gov (United States)

    Cacciapuoti, Federico

    2014-01-01

    Cardiac hypertrophy is a key compensatory mechanism acting in response to pressure or volume overload, involving some alterations in signaling transduction pathways and transcription factors-regulation. These changes result in enhanced proteins' synthesis leading to Left Ventricular Hypertrophy (LVH). It is known that the main function of Ubiquitin-Proteasome System (UPS) is to prevent accumulation of damaged, misfolded and mutant proteins by proteolysis. But emerging evidences suggest that UPS also attends to the cells' growth, favoring proteins' synthesis, subsequently evolving in LVH. The role of the proteasome in to favor cellular hypertrophy consists in upregulation of the catalytic proteasome subunit, with prevalence of proteins-synthesis on proteins degradation. It is also evident that UPS inhibition may prevent cells' growth opposing to the hypertrophy. In fact in several experimental models, UPS inhibition demonstrated to be able to prevent or reverse cardiac hypertrophy induced by abdominal aortic banding (AAB). That can happen with several proteasome inhibitors acting by multifactorial mechanisms. These evidences induce to hypothesize that, in the future, in patients with the increased volume overload by systemic hypertension, some proteasome-inhibitors could be used to antagonize or prevent LVH without reducing peripheral high blood pressure levels too.

  19. Regulation of the instantaneous inward rectifier and the delayed outward rectifier potassium channels by Captopril and Angiotensin II via the Phosphoinositide-3 kinase pathway in volume-overload-induced hypertrophied cardiac myocytes

    Science.gov (United States)

    Alvin, Zikiar; Laurence, Graham G.; Coleman, Bernell R.; Zhao, Aiqiu; Hajj-Moussa, Majd; Haddad, Georges E.

    2011-01-01

    Summary Background Early development of cardiac hypertrophy may be beneficial but sustained hypertrophic activation leads to myocardial dysfunction. Regulation of the repolarizing currents can be modulated by the activation of humoral factors, such as angiotensin II (ANG II) through protein kinases. The aim of this work is to assess the regulation of IK and IK1 by ANG II through the PI3-K pathway in hypertrophied ventricular myocytes. Material/Methods Cardiac eccentric hypertrophy was induced through volume-overload in adult male rats by aorto-caval shunt (3 weeks). After one week half of the rats were given captopril (2 weeks; 0.5 g/l/day) and the other half served as control. The voltage-clamp and western blot techniques were used to measure the delayed outward rectifier potassium current (IK) and the instantaneous inward rectifier potassium current (IK1) and Akt activity, respectively. Results Hypertrophied cardiomyocytes showed reduction in IK and IK1. Treatment with captopril alleviated this difference seen between sham and shunt cardiomyocytes. Acute administration of ANG II (10−6M) to cardiocytes treated with captopril reduced IK and IK1 in shunts, but not in sham. Captopril treatment reversed ANG II effects on IK and IK1 in a PI3-K-independent manner. However in the absence of angiotensin converting enzyme inhibition, ANG II increased both IK and IK1 in a PI3-K-dependent manner in hypertrophied cardiomyocytes. Conclusions Thus, captopril treatment reveals a negative effect of ANG II on IK and IK1, which is PI3-K independent, whereas in the absence of angiotensin converting enzyme inhibition IK and IK1 regulation is dependent upon PI3-K. PMID:21709626

  20. Alpinate Oxyphyllae Fructus Inhibits IGFII-Related Signaling Pathway to Attenuate Ang II-Induced Pathological Hypertrophy in H9c2 Cardiomyoblasts.

    Science.gov (United States)

    Tsai, Chuan-Te; Chang, Yung-Ming; Lin, Shu-Luan; Chen, Yueh-Sheng; Yeh, Yu-Lan; Padma, Viswanadha Vijaya; Tsai, Chin-Chuan; Chen, Ray-Jade; Ho, Tsung-Jung; Huang, Chih-Yang

    2016-03-01

    Angiotensin II (Ang II) is a very important cardiovascular disease inducer and may cause cardiac pathological hypertrophy and remodeling. We evaluated a Chinese traditional medicine, alpinate oxyphyllae fructus (AOF), for therapeutic efficacy for treating Ang II-induced cardiac hypertrophy. AOF has been used to treat patients with various symptoms accompanying hypertension and cerebrovascular disorders in Korea. We investigated its protective effect against Ang II-induced cytoskeletal change and hypertrophy in H9c2 cells. The results showed that treating cells with Ang II resulted in pathological hypertrophy, such as increased expression of transcription factors NFAT-3/p-NFAT-3, hypertrophic response genes (atrial natriuretic peptide [ANP] and b-type natriuretic peptide [BNP]), and Gαq down-stream effectors (PLCβ3 and calcineurin). Pretreatment with AOF (60-100 μg/mL) led to significantly reduced hypertrophy. We also found that AOF pretreatment significantly suppressed the cardiac remodeling proteins, metalloproteinase (MMP9 and MMP2), and tissue plasminogen activator (tPA), induced by Ang II challenge. In conclusion, we provide evidence that AOF protects against Ang II-induced pathological hypertrophy by specifically inhibiting the insulin-like growth factor (IGF) II/IIR-related signaling pathway in H9c2 cells. AOF might be a candidate for cardiac hypertrophy and ventricular remodeling prevention in chronic cardiovascular diseases.

  1. Characteristics of left ventricular hypertrophy estimated by MIBG and BMIPP cardiac scintigraphy in patients undergoing peritoneal dialysis

    Energy Technology Data Exchange (ETDEWEB)

    Ohashi, Hiroshige; Oda, Hiroshi; Ohno, Michiya; Watanabe, Sachirow; Kotoo, Yasunori; Matsuno, Yukihiko [Gifu Prefectural Hospital (Japan)

    2002-12-01

    Left ventricular hypertrophy (LVH) has been reported as a major factor in morbidity and mortality in chronic dialysis patients. However, cardiovascular mortality in peritoneal dialysis (PD) patients with LVH is substantially similar to that in hemodialysis (HD) patients. The present study sought to study whether sympathetic nerve activity and fatty acid metabolism of the myocardium estimated by {sup 123}I metaiodobenzylguanidine (MIBG) and {sup 123}I {beta}-methyl-p-iodophenyl-pentadecanoic acid (BMIPP) myocardial scintigraphy are impaired or not in PD patients with LVH. The underlying disease of 45 PD patients enrolled in this study was chronic glomerulonephritis in all cases. Serum levels of natriuretic peptides (arterial natriuretic peptide (ANP), brain natriuretic peptide (BNP)) and free carnitine and MIBG, BMIPP myocardial scintigraphy and 2-dimensional echocardiography were measured in these 45 PD patients. The following results were obtained. The prevalence of increased left ventricular mass index (LVMI) was 84.4%. LVMI correlated with age, and serum levels of ANP and BNP, and inversely correlated with a heart-to-mediastinum ratio (H/M) estimated by MIBG and BMIPP myocardial scintigraphy. Percentages of the normal image of MIBG and BMIPP measured with a single photon emission computed tomography (SPECT) were 37.8% and 62.2%, respectively. The PD patients showing the diffuse defect of MIBG or BMIPP imaging had the decrease in left ventricular ejection fraction (LVEF). Especially, the serum level of free carnitine was reduced in the PD patients with diffuse defect of BMIPP SPECT. From these results, we concluded that PD patients with LVH showed impaired sympathetic nerve activity and fatty acid metabolism of the myocardium. Metabolic and functional disturbances of the myocardium may influence mortality in PD patients. (author)

  2. Electrocardiographic measures of left ventricular hypertrophy in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.

    Science.gov (United States)

    Ernst, Michael E; Davis, Barry R; Soliman, Elsayed Z; Prineas, Ronald J; Okin, Peter M; Ghosh, Alokananda; Cushman, William C; Einhorn, Paula T; Oparil, Suzanne; Grimm, Richard H

    2016-12-01

    Left ventricular hypertrophy (LVH) predicts cardiovascular risk in hypertensive patients. We analyzed baseline/follow-up electrocardiographies in 26,376 Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial participants randomized to amlodipine (A), lisinopril (L), or chlorthalidone (C). Prevalent/incident LVH was examined using continuous and categorical classifications of Cornell voltage. At 2 and 4 years, prevalence of LVH in the C group (5.57%; 6.14%) was not statistically different from A group (2 years: 5.47%; P = .806, 4 years: 6.54%; P = .857) or L group (2 years: 5.64%; P = .857, 4 years: 6.50%; P = .430). Incident LVH followed similarly, with no difference at 2 years for C (2.99%) compared to A (2.57%; P = .173) or L (3.16%; P = .605) and at 4 years (C = 3.52%, A = 3.29%, L = 3.71%; P = .521 C vs. A, P = .618 C vs. L). Mean Cornell voltage decreased comparably across treatment groups (Δ baseline, 2 years = +3 to -27 μV, analysis of variance P = .8612; 4 years = +10 to -17 μV, analysis of variance P = .9692). We conclude that risk reductions associated with C treatment in secondary end points of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial cannot be attributed to differential improvements in electrocardiography LVH. Copyright © 2016 American Society of Hypertension. All rights reserved.

  3. The involvement of vimentin in copper-induced regression of cardiomyocyte hypertrophy.

    Science.gov (United States)

    Li, Rui; Bourcy, Katherine; Wang, Tao; Sun, Miao; Kang, Y James

    2015-09-01

    Dietary copper supplementation reverses the pressure overload-induced cardiac hypertrophy. Activation of vascular endothelial growth factor receptor-1 (VEGFR-1) and cyclic guanosine monophosphate (cGMP)-dependent protein kinase-1 (PKG-1) is required for the regression. The present study was undertaken to determine the link between VEGFR-1 and PKG-1 in copper regression of cardiomyocyte hypertrophy. Human cardiac myocytes (HCM) or primary cultures of neonatal rat cardiomyocytes were exposed to phenylephrine (PE) at a final concentration of 100 μM for 48 h to induce cell hypertrophy. Copper sulfite was added to cultures of hypertrophic cardiomyocytes at a final concentration of 5 μM elemental copper and incubated for 24 h to reverse cell hypertrophy. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis identified a 56 kDa copper-binding protein, vimentin, which was co-immunoprecipitated with VEGFR-1 and PKG-1. Copper supplementation increased vimentin levels and enhanced PKG-1 activity. Gene silencing using siRNA targeting vimentin prevented copper-induced elevation of vimentin, depressed the activity of PKG-1, and blocked the copper-induced regression of cardiomyocyte hypertrophy. This study demonstrates that vimentin is critically involved in the VEGFR-1 mediated activation of the PKG-1 signaling pathway, leading to regression of cardiomyocyte hypertrophy.

  4. High molecular weight fibroblast growth factor-2 in the human heart is a potential target for prevention of cardiac remodeling.

    Science.gov (United States)

    Santiago, Jon-Jon; McNaughton, Leslie J; Koleini, Navid; Ma, Xin; Bestvater, Brian; Nickel, Barbara E; Fandrich, Robert R; Wigle, Jeffrey T; Freed, Darren H; Arora, Rakesh C; Kardami, Elissavet

    2014-01-01

    Fibroblast growth factor 2 (FGF-2) is a multifunctional protein synthesized as high (Hi-) and low (Lo-) molecular weight isoforms. Studies using rodent models showed that Hi- and Lo-FGF-2 exert distinct biological activities: after myocardial infarction, rat Lo-FGF-2, but not Hi-FGF-2, promoted sustained cardioprotection and angiogenesis, while Hi-FGF-2, but not Lo-FGF-2, promoted myocardial hypertrophy and reduced contractile function. Because there is no information regarding Hi-FGF-2 in human myocardium, we undertook to investigate expression, regulation, secretion and potential tissue remodeling-associated activities of human cardiac (atrial) Hi-FGF-2. Human patient-derived atrial tissue extracts, as well as pericardial fluid, contained Hi-FGF-2 isoforms, comprising, respectively, 53%(±20 SD) and 68% (±25 SD) of total FGF-2, assessed by western blotting. Human atrial tissue-derived primary myofibroblasts (hMFs) expressed and secreted predominantly Hi-FGF-2, at about 80% of total. Angiotensin II (Ang II) up-regulated Hi-FGF-2 in hMFs, via activation of both type 1 and type 2 Ang II receptors; the ERK pathway; and matrix metalloprotease-2. Treatment of hMFs with neutralizing antibodies selective for human Hi-FGF-2 (neu-AbHi-FGF-2) reduced accumulation of proteins associated with fibroblast-to-myofibroblast conversion and fibrosis, including α-smooth muscle actin, extra-domain A fibronectin, and procollagen. Stimulation of hMFs with recombinant human Hi-FGF-2 was significantly more potent than Lo-FGF-2 in upregulating inflammation-associated proteins such as pro-interleukin-1β and plasminogen-activator-inhibitor-1. Culture media conditioned by hMFs promoted cardiomyocyte hypertrophy, an effect that was prevented by neu-AbHi-FGF-2 in vitro. In conclusion, we have documented that Hi-FGF-2 represents a substantial fraction of FGF-2 in human cardiac (atrial) tissue and in pericardial fluid, and have shown that human Hi-FGF-2, unlike Lo-FGF-2, promotes deleterious

  5. Calpastatin overexpression in the skeletal muscle of mice prevents clenbuterol-induced muscle hypertrophy and phenotypic shift.

    Science.gov (United States)

    Douillard, Aymeric; Galbes, Olivier; Begue, Gwenaelle; Rossano, Bernadette; Levin, John; Vernus, Barbara; Bonnieu, Anne; Candau, Robin; Py, Guillaume

    2012-04-01

    Accumulating evidence suggests that the calpain/calpastatin system is involved in skeletal muscle remodelling induced by β(2) -adrenoceptor agonist treatment. In addition to other pathways, the Akt/mammalian target of rapamycin (mTOR) pathway, controlling protein synthesis, and the calcium/calmodulin-dependent protein kinase 2 (CamK2) and AMP-activated protein kinase (AMPK) pathways, recently identified as calpain substrates, could be relevant in β(2) -adrenoceptor agonist-induced skeletal muscle remodelling. In the present study we investigated muscle hypertrophy and phenotypic shifts, as well as the molecular response of components of the Akt/mTOR pathway (i.e. Akt, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), ribosomal protein S6 (rpS6), CamK2 and AMPK), in response to calpastatin overexpression in the skeletal muscle of mice treated with 1 mg/kg per day clenbuterol for 21 days. Using gene electrotransfer of a calpastatin expression vector into the tibialis anterior of adult mice, we found that calpastatin overexpression attenuates muscle hypertrophy and phenotypic shifts induced by clenbuterol treatment. At the molecular level, calpastatin overexpression markedly decreased calpain activity, but was ineffective in altering the phosphorylation of Akt, 4E-BP1 and rpS6. In contrast, calpastatin overexpression increased the protein expression of both total AMPK and total CamK2. In conclusion, the results support the contention that the calpain/calpastatin system plays a crucial role in skeletal muscle hypertrophy and phenotypic shifts under chronic clenbuterol treatment, with AMPK and CamK2 probably playing a minor role. Moreover, the calpastatin-induced inhibition of hypertrophy under clenbuterol treatment was not related to a decreased mTOR-dependent initiation of protein translation. © 2012 The Authors Clinical and Experimental Pharmacology and Physiology © 2012 Blackwell Publishing Asia Pty Ltd.

  6. Mitochondrial Reprogramming Induced by CaMKII delta Mediates Hypertrophy Decompensation

    NARCIS (Netherlands)

    Westenbrink, B. Daan; Ling, Haiyun; Divakaruni, Ajit S.; Gray, Charles B. B.; Zambon, Alexander C.; Dalton, Nancy D.; Peterson, Kirk L.; Gu, Yusu; Matkovich, Scot J.; Murphy, Anne N.; Miyamoto, Shigeki; Dorn, Gerald W.; Brown, Joan Heller

    2015-01-01

    Rationale: Sustained activation of Gq transgenic (Gq) signaling during pressure overload causes cardiac hypertrophy that ultimately progresses to dilated cardiomyopathy. The molecular events that drive hypertrophy decompensation are incompletely understood. Ca2+/calmodulin-dependent protein kinase

  7. Myocardial hypertrophy in the recipient with twin-to-twin transfusion syndrome

    DEFF Research Database (Denmark)

    Jeppesen, D.L.; Jorgensen, F.S.; Pryds, O.A.

    2008-01-01

    pressure measurements revealed persistent systemic hypertension. Biventricular hypertrophy was demonstrated by echocardiography. Blood pressure normalised after treatment with Nifedipine and the cardiac hypertrophy subsided over the following weeks. A potential contributing mechanism is intrauterine...

  8. Amlodipine and atorvastatin improved hypertensive cardiac hypertrophy through regulation of receptor activator of nuclear factor kappa B ligand/receptor activator of nuclear factor kappa B/osteoprotegerin system in spontaneous hypertension rats.

    Science.gov (United States)

    Lu, Jingchao; Liu, Fan; Liu, Demin; Du, Hong; Hao, Jie; Yang, Xiuchun; Cui, Wei

    2016-06-01

    The present study aims to study the role of receptor activator of nuclear factor kappa B ligand/receptor activator of nuclear factor kappa B/osteoprotegerin (RANKL/RANK/OPG) system in cardiac hypertrophy in a spontaneous hypertension rat (SHR) model and the effects of amlodipine and atorvastatin intervention. Thirty-six-week-old male SHRs were randomly divided into four groups: 1) SHR control group; 2) amlodipine alone (10 mg/kg/d) group, 3) atorvastatin alone (10 mg/kg/d) group, 4) combination of amlodinpine and atorvastatin (10 mg/kg/d for each) group. Same gender, weight, and age of Wistar-Kyoto (WKY) rats with normal blood pressure were used as normal control. Drugs were administered by oral gavage over 12 weeks. The thicknesses of left ventricle walls, left ventricle weight, and cardiac function were measured by transthoracic echocardiography. Left ventricular pressure and function were assessed by hemodynamic examination. Cardiomyocyte hypertrophy and collagen accumulation in cardiac tissue were measured by hematoxylin and eosin (HE) and Masson staining, respectively. The hydroxyproline content of cardiac tissue was examined by biochemistry technique. RANKL, RANK and OPG mRNA, protein expression and tissue localization were studied by RT-PCR, Immunohistochemistry and Western blot. Treatment with amlodipine or atorvastatin alone significantly decreased left ventricular mass index, cardiomyocyte cross-sectional area and interstitial fibrosis in SHR (each P < 0.05). Moreover, combined amlodipine and atorvastatin treatment induced significant reversal of left ventricular hypertrophy and decreased cardiomyocyte cross-sectional area and interstitial fibrosis in SHR to a greater extent than each agent alone (P < 0.05). Compared with WKY rats, the myocardial expression of RANKL, RANK, and OPG was increased. Both amlodipine and atorvastatin reduced RANKL, RANK, and OPG expression, with the best effects seen with the combination. Based on our results

  9. Arterial hypertension and stroke: cardiac and neurological aspects of secondary prevention

    Directory of Open Access Journals (Sweden)

    L.A. Geraskina

    2014-01-01

    Full Text Available This article considers the pathogenetic mechanisms of stroke in arterial hypertension (AH with special emphasis on comorbid neurological and cardiac disorders. It presents the cardiac and neurological aspects of the current strategy of medical therapy within the secondary prevention of poststroke cardiovascular events. The secondary prevention of cardiovascular events in patients who have sustained ischemic stroke in the presence of AH involves the use of not only antihypertensive drugs, but also adequate antiplatelet therapy and statins. The most important part is assigned to the prevention and treatment of cognitive impairments, which also promotes increased patient treatment adherence and improved poststroke prognosis, including longer survival and better quality of life.

  10. SDF-1α (Stromal Cell-Derived Factor 1α) Induces Cardiac Fibroblasts, Renal Microvascular Smooth Muscle Cells, and Glomerular Mesangial Cells to Proliferate, Cause Hypertrophy, and Produce Collagen.

    Science.gov (United States)

    Jackson, Edwin K; Zhang, Yumeng; Gillespie, Delbert D; Zhu, Xiao; Cheng, Dongmei; Jackson, Travis C

    2017-11-07

    Activated cardiac fibroblasts (CFs), preglomerular vascular smooth muscle cells (PGVSMCs), and glomerular mesangial cells (GMCs) proliferate, cause hypertrophy, and produce collagen; in this way, activated CFs contribute to cardiac fibrosis, and activated PGVSMCs and GMCs promote renal fibrosis. In heart and kidney diseases, SDF-1α (stromal cell-derived factor 1α; endogenous CXCR4 [C-X-C motif chemokine receptor 4] receptor agonist) levels are often elevated; therefore, it is important to know whether and how the SDF-1α/CXCR4 axis activates CFs, PGVSMCs, or GMCs. Here we investigated whether SDF-1α activates CFs, PGVSMCs, and GMCs to proliferate, hypertrophy, or produce collagen. DPP4 (dipeptidyl peptidase 4) inactivates SDF-1α and previous experiments show that growth-promoting peptides have greater effects in cells from genetically-hypertensive animals. Therefore, we performed experiments in the absence and presence of sitagliptin (DPP4 inhibitor) and in cells from normotensive Wistar-Kyoto rats and spontaneously hypertensive rats. Our studies show (1) that spontaneously hypertensive and Wistar-Kyoto rat CFs, PGVSMCs, and GMCs express CXCR4 receptors and DPP4 activity; (2) that chronic treatment with physiologically relevant concentrations of SDF-1α causes concentration-dependent increases in the proliferation (cell number) and hypertrophy ( 3 H-leucine incorporation) of and collagen production ( 3 H-proline incorporation) by CFs, PGVSMCs, and GMCs; (3) that sitagliptin augments these effects of SDF-1α; (4) that interactions between SDF-1α and sitagliptin are greater in spontaneously hypertensive rat cells; (5) that CXCR4 antagonism (AMD3100) blocks all effects of SDF-1α; and (6) that SDF-1α/CXCR4 signal transduction likely involves the RACK1 (receptor for activated C kinase 1)/Gβγ/PLC (phospholipase C)/PKC (protein kinase C) signaling complex. The SDF-1α/CXCR4 axis drives proliferation and hypertrophy of and collagen production by CFs, PGVSMCs, and

  11. Aldosterone inhibits the fetal program and increases hypertrophy in the heart of hypertensive mice.

    Directory of Open Access Journals (Sweden)

    Feriel Azibani

    Full Text Available BACKGROUND: Arterial hypertension (AH induces cardiac hypertrophy and reactivation of "fetal" gene expression. In rodent heart, alpha-Myosin Heavy Chain (MyHC and its micro-RNA miR-208a regulate the expression of beta-MyHC and of its intronic miR-208b. However, the role of aldosterone in these processes remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: RT-PCR and western-blot were used to investigate the genes modulated by arterial hypertension and cardiac hyperaldosteronism. We developed a model of double-transgenic mice (AS-Ren with cardiac hyperaldosteronism (AS mice and systemic hypertension (Ren. AS-Ren mice had increased (x2 angiotensin II in plasma and increased (x2 aldosterone in heart. Ren and AS-Ren mice had a robust and similar hypertension (+70% versus their controls. Anatomical data and echocardiography showed a worsening of cardiac hypertrophy (+41% in AS-Ren mice (P<0.05 vs Ren. The increase of ANP (x 2.5; P<0.01 mRNA observed in Ren mice was blunted in AS-Ren mice. This non-induction of antitrophic natriuretic peptides may be involved in the higher trophic cardiac response in AS-Ren mice, as indicated by the markedly reduced cardiac hypertrophy in ANP-infused AS-Ren mice for one month. Besides, the AH-induced increase of ßMyHC and its intronic miRNA-208b was prevented in AS-Ren. The inhibition of miR 208a (-75%, p<0.001 in AS-Ren mice compared to AS was associated with increased Sox 6 mRNA (x 1.34; p<0.05, an inhibitor of ßMyHC transcription. Eplerenone prevented all aldosterone-dependent effects. CONCLUSIONS/SIGNIFICANCE: Our results indicate that increased aldosterone in heart inhibits the induction of atrial natriuretic peptide expression, via the mineralocorticoid receptor. This worsens cardiac hypertrophy without changing blood pressure. Moreover, this work reveals an original aldosterone-dependent inhibition of miR-208a in hypertension, resulting in the inhibition of β-myosin heavy chain expression through the induction

  12. Influence of strength training on cardiac risk prevention in ...

    African Journals Online (AJOL)

    It has widely been shown that exercise, particularly aerobic exercise, has extensive cardioprotective benefits and is an important tool in the prevention of coronary heart disease (CHD). The present investigation aimed to determine the multivariate impact of strength training, designed to prevent the development of CHD, on ...

  13. Pediatric Cardiac Anamnesis: Prevention of Additional Diagnostic Tests.

    Science.gov (United States)

    Masic, Izet; Begic, Zijo; Naser, Nabil; Begic, Edin

    2018-01-01

    Pediatrics is defined as the science of a healthy and sick child from birth to end of adolescence. Diseases of the cardiovascular system are the leading causes of mortality in adults, with frequent onset in childhood. The cardiologic examination starts with anamnesis in a pleasant atmosphere, refined space, enough time and patience, detailed measurements, and preferably a noncrying child. Anamnesis, regardless of the development of diagnostic procedures, still constitutes the basis of every clinical examination. The basic characteristics of pediatric cardiac anamnesis are comprehensiveness, that is, details, clarity, concurrency, and chronology. Proper and conscientiously taken anamnesis with a thorough clinical examination of a sick child is a solid protection against dehumanizing the relationship between a physician and patient. Pediatric cardiac anamnesis can be variable, completely negative, but very rich. Anamnesis should, first of all, clarify whether only a child is sick or it is perceived like that be his or her environment. Preschool and school-age children are normally attending anamnesis. High-quality, comprehensive medical history can keep the patient at one level of health care, with a strict focus primarily on the diagnostic processes, reduce crowds in specialist and subspecialist institutions, and make economic savings. A large number of patients in specialist and subspecialist clinics can be reduced by proper screening and by developing primary health-care system (from the local health-care center). Taking patient's medical history with thoroughness has a strong educative character for young doctors at the beginning of their careers.

  14. miR133a regulates cardiomyocyte hypertrophy in diabetes.

    Science.gov (United States)

    Feng, Biao; Chen, Shali; George, Biju; Feng, Qingping; Chakrabarti, Subrata

    2010-01-01

    Diabetic cardiomyopathy, characterized by cardiac hypertrophy and contractile dysfunction, eventually leads to heart failure. We have previously shown that alterations of a number of key molecules are involved in producing cardiomyocyte hypertrophy in diabetes. The aim of the present study was to determine whether microRNAs (miRNA) play a role in mediating altered gene expression and structural/functional deficits in the heart in diabetes. STZ-induced diabetic mice were haemodynamically investigated after 2 months of diabetes to establish the development of cardiomyopathy. The tissues were then examined for gene expression and microRNA analysis. We further investigated neonatal rat cardiomyocytes to identify the mechanisms of glucose-induced hypertrophy and the potential role of miR133a. Diabetic mice showed myocardial contractile dysfunction and augmented mRNA expression of atrial and brain natriuretic peptides (ANP, BNP), MEF2A and MEF2C, SGK1 and IGF1R compared to age- and sex-matched controls. Cardiac tissues from these mice showed alteration of multiple miRNAs by array analysis including miR133a, which was confirmed by RT-PCR. In vitro exposure of cardiomyocytes to high levels of glucose produced hypertrophic changes and reduced expression of miRNA133a. Finally, transfection of miR133a mimics prevented altered gene expression and hypertrophic changes. Data from these studies demonstrate a novel glucose-induced mechanism regulating gene expression and cardiomyocyte hypertrophy in diabetes which is mediated through miR133a. Copyright (c) 2009 John Wiley & Sons, Ltd.

  15. [Experimental Approach to Analysis of the Relationship between Food Environments and Lifestyle-Related Diseases, Including Cardiac Hypertrophy, Fatty Liver, and Fatigue Symptoms].

    Science.gov (United States)

    Horiuchi, Masahisa; Nakakuma, Miwa; Arimura, Emi; Ushikai, Miharu; Yoshida, Goichiro

    2015-01-01

    The food habit is involved in the onset and development of lifestyle-related diseases. In this review I would like to describe a historical case of vitamin B1 deficiency, as well as our case study of fatty acid metabolism abnormality due to carnitine deficiency. In history, the army and navy personnel in Japan at the end of the 19th century received food rations based on a high-carbohydrate diet including white rice, resulting in the onset of beriberi. An epidemiological study by Kenkan Takaki revealed the relationship between the onset of beriberi and rice intake. Then, Takaki was successful in preventing the onset of beriberi by changing the diet. However, the primary cause had yet to be elucidated. Finally, Christian Eijkman established an animal model of beriberi (chickens) showing peripheral neuropathy, and he identified the existence of an anti-beriberi substance, vitamin B1. This is an example of the successful control of a disease by integrating the results of epidemiological and experimental studies. In our study using a murine model of fatty acid metabolism abnormality caused by carnitine deficiency, cardiac abnormality and fatty liver developed depending on the amount of dietary fat. In addition, the mice showed disturbance of orexin neuron activity related to the sleep-arousal system, which is involved in fatigue symptoms under fasting condition, one of the states showing enhanced fatty acid metabolism. These findings suggest that fatty acid toxicity is enhanced when the mice are more dependent on fatty acid metabolism. Almost simultaneously, a human epidemiological study showed that narcolepsy, which is caused by orexin system abnormality, is associated with the polymorphism of the gene coding for carnitine palmitoyltransferase 1B, which is involved in carnitine metabolism. To understand the pathological mechanism of fatty acid toxicity, not only an experimental approach using animal models, but also an epidemiological approach is necessary. The

  16. Follistatin-Like 1 Regulates Hypertrophy in Heart Failure With Preserved Ejection Fraction

    Directory of Open Access Journals (Sweden)

    Komei Tanaka, MD, PhD

    2016-06-01

    Full Text Available Heart failure with preserved ejection fraction (HFpEF accounts for ∼50% of all clinical presentations of heart failure, (HF and its prevalence is expected to increase. However, there are no evidence-based therapies for HFpEF; thus, HFpEF represents a major unmet need. Although hypertension is the single most important risk factor for HFpEF, with a prevalence of 60% to 89% from clinical trials and human HF registries, blood pressure therapy alone is insufficient to prevent and treat HFpEF. Follistatin-like 1 (Fstl1, a divergent member of the follistatin family of extracellular glycoproteins, has previously been shown to be elevated in HF with reduced ejection fraction and associated with increased left ventricular mass. In this study, blood levels of Fstl1 were increased in humans with HFpEF. This increase was also evident in mice with hypertension-induced HFpEF and adult rat ventricular myocytes stimulated with aldosterone. Treatment with recombinant Fstl1 abrogated aldosterone-induced cardiac myocyte hypertrophy, suggesting a role for Fstl1 in the regulation of hypertrophy in HFpEF. There was also a reduction in the E/A ratio, a measure of diastolic dysfunction. Furthermore, HFpEF induced in a mouse model that specifically ablates Fstl1 in cardiac myocytes (cardiac myocyte-specific Fstl1 knockout [cFstl1-KO] showed exacerbation of HFpEF with worsened diastolic dysfunction. In addition, cFstl1-KO-HFpEF mice demonstrated more marked cardiac myocyte hypertrophy with increased molecular markers of atrial natriuretic peptide and brain natriuretic peptide expression. These findings indicate that Fstl1 exerts therapeutic effects by modulating cardiac hypertrophy in HFpEF.

  17. Preventive role of Withania somnifera on hyperlipidemia and cardiac ...

    African Journals Online (AJOL)

    Purpose: The present study was intended to investigate the preventive role of Withania somnifera (WS) on hyperlipidemia and oxidative stress in the heart of streptozotocin (STZ)-induced type 2 diabetic rats. Methods: Single intraperitoneal injection of STZ (100 mg/kg) was given to 2 days rat pups to induce type 2 diabetes ...

  18. Prevention of cardiac complications in peripheral vascular surgery

    Energy Technology Data Exchange (ETDEWEB)

    Cutler, B.S.

    1986-04-01

    The prevalence of severe coronary artery disease in peripheral vascular patients exceeds 50 per cent. Complications of coronary artery disease are the most common causes of mortality following peripheral vascular operations. To reduce the incidence of cardiac complications, it is first necessary to identify patients at risk through screening tests. Screening methods in current use include risk factor analysis, exercise testing, routine coronary angiography, and dipyridamole thallium-201 scintigraphy. The risk factor approach has the advantage of being widely applicable since it makes use of historical, physical, and electrocardiographic findings that are already familiar to surgeons and anesthesiologists. It is also inexpensive. However, it may overlook the patient who has no symptoms of coronary artery disease, possibly as a result of the sedentary lifestyle imposed by complications of peripheral vascular disease. The electrocardiographically monitored stress test will identify the asymptomatic patient with occult coronary disease and is helpful in predicting operative risk. However, a meaningful test is dependent on the patient's ability to exercise--an activity that is frequently limited by claudication, amputation, or arthritis. Exercise testing also suffers from a lack of sensitivity and specificity when compared with coronary arteriography. Routine preoperative coronary angiography overcomes the exercise limitation of treadmill testing but is not widely applicable as a screening test for reasons of cost and inherent risk. Dipyridamole thallium-201 scanning, on the other hand, is safe and of relatively low cost and does not require exercise.

  19. Prevention of cardiac complications in peripheral vascular surgery

    International Nuclear Information System (INIS)

    Cutler, B.S.

    1986-01-01

    The prevalence of severe coronary artery disease in peripheral vascular patients exceeds 50 per cent. Complications of coronary artery disease are the most common causes of mortality following peripheral vascular operations. To reduce the incidence of cardiac complications, it is first necessary to identify patients at risk through screening tests. Screening methods in current use include risk factor analysis, exercise testing, routine coronary angiography, and dipyridamole thallium-201 scintigraphy. The risk factor approach has the advantage of being widely applicable since it makes use of historical, physical, and electrocardiographic findings that are already familiar to surgeons and anesthesiologists. It is also inexpensive. However, it may overlook the patient who has no symptoms of coronary artery disease, possibly as a result of the sedentary lifestyle imposed by complications of peripheral vascular disease. The electrocardiographically monitored stress test will identify the asymptomatic patient with occult coronary disease and is helpful in predicting operative risk. However, a meaningful test is dependent on the patient's ability to exercise--an activity that is frequently limited by claudication, amputation, or arthritis. Exercise testing also suffers from a lack of sensitivity and specificity when compared with coronary arteriography. Routine preoperative coronary angiography overcomes the exercise limitation of treadmill testing but is not widely applicable as a screening test for reasons of cost and inherent risk. Dipyridamole thallium-201 scanning, on the other hand, is safe and of relatively low cost and does not require exercise

  20. Role of diclofenac in the prevention of postpericardiotomy syndrome after cardiac surgery

    Science.gov (United States)

    Sevuk, Utkan; Baysal, Erkan; Altindag, Rojhat; Yaylak, Baris; Adiyaman, Mehmet Sahin; Ay, Nurettin; Alp, Vahhac; Beyazit, Unal

    2015-01-01

    Objective Postpericardiotomy syndrome (PPS), which is thought to be related to autoimmune phenomena, represents a common postoperative complication in cardiac surgery. Late pericardial effusions after cardiac surgery are usually related to PPS and can progress to cardiac tamponade. Preventive measures can reduce postoperative morbidity and mortality related to PPS. In a previous study, diclofenac was suggested to ameliorate autoimmune diseases. The aim of this study was to determine whether postoperative use of diclofenac is effective in preventing early PPS after cardiac surgery. Methods A total of 100 patients who were administered oral diclofenac for postoperative analgesia after cardiac surgery and until hospital discharge were included in this retrospective study. As well, 100 patients undergoing cardiac surgery who were not administered nonsteroidal anti-inflammatory drugs were included as the control group. The existence and severity of pericardial effusion were determined by echocardiography. The existence and severity of pleural effusion were determined by chest X-ray. Results PPS incidence was significantly lower in patients who received diclofenac (20% vs 43%) (Pdiclofenac had a significantly lower incidence of pericardial effusion (15% vs 30%) (P=0.01). Although not statistically significant, pericardial and pleural effusion was more severe in the control group than in the diclofenac group. The mean duration of diclofenac treatment was 5.11±0.47 days in patients with PPS and 5.27±0.61 days in patients who did not have PPS (P=0.07). Logistic regression analysis demonstrated that diclofenac administration (odds ratio [OR] 0.34, 95% confidence interval [CI] 0.18–0.65, P=0.001) was independently associated with PPS occurrence. Conclusion Postoperative administration of diclofenac may have a protective role against the development of PPS after cardiac surgery. PMID:26170687

  1. Colchicine in prevention of atrial fibrillation following cardiac surgery: Systematic review and meta-analysis

    Science.gov (United States)

    Trivedi, Chintan; Sadadia, Mihir

    2014-01-01

    Objectives: Inflammation is one of the predictors of atrial fibrillation (AF) following surgical or interventional cardiac procedures. Recent evidence suggests that colchicine may represent a new strategy to prevent AF following cardiac procedures. This study aims to assess the antiinflammatory efficacy of colchicine in prevention of early AF event (EAFE). Materials and Methods: We reviewed all available studies that assessed the effectiveness of colchicine therapy on the occurrence of AF in patients undergoing cardiac procedures. Meta-analysis was performed by random effect inverse variance-weighted method by entering AF events and the total population from each study. Results: After thorough review of the databases, we found three studies comparing colchicine and placebo which had EAFE as the outcome. Of 584 patients, 286 patients were on colchicine and 298 on placebo. All the three studies were randomized. After pooled analysis, colchicine was associated with significant reduction in AF events compared to placebo (odds ratio = 0.44 [0.29, 0.66], P Colchicine may prove beneficial in the prevention of AF following cardiac surgery. Further research is warranted. PMID:25538328

  2. Perioperative management for the prevention of bacterial infection in cardiac implantable electronic device placement

    Directory of Open Access Journals (Sweden)

    Katsuhiko Imai

    2016-08-01

    Full Text Available Cardiac implantable electronic devices (CIEDs have become important in the treatment of cardiac disease and placement rates increased significantly in the last decade. However, despite the use of appropriate antimicrobial prophylaxis, CIED infection rates are increasing disproportionately to the implantation rate. CIED infection often requires explantation of all hardware, and at times results in death. Surgical site infection (SSI is the most common cause of CIED infection as a pocket infection. The best method of combating CIED infection is prevention. Prevention of CIED infections comprises three phases: before, during, and after device implantation. The most critical factors in the prevention of SSIs are detailed operative techniques including the practice of proper technique by the surgeon and surgical team.

  3. Sudden infant death syndrome and cardiac channelopathies: from mechanisms to prevention of avoidable tragedies

    Directory of Open Access Journals (Sweden)

    Peter J. Schwartz

    2011-12-01

    Full Text Available The sudden infant death syndrome (SIDS, with the load of mystery surrounding its causes and with the devastating impact on the affected families, remains the greatest contributor to post-neonatal mortality during the first year of life. Following a succinct review of the non-cardiac genetic factors, which have been associated with SIDS, we focus on the cardiac hypothesis for SIDS and specifically on those diseases produced by cardiac ion channel mutations, the so-called channelopathies. Special attention is devoted to the fact that these causes of SIDS, and especially the long QT syndrome, are preventable if diagnosed in time. This highlights the importance of neonatal ECG screening and carries a number of practical implications, including medico-legal considerations.

  4. Soluble epoxide hydrolase inhibition improves coronary endothelial function and prevents the development of cardiac alterations in obese insulin-resistant mice.

    Science.gov (United States)

    Roche, Clothilde; Besnier, Marie; Cassel, Roméo; Harouki, Najah; Coquerel, David; Guerrot, Dominique; Nicol, Lionel; Loizon, Emmanuelle; Remy-Jouet, Isabelle; Morisseau, Christophe; Mulder, Paul; Ouvrard-Pascaud, Antoine; Madec, Anne-Marie; Richard, Vincent; Bellien, Jeremy

    2015-05-01

    This study addressed the hypothesis that inhibiting the soluble epoxide hydrolase (sEH)-mediated degradation of epoxy-fatty acids, notably epoxyeicosatrienoic acids, has an additional impact against cardiovascular damage in insulin resistance, beyond its previously demonstrated beneficial effect on glucose homeostasis. The cardiovascular and metabolic effects of the sEH inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB; 10 mg/l in drinking water) were compared with those of the sulfonylurea glibenclamide (80 mg/l), both administered for 8 wk in FVB mice subjected to a high-fat diet (HFD; 60% fat) for 16 wk. Mice on control chow diet (10% fat) and nontreated HFD mice served as controls. Glibenclamide and t-AUCB similarly prevented the increased fasting glycemia in HFD mice, but only t-AUCB improved glucose tolerance and decreased gluconeogenesis, without modifying weight gain. Moreover, t-AUCB reduced adipose tissue inflammation, plasma free fatty acids, and LDL cholesterol and prevented hepatic steatosis. Furthermore, only the sEH inhibitor improved endothelium-dependent relaxations to acetylcholine, assessed by myography in isolated coronary arteries. This improvement was related to a restoration of epoxyeicosatrienoic acid and nitric oxide pathways, as shown by the increased inhibitory effects of the nitric oxide synthase and cytochrome P-450 epoxygenase inhibitors l-NA and MSPPOH on these relaxations. Moreover, t-AUCB decreased cardiac hypertrophy, fibrosis, and inflammation and improved diastolic function, as demonstrated by the increased E/A ratio (echocardiography) and decreased slope of the end-diastolic pressure-volume relation (invasive hemodynamics). These results demonstrate that sEH inhibition improves coronary endothelial function and prevents cardiac remodeling and diastolic dysfunction in obese insulin-resistant mice. Copyright © 2015 the American Physiological Society.

  5. Twinkle overexpression prevents cardiac rupture after myocardial infarction by alleviating impaired mitochondrial biogenesis.

    Science.gov (United States)

    Inoue, Takahiro; Ikeda, Masataka; Ide, Tomomi; Fujino, Takeo; Matsuo, Yuka; Arai, Shinobu; Saku, Keita; Sunagawa, Kenji

    2016-09-01

    Cardiac rupture is a fatal complication after myocardial infarction (MI). However, the detailed mechanism underlying cardiac rupture after MI remains to be fully elucidated. In this study, we investigated the role of mitochondrial DNA (mtDNA) and mitochondria in the pathophysiology of cardiac rupture by analyzing Twinkle helicase overexpression mice (TW mice). Twinkle overexpression increased mtDNA copy number approximately twofold and ameliorated ischemic cardiomyopathy at day 28 after MI. Notably, Twinkle overexpression markedly prevented cardiac rupture and improved post-MI survival, accompanied by the suppression of MMP-2 and MMP-9 in the MI border area at day 5 after MI when cardiac rupture frequently occurs. Additionally, these cardioprotective effects of Twinkle overexpression were abolished in transgenic mice overexpressing mutant Twinkle with an in-frame duplication of amino acids 353-365, which resulted in no increases in mtDNA copy number. Furthermore, although apoptosis and oxidative stress were induced and mitochondria were damaged in the border area, these injuries were improved in TW mice. Further analysis revealed that mitochondrial biogenesis, including mtDNA copy number, transcription, and translation, was severely impaired in the border area at day 5 In contrast, Twinkle overexpression maintained mtDNA copy number and restored the impaired transcription and translation of mtDNA in the border area. These results demonstrated that Twinkle overexpression alleviated impaired mitochondrial biogenesis in the border area through maintained mtDNA copy number and thereby prevented cardiac rupture accompanied by the reduction of apoptosis and oxidative stress, and suppression of MMP activity. Copyright © 2016 the American Physiological Society.

  6. Preadmission interventions to prevent postoperative complications in older cardiac surgery patients: a systematic review.

    Science.gov (United States)

    Ettema, Roelof G A; Van Koeven, Heleen; Peelen, Linda M; Kalkman, Cor J; Schuurmans, Marieke J

    2014-02-01

    The literature on postoperative complications in cardiac surgery patients shows high incidences of postoperative complications such as delirium, depression, pressure ulcer, infection, pulmonary complications and atrial fibrillation. These complications are associated with functional and cognitive decline and a decrease in the quality of life after discharge. Several studies attempted to prevent one or more postoperative complications by preoperative interventions. Here we provide a comprehensive overview of both single and multiple component preadmission interventions designed to prevent postoperative complications. We systematically reviewed the literature following the PRISMA statement guidelines. Of 1335 initial citations, 31 were subjected to critical appraisal. Finally, 23 studies were included, of which we derived a list of interventions that can be applied in the preadmission period to effectively reduce postoperative depression, infection, pulmonary complications, atrial fibrillation, prolonged intensive care unit stay and hospital stay in older elective cardiac surgery patients. No high quality studies were found describing effective interventions to prevent postoperative delirium. We did not find studies specifically targeting the prevention of pressure ulcers in this patient population. Multi-component approaches that include different single interventions have the strongest effect in preventing postoperative depression, pulmonary complications, prolonged intensive care unit stay and hospital stay. Postoperative infection can be best prevented by disinfection with chlorhexidine combined with immune-enhancing nutritional supplements. Atrial fibrillation might be prevented by ingestion of N-3 polyunsaturated fatty acids. High quality studies are urgently needed to evaluate preadmission preventive strategies to reduce postoperative delirium or pressure ulcers in older elective cardiac surgery patients. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Secondary prevention through cardiac rehabilitation: from knowledge to implementation. A position paper from the Cardiac Rehabilitation Section of the European Association of Cardiovascular Prevention and Rehabilitation

    DEFF Research Database (Denmark)

    Piepoli, Massimo Francesco; Corrà, Ugo; Benzer, Werner

    2010-01-01

    ) to cardiovascular health outcomes. Secondary prevention through exercise-based CR is the intervention with the best scientific evidence to contribute to decrease morbidity and mortality in coronary artery disease, in particular after myocardial infarction but also incorporating cardiac interventions and chronic...... makers and consumers in the recognition of the comprehensive nature of CR. Those charged with responsibility for secondary prevention of cardiovascular disease, whether at European, national or individual centre level, need to consider where and how structured programmes of CR can be delivered to all...... patients eligible. Thus a novel, disease-oriented document has been generated, where all components of CR for cardiovascular conditions have been revised, presenting both well-established and controversial aspects. A general table applicable to all cardiovascular conditions and specific tables for each...

  8. Efficacy of ranolazine in preventing atrial fibrillation following cardiac surgery: Results from a meta-analysis

    Directory of Open Access Journals (Sweden)

    Chintan Trivedi, MD, MPH

    2017-06-01

    Conclusions: Ranolazine may prove beneficial in POAF prevention following cardiac surgeries. Although the pooled treatment effect is quite impressive with a reduction of more than 50% of risk of developing POAF, small number of studies and variation in ranolazine dose regimen in each study make our results inconclusive, but worthy of further investigation. That is why this result has to be interpreted as only hypothesis generating, rather than conclusion drawing.

  9. Practical prevention of cardiac remodeling and atrial fibrillation with full-spectrum antioxidant therapy and ancillary strategies.

    Science.gov (United States)

    McCarty, Mark F

    2010-08-01

    A wealth of research data points to increased oxidative stress as a key driver of the cardiac remodeling triggered by chronic pressure overload, loss of functional myocardial tissue, or atrial fibrillation. Oxidative stress is a mediator of the cardiomyocyte hypertrophy and apoptosis, the cardiac fibrosis, and the deficits in cardiac function which typify this syndrome, and may play a role in initiating and sustaining atrial fibrillation. Nox2- and Nox4-dependent NADPH oxidase activity appears to be a major source of this oxidative stress, and oxidants can induce conformational changes in xanthine dehydrogenase, nitric oxide synthase, and the mitochondrial respiratory chain which increase their capacity to generate superoxide as well. Consistent with these insights, various synthetic antioxidants have been shown to suppress cardiac remodeling in rodents subjected to myocardial infarction, aortic constriction, or rapid atrial pacing. It may prove feasible to achieve comparable benefits in humans through use of a "full-spectrum antioxidant therapy" (FSAT) that features a complementary array of natural antioxidants. Spirulina is a rich source of phycocyanobilin, a derivative and homolog of biliverdin that appears to mimic the potent inhibitory impact of biliverdin and free bilirubin on NADPH oxidase activity. Mega-doses of folate can markedly increase intracellular levels of tetrahydrofolates which have potent and versatile radical-scavenging activities - including efficient quenching of peroxynitrite-derived radicals Supplemental coenzyme Q10, already shown to improve heart function in clinical congestive failure, can provide important antioxidant protection to mitochondria. Phase 2 inducer nutraceuticals such as lipoic acid, administered in conjunction with N-acetylcysteine, have the potential to blunt the impact of oxidative stress by boosting myocardial levels of glutathione. While taurine can function as an antioxidant for myeloperoxidase-derived radicals, its

  10. Secondary prevention through cardiac rehabilitation: physical activity counselling and exercise training: key components of the position paper from the Cardiac Rehabilitation Section of the European Association of Cardiovascular Prevention and Rehabilitation

    DEFF Research Database (Denmark)

    Corrà, Ugo; Piepoli, Massimo F; Carré, François

    2010-01-01

    and global long-term care of cardiac patients. The CR approach is delivered in tandem with a flexible follow-up strategy and easy access to a specialized team. To promote implementation of cardiac prevention and rehabilitation, the CR Section of the EACPR (European Association of Cardiovascular Prevention......, exercise training, diet/nutritional counselling, weight control management, lipid management, blood pressure monitoring, smoking cessation, and psychosocial management. Cardiac rehabilitation services are by definition multi-factorial and comprehensive, with physical activity counselling and exercise...

  11. Atrial fibrillation after cardiac surgery: Prevention and management: The Australasian experience.

    Science.gov (United States)

    Alawami, Mohammed; Chatfield, Andrew; Ghashi, Rajaie; Walker, Laurence

    2018-01-01

    Atrial fibrillation (AF) after cardiac surgery is a major health problem that is associated with a significant financial burden. This paper aims to highlight this problem and review the current guidelines in the prevention and management of AF after cardiac surgery, providing our experience in the Australasian centers. We conducted a literature review using mainly PubMed to compare the current practice with the available evidence. EMBASE and Cochrane library were also searched. We concurrently developed an online questionnaire to collect data from other Australasian centers regarding their approach to this problem. We identified 194 studies that were considered relevant to our research. We did not find any formal protocols published in the literature. From our Australasian experience; seven centers (58%) had a protocol for AF prophylaxis. The protocols included electrolytes replacement, use of amiodarone and/or β-blockers. Other strategies were occasionally used but were not part of a structured protocol. The development of an integrated medical and surgical protocol for the prophylaxis of AF after cardiac surgery is an important aspect for the care of postoperative cardiac patients. Considerations of prophylactic strategies other than those routinely used should be included in the protocol. This area should receive considerable attention in order to reduce the postoperative complications and health costs.

  12. Exercise-induced cardiac remodeling in non-elite endurance athletes: Comparison of 2-tiered and 4-tiered classification of left ventricular hypertrophy.

    Science.gov (United States)

    Trachsel, Lukas D; Ryffel, Christoph P; De Marchi, Stefano; Seiler, Christian; Brugger, Nicolas; Eser, Prisca; Wilhelm, Matthias

    2018-01-01

    Long-term endurance sport practice leads to eccentric left ventricular hypertrophy (LVH). We aimed to compare the new 4-tiered classification (4TC) for LVH with the established 2-tiered classification (2TC) in a cohort of normotensive non-elite endurance athletes. Male participants of a 10-mile race were recruited and included when blood pressure (BP) was normal (athletes recruited, 174 were included. Mean age was 41.6±7.5 years. Forty-two (24%) athletes had LVH. Allocation in the 2TC was: 32 (76%) eccentric LVH and 10 (24%) concentric LVH. Using the 4TC 12 were reclassified to concentric LVH, and 2 to eccentric LVH, resulting in 22 (52%) eccentric LVH (7 non-dilated, 15 dilated), and 20 (48%) concentric LVH (all non-dilated). Based on the 2TC, markers of endurance training did not differ between eccentric and concentric LVH. Based on the 4TC, athletes with eccentric LVH had more cumulative training hours and faster race times, with highest values thereof in athletes with eccentric dilated LVH. In our cohort of normotensive endurance athletes, the new 4TC demonstrated a superior discrimination of exercise-induced LVH patterns, compared to the established 2TC, most likely because it takes three-dimensional information of the ventricular geometry into account.

  13. [Primary and secondary prevention of sudden cardiac death in the ICD Registry-Latin America].

    Science.gov (United States)

    Ramos, Jose L; Muratore, Claudio; Pachón Mateos, José C; Rodríguez, Angel; González Hermosillo, Antonio; Asenjo, René; Rodríguez, Diego; Galvao, Silas; Duque, Mauricio; Escudero, Jaime; Reyes Caorsi, Walter; Cuvillier, Erick; Maloney, Jennifer

    2008-01-01

    The ICD Registry is an observational study conducted in Latin America to collect data on indications and follow-up care for primary or secondary prevention of sudden cardiac death patients. The objective of this study is to compare and evaluate the characteristics of primary versus secondary prevention in the patient population enrolled in the registry. Demographic data, indication, etiology, NYHA functional class and left ventricular ejection fraction (LVEF), pharmacological treatment at implant and the type of ICD implanted were also collected. During the follow-up period the ICD therapies delivered, patient hospitalizations and mortality were evaluated. 507 patients were evaluated. Average age 60 +/- 14 years old, 78% male. Coronary heart disease was the most common etiology (43.6%). NYHA Functional Class I/II at the time of implant (73.6%). Average LVEF was 34 +/- 16%. Out of 507 patients, 189 received an ICD for primary prevention; 318 for secondary prevention. Primary prevention patients were older, predominantly male and had a lower EF. The rate of mortality and hospitalizations were similar between both groups with a higher rate of appropriate therapies in secondary prevention patients. This is the first study to demonstrate clinical characteristics of primary prevention patients in Latin America. There were no significant statistically differences in a short follow-up period in mortality or hospitalization as compared to the secondary prevention patient population in the Registry.

  14. Garlic activates SIRT-3 to prevent cardiac oxidative stress and mitochondrial dysfunction in diabetes.

    Science.gov (United States)

    Sultana, Md Razia; Bagul, Pankaj K; Katare, Parameshwar B; Anwar Mohammed, Soheb; Padiya, Raju; Banerjee, Sanjay K

    2016-11-01

    Cardiac complications are major contributor in the mortality of diabetic people. Mitochondrial dysfunctioning is a crucial contributor for the cardiac complications in diabetes, and SIRT-3 remains the major mitochondrial deacetylase. We hypothesized whether garlic has any role on SIRT-3 to prevent mitochondrial dysfunction in diabetic heart. Rats with developed hyperglycemia after STZ injection were divided into two groups; diabetic (Dia) and diabetic+garlic (Dia+Garl). Garlic was administered at a dose of 250mg/kg/day, orally for four weeks. An additional group was maintained to evaluate the effect of raw garlic administration on control rat heart. We have observed altered functioning of cardiac mitochondrial enzymes involved in metabolic pathways, and increased levels of cardiac ROS with decreased activity of catalase and SOD in diabetic rats. Cardiac mRNA expression of TFAM, PGC-1α, and CO1 was also altered in diabetes. In addition, reduced levels of electron transport chain complexes that observed in Dia group were normalized with garlic administration. This indicates the presence of increased oxidative stress with mitochondrial dysfunctioning in diabetic heart. We have observed reduced activity of SIRT3 and increased acetylation of MnSOD. Silencing SIRT-3 in cells also revealed the same. However, administration of garlic improved the SIRT-3 and MnSOD activity, by deacetylating MnSOD. Increased SOD activity was correlated with reduced levels of ROS in garlic-administered rat hearts. Collectively, our results provide an insight into garlic's protection to T1DM heart through activation of SIRT3-MnSOD pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Oral triiodothyronine for the prevention of thyroid hormone reduction in adult valvular cardiac surgery

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    A.P.A. Magalhães

    2006-07-01

    Full Text Available Treatment of non-thyroidal illness by intravenous triiodothyronine (T3 after cardiac surgery causes a disproportional elevation of hormone levels. The administration of oral T3, which has never been studied in this context, could cause physiological hormone levels. The aim of this study was to test oral T3 for the prevention of T3 reduction during the postoperative period of valvular cardiac surgery in adults. Eighteen patients who underwent cardiac surgery for valvular disease with invasive hemodynamic monitoring were randomly assigned to 2 groups: the T group received oral T3 (N = 8, 25 µg three times/day, initiated 24 h before surgery and maintained for 48 h and the NT group (N = 10 received placebo. Serum T3, thyroxine and thyrotropin were determined at baseline, 1 h before surgery, within 30 min of cardiopulmonary bypass and 6, 12, 24, and 48 h after removal of the aortic cross-clamp. Baseline T3 was similar in both groups (T: 119 ± 13; NT: 131 ± 9 ng/dL. Serum T3 increased during the first 24 h in the T group compared to the NT group (232 ± 18 vs 151 ± 13 ng/dL; P < 0.001. In the NT group, T3 was reduced by 24% (P = 0.007 6 h after removal of the aortic cross-clamp, confirming the non-thyroidal illness syndrome. There were no differences in clinical or hemodynamic parameters between groups. Administration of oral T3 prevented its serum reduction after valvular cardiac surgery in adults, with normal serum levels for 48 h without disproportional elevations.

  16. Sudden cardiac death in athletes and its preventive strategies: review article

    Directory of Open Access Journals (Sweden)

    Farzin Halabchi

    2017-12-01

    Full Text Available Sudden cardiac death in sport, although rare, but is a tragic event, attracting the media and public attention. Sport and exercise may act as a trigger for sudden cardiac death. Risk of sudden death in young athletes with cardiovascular disease is 2.5 times more frequent than non-athlete individuals. More than 90% of cases of sudden death occur during or immediately after training or competition. Incidence of sudden cardiac death in any population, including athletes, is related to multiple factors such as gender, age, race, nationality, diagnostic screening methods and preventive measures for sudden cardiac death. Otherwise, incidence rate of sudden cardiac death is linked to the used definition and method of diagnosis. Different cardiovascular disorders may result in death of young athletes and hypertrophic cardiomyopathy, congenital coronary anomalies, arrhythmogenic right ventricular dysplasia and aortic rupture are among the most common causes. Marfan syndrome, dilated cardiomyopathy, viral myocarditis, Wolff-Parkinson-White (WPW syndrome, congenital long QT syndrome, Brugada syndrome and commotio cordis are reported as other etiologies. In older athletes (more than 35 years, ischemic coronary heart disease is responsible for majority of the cases similar to the general population. Because the outcome of sudden cardiac arrest in sports is very poor except in few cases, proper national strategies are needed to diminish the burden of sudden death in young athletes. It seems that there are two main strategies to achieve this goal: A Primary prevention with use of purposeful pre-participation evaluation programs. This evaluation should focuss on the proper history and physical examination. Nevertheless, there is significant debate between American and European countries regarding the use of paraclinical investigations (especially ECG. American heart association does not recommend ECG as an essential part of evaluation. In contrast, European

  17. Left ventricular hypertrophy index based on a combination of frontal and transverse planes in the ECG and VCG: Diagnostic utility of cardiac vectors

    Science.gov (United States)

    Bonomini, Maria Paula; Juan Ingallina, Fernando; Barone, Valeria; Antonucci, Ricardo; Valentinuzzi, Max; Arini, Pedro David

    2016-04-01

    The changes that left ventricular hypertrophy (LVH) induces in depolarization and repolarization vectors are well known. We analyzed the performance of the electrocardiographic and vectorcardiographic transverse planes (TP in the ECG and XZ in the VCG) and frontal planes (FP in the ECG and XY in the VCG) to discriminate LVH patients from control subjects. In an age-balanced set of 58 patients, the directions and amplitudes of QRS-complexes and T-wave vectors were studied. The repolarization vector significantly decreased in modulus from controls to LVH in the transverse plane (TP: 0.45±0.17mV vs. 0.24±0.13mV, p<0.0005 XZ: 0.43±0.16mV vs. 0.26±0.11mV, p<0.005) while the depolarization vector significantly changed in angle in the electrocardiographic frontal plane (Controls vs. LVH, FP: 48.24±33.66° vs. 46.84±35.44°, p<0.005, XY: 20.28±35.20° vs. 19.35±12.31°, NS). Several LVH indexes were proposed combining such information in both ECG and VCG spaces. A subset of all those indexes with AUC values greater than 0.7 was further studied. This subset comprised four indexes, with three of them belonging to the ECG space. Two out of the four indexes presented the best ROC curves (AUC values: 0.78 and 0.75, respectively). One index belonged to the ECG space and the other one to the VCG space. Both indexes showed a sensitivity of 86% and a specificity of 70%. In conclusion, the proposed indexes can favorably complement LVH diagnosis

  18. Nitroxyl (HNO stimulates soluble guanylyl cyclase to suppress cardiomyocyte hypertrophy and superoxide generation.

    Directory of Open Access Journals (Sweden)

    Eliane Q Lin

    Full Text Available New therapeutic targets for cardiac hypertrophy, an independent risk factor for heart failure and death, are essential. HNO is a novel redox sibling of NO• attracting considerable attention for the treatment of cardiovascular disorders, eliciting cGMP-dependent vasodilatation yet cGMP-independent positive inotropy. The impact of HNO on cardiac hypertrophy (which is negatively regulated by cGMP however has not been investigated.Neonatal rat cardiomyocytes were incubated with angiotensin II (Ang II in the presence and absence of the HNO donor Angeli's salt (sodium trioxodinitrate or B-type natriuretic peptide, BNP (all 1 µmol/L. Hypertrophic responses and its triggers, as well as cGMP signaling, were determined.We now demonstrate that Angeli's salt inhibits Ang II-induced hypertrophic responses in cardiomyocytes, including increases in cardiomyocyte size, de novo protein synthesis and β-myosin heavy chain expression. Angeli's salt also suppresses Ang II induction of key triggers of the cardiomyocyte hypertrophic response, including NADPH oxidase (on both Nox2 expression and superoxide generation, as well as p38 mitogen-activated protein kinase (p38MAPK. The antihypertrophic, superoxide-suppressing and cGMP-elevating effects of Angeli's salt were mimicked by BNP. We also demonstrate that the effects of Angeli's salt are specifically mediated by HNO (with no role for NO• or nitrite, with subsequent activation of cardiomyocyte soluble guanylyl cyclase (sGC and cGMP signaling (on both cGMP-dependent protein kinase, cGK-I and phosphorylation of vasodilator-stimulated phosphoprotein, VASP.Our results demonstrate that HNO prevents cardiomyocyte hypertrophy, and that cGMP-dependent NADPH oxidase suppression contributes to these antihypertrophic actions. HNO donors may thus represent innovative pharmacotherapy for cardiac hypertrophy.

  19. Sensibilidade do eletrocardiograma na hipertrofia ventricular de acordo com gênero e massa cardíaca Electrocardiogram sensitivity in left ventricular hypertrophy according to gender and cardiac mass

    Directory of Open Access Journals (Sweden)

    Ana P. Colossimo

    2011-09-01

    Full Text Available FUNDAMENTO: Sabe-se que vários fatores interferem na sensibilidade do Eletrocardiograma (ECG no diagnóstico da Hipertrofia Ventricular Esquerda (HVE, sendo o gênero e a massa cardíaca alguns dos principais. OBJETIVO: Avaliar a influência do sexo na sensibilidade de alguns dos critérios utilizados para a detecção de HVE, de acordo com a progressão do grau de hipertrofia ventricular. MÉTODOS: De acordo com o gênero e com o grau de HVE ao ecocardiograma, os pacientes foram divididos em três grupos: HVE leve, moderada e severa. Avaliou-se a sensibilidade do ECG para detectar HVE entre homens e mulheres, conforme o grau de HVE. RESULTADOS: Dos 874 pacientes, 265 eram homens (30,3% e 609, mulheres (69,7%. Os critérios [(S + R X QRS], Sokolow-Lyon, Romhilt-Estes, Perúgia e padrão strain mostraram alto poder discriminatório no diagnóstico de HVE entre homens e mulheres nos três grupos de HVE, com desempenho superior na população masculina e destaque para os escores [(S + R X QRS] e Perúgia. CONCLUSÃO: A sensibilidade diagnóstica do ECG é maior com o aumento da massa cardíaca. O exame é mais sensível entre homens, destacando-se os escores [(S + R X QRS] e Perúgia.BACKGROUND: Several factors are known to interfere with electrocardiogram (ECG sensitivity when diagnosing Left Ventricular Hypertrophy (LVH, with gender and cardiac mass being two of the most important ones OBJECTIVE: To evaluate the influence of gender on the sensitivity of some of the criteria used to detect LVH, according to the progression of ventricular hypertrophy degree. METHODS: According to gender and the degree of LVH at the echocardiogram, the patients were divided in three groups: mild, moderate and severe LVH. ECG sensitivity to detect LVH was assessed between men and women, according to the LVH degree. RESULTS: Of the 874 patients, 265 were males (30.3% and 609, females (69.7%. The [(S + R X QRS], Sokolow-Lyon, Romhilt-Estes, Perugia and strain criteria

  20. Cardiomyopathies as a Cause of Sudden Cardiac Death (SCD in Egypt: Recognition and Preventive Strategies Needed

    Directory of Open Access Journals (Sweden)

    Nora Fnon

    2016-06-01

    Full Text Available This study aimed at evaluating the epidemiological characteristics and pathological features of different types of cardiomyopathies in Egypt, highlighting the role of the forensic pathologist in identifying cases of cardiomyopathies and initiating for their families a possible genetic study aiming at prevention of sudden death. All cases with sudden cardiac death (SCD due to cardiomyopathies during the period from the beginning of January 2010 until the end of December 2014 (5 years were included in this study. All hearts underwent detailed gross and histological examination. Circumstances of death, medical history, and post-mortem pathological findings were thoroughly  investigated. Out of 535 cases of sudden cardiac death, there were 22 cases (4.1% diagnosed as having cardiomyopathies; sudden death was their first presentation. Eighteen cases (81.8% were male, with the 4th decade (11 cases, 50% being the most affected age; severe physical activity and exertion were evident in death circumstances of 14 cases (63.6%; pathological evaluation revealed that hypertrophic cardiomyopathy was the most frequent type, being diagnosed in 10 cases (45%. Cardiomyopathies are an infrequent cause of sudden cardiac death. Most deaths are in children and adults, so cases are of high social impact that demands multidisciplinary research and resources. In all cases of SCD, forensic autopsy should be done. Forensic study is the key to identifying an affected family and the starting point regarding assessing them.

  1. Humanin prevents brain mitochondrial dysfunction in a cardiac ischaemia-reperfusion injury model.

    Science.gov (United States)

    Kumfu, Sirinart; Charununtakorn, Savitree T; Jaiwongkam, Thidarat; Chattipakorn, Nipon; Chattipakorn, Siriporn C

    2016-06-01

    What is the central question of this study? Myocardial ischaemia-reperfusion (I/R) injury causes interference in the systemic circulation and damages not only the heart but also several vital organs, including the brain. Recently, a novel peptide called humanin has been shown to exert potent neuroprotective effects. However, the effect of humanin on the brain during cardiac I/R injury has not yet been investigated. What is the main finding and its importance? The I/R injury caused blood-brain barrier breakdown, increased brain oxidative stress and resulted in mitochondrial dysfunction. Only the humanin treatment before ischaemia attenuated brain mitochondrial dysfunction, but it did not prevent blood-brain barrier breakdown or brain oxidative stress. Humanin treatment during ischaemia and in the reperfusion period provided no neuroprotection. These findings indicate that humanin exerted neuroprotection during cardiac I/R injury via improved brain mitochondrial function. Myocardial ischaemia-reperfusion (I/R) injury causes interference in the systemic circulation and damages not only the heart but also several vital organs, including the brain. Nevertheless, limited information is available regarding the effect of cardiac I/R injury on the brain, including blood-brain barrier (BBB) breakdown, brain oxidative stress and mitochondrial function. Recently, a novel peptide called humanin has been shown to exert potent neuroprotective effects. However, the effect of humanin on the brain during cardiac I/R injury has not yet been investigated. Forty-two male Wistar rats were divided into the following two groups: an I/R group, which was subjected to a 30 min left anterior descending coronary artery occlusion followed by 120 min reperfusion (I/R group; n = 36); and a sham group (n = 6). The I/R group was divided into six subgroups. Each subgroup was given either vehicle or humanin analogue (84 μg kg(-1) , i.v.) at three different time points, namely before

  2. Prevention of Cardiomyopathy in Transfusion-Dependent Homozygous Thalassaemia Today and the Role of Cardiac Magnetic Resonance Imaging

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    Athanassios Aessopos

    2009-01-01

    Full Text Available Transfusion and iron chelation therapy revolutionised survival and reduced morbidity in patients with transfusion-dependent beta thalassaemia major. Despite these improvements, cardiac disease remained the most common cause of death in those patients. Recently the ability to determine the degree of cardiac iron overload, through cardiac magnetic resonance imaging (CMR has allowed more logical approaches to iron removal, particularly from the heart. The availability of two oral chelators, deferiprone and deferasirox has reduced the need for the injectable chelator deferrioxamine and an additional benefit has been that deferiprone has been shown to be more cardioprotective than deferrioxamine. This review on the prevention of cardiac disease makes recommendations on the chelation regime that would be desirable for patients according to their cardiac iron status as determined by CMR determined by CMR. It also discusses approaches to chelation management should CMR not be available.

  3. Manual hyperinflation partly prevents reductions of functional residual capacity in cardiac surgical patients--a randomized controlled trial

    NARCIS (Netherlands)

    Paulus, Frederique; Veelo, Denise P.; de Nijs, Selma B.; Beenen, Ludo F. M.; Bresser, Paul; de Mol, Bas A. J. M.; Binnekade, Jan M.; Schultz, Marcus J.

    2011-01-01

    Cardiac surgery is associated with post-operative reductions of functional residual capacity (FRC). Manual hyperinflation (MH) aims to prevent airway plugging, and as such could prevent the reduction of FRC after surgery. The main purpose of this study was to determine the effect of MH on

  4. Galectin-1 Prevents Infection and Damage Induced by Trypanosoma cruzi on Cardiac Cells

    Science.gov (United States)

    Benatar, Alejandro F.; García, Gabriela A.; Bua, Jacqeline; Cerliani, Juan P.; Postan, Miriam; Tasso, Laura M.; Scaglione, Jorge; Stupirski, Juan C.; Toscano, Marta A.

    2015-01-01

    Background Chronic Chagas cardiomyopathy caused by Trypanosoma cruzi is the result of a pathologic process starting during the acute phase of parasite infection. Among different factors, the specific recognition of glycan structures by glycan-binding proteins from the parasite or from the mammalian host cells may play a critical role in the evolution of the infection. Methodology and Principal Findings Here we investigated the contribution of galectin–1 (Gal–1), an endogenous glycan-binding protein abundantly expressed in human and mouse heart, to the pathophysiology of T. cruzi infection, particularly in the context of cardiac pathology. We found that exposure of HL–1 cardiac cells to Gal–1 reduced the percentage of infection by two different T. cruzi strains, Tulahuén (TcVI) and Brazil (TcI). In addition, Gal–1 prevented exposure of phosphatidylserine and early events in the apoptotic program by parasite infection on HL–1 cells. These effects were not mediated by direct interaction with the parasite surface, suggesting that Gal–1 may act through binding to host cells. Moreover, we also observed that T. cruzi infection altered the glycophenotype of cardiac cells, reducing binding of exogenous Gal–1 to the cell surface. Consistent with these data, Gal–1 deficient (Lgals1 -/-) mice showed increased parasitemia, reduced signs of inflammation in heart and skeletal muscle tissues, and lower survival rates as compared to wild-type (WT) mice in response to intraperitoneal infection with T. cruzi Tulahuén strain. Conclusion/Significance Our results indicate that Gal–1 modulates T. cruzi infection of cardiac cells, highlighting the relevance of galectins and their ligands as regulators of host-parasite interactions. PMID:26451839

  5. Gender and post-ischemic recovery of hypertrophied rat hearts

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    Popov Kirill M

    2006-03-01

    Full Text Available Abstract Background Gender influences the cardiac response to prolonged increases in workload, with differences at structural, functional, and molecular levels. However, it is unknown if post-ischemic function or metabolism of female hypertrophied hearts differ from male hypertrophied hearts. Thus, we tested the hypothesis that gender influences post-ischemic function of pressure-overload hypertrophied hearts and determined if the effect of gender on post-ischemic outcome could be explained by differences in metabolism, especially the catabolic fate of glucose. Methods Function and metabolism of isolated working hearts from sham-operated and aortic-constricted male and female Sprague-Dawley rats before and after 20 min of no-flow ischemia (N = 17 to 27 per group were compared. Parallel series of hearts were perfused with Krebs-Henseleit solution containing 5.5 mM [5-3H/U-14C]-glucose, 1.2 mM [1-14C]-palmitate, 0.5 mM [U-14C]-lactate, and 100 mU/L insulin to measure glycolysis and glucose oxidation in one series and oxidation of palmitate and lactate in the second. Statistical analysis was performed using two-way analysis of variance. The sequential rejective Bonferroni procedure was used to correct for multiple comparisons and tests. Results Female gender negatively influenced post-ischemic function of non-hypertrophied hearts, but did not significantly influence function of hypertrophied hearts after ischemia such that mass-corrected hypertrophied heart function did not differ between genders. Before ischemia, glycolysis was accelerated in hypertrophied hearts, but to a greater extent in males, and did not differ between male and female non-hypertrophied hearts. Glycolysis fell in all groups after ischemia, except in non-hypertrophied female hearts, with the reduction in glycolysis after ischemia being greatest in males. Post-ischemic glycolytic rates were, therefore, similarly accelerated in hypertrophied male and female hearts and higher in

  6. Hypertrophy signaling pathways in experimental chronic aortic regurgitation

    DEFF Research Database (Denmark)

    Olsen, Niels Thue; Dimaano, Veronica L; Fritz-Hansen, Thomas

    2013-01-01

    The development of left ventricular hypertrophy and dysfunction in aortic regurgitation (AR) has only been sparsely studied experimentally. In a new model of chronic AR in rats, we examined activation of molecular pathways involved in myocardial hypertrophy. Chronic AR was produced by damaging one...... at both 2 and 12 weeks, while activation of calcium/calmodulin-dependent protein kinase II and extracellular regulated kinase 1/2 was unchanged. Expression of calcineurin and ANF was also unchanged. Eccentric hypertrophy and early cardiac dysfunction in experimental AR are associated with a pattern...... of activation of intracellular pathways different from that seen with pathological hypertrophy in pressure overload, and more similar to that associated with benign physiological hypertrophy....

  7. PONTIAC (NT-proBNP selected prevention of cardiac events in a population of diabetic patients without a history of cardiac disease): a prospective randomized controlled trial.

    Science.gov (United States)

    Huelsmann, Martin; Neuhold, Stephanie; Resl, Michael; Strunk, Guido; Brath, Helmut; Francesconi, Claudia; Adlbrecht, Christopher; Prager, Rudolf; Luger, Anton; Pacher, Richard; Clodi, Martin

    2013-10-08

    The study sought to assess the primary preventive effect of neurohumoral therapy in high-risk diabetic patients selected by N-terminal pro-B-type natriuretic peptide (NT-proBNP). Few clinical trials have successfully demonstrated the prevention of cardiac events in patients with diabetes. One reason for this might be an inaccurate selection of patients. NT-proBNP has not been assessed in this context. A total of 300 patients with type 2 diabetes, elevated NT-proBNP (>125 pg/ml) but free of cardiac disease were randomized. The "control" group was cared for at 4 diabetes care units; the "intensified" group was additionally treated at a cardiac outpatient clinic for the up-titration of renin-angiotensin system (RAS) antagonists and beta-blockers. The primary endpoint was hospitalization/death due to cardiac disease after 2 years. At baseline, the mean age of the patients was 67.5 ± 9 years, duration of diabetes was 15 ± 12 years, 37% were male, HbA1c was 7 ± 1.1%, blood pressure was 151 ± 22 mm Hg, heart rate was 72 ± 11 beats/min, median NT-proBNP was 265.5 pg/ml (interquartile range: 180.8 to 401.8 pg/ml). After 12 months there was a significant difference between the number of patients treated with a RAS antagonist/beta-blocker and the dosage reached between groups (p titration of RAS antagonists and beta-blockers to maximum tolerated dosages is an effective and safe intervention for the primary prevention of cardiac events for diabetic patients pre-selected using NT-proBNP. (Nt-proBNP Guided Primary Prevention of CV Events in Diabetic Patients [PONTIAC]; NCT00562952). Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  8. Cure and prevention strategy for postoperative gastrointestinal fistula after esophageal and gastric cardiac cancer surgery.

    Science.gov (United States)

    Han, Youkui; Zhao, Hui; Xu, HongRui; Liu, Shuzhong; Li, Li; Jiang, Chunyang; Yang, Bingjun

    2014-01-01

    Gastrointestinal fistula is the most serious complication of esophageal and gastric cardiac cancer surgery. According to occurrence of organ, gastrointestinal fistula can be divided into anastomotic fistula, gastric fistula; According to occurrence site, fistula can be divided into cervical fistula, thoracic fistula; According to time of occurrence, can be divided into early, middle and late fistula. There are special types of fistula including ‘thoracic cavity’-stomach-bronchial fistula, ‘thoracic cavity’-stomach-aortic fistula. Early diagnosis needs familiarity with various types of clinical gastrointestinal fistulas. However, Prevention of gastrointestinal fistula is better than cure, including perioperative nutritional support, respiratory tract management, and acid suppression, positive treatment of complications, antibiotic prophylaxis, and gastrointestinal decompression and eating timing. Prevention can effectively reduce the incidence of postoperative gastrointestinal fistula. Collectively, early diagnosis and treatment, nutritional supports are key to reducing mortality of gastrointestinal fistula.

  9. The Amino-Terminal Domain of GRK5 Inhibits Cardiac Hypertrophy through the Regulation of Calcium-Calmodulin Dependent Transcription Factors.

    Science.gov (United States)

    Sorriento, Daniela; Santulli, Gaetano; Ciccarelli, Michele; Maione, Angela Serena; Illario, Maddalena; Trimarco, Bruno; Iaccarino, Guido

    2018-03-15

    We have recently demonstrated that the amino-terminal domain of G protein coupled receptor kinase (GRK) type 5, (GRK5-NT) inhibits NFκB activity in cardiac cells leading to a significant amelioration of LVH. Since GRK5-NT is known to bind calmodulin, this study aimed to evaluate the functional role of GRK5-NT in the regulation of calcium-calmodulin-dependent transcription factors. We found that the overexpression of GRK5-NT in cardiomyoblasts significantly reduced the activation and the nuclear translocation of NFAT and its cofactor GATA-4 in response to phenylephrine (PE). These results were confirmed in vivo in spontaneously hypertensive rats (SHR), in which intramyocardial adenovirus-mediated gene transfer of GRK5-NT reduced both wall thickness and ventricular mass by modulating NFAT and GATA-4 activity. To further verify in vitro the contribution of calmodulin in linking GRK5-NT to the NFAT/GATA-4 pathway, we examined the effects of a mutant of GRK5 (GRK5-NTPB), which is not able to bind calmodulin. When compared to GRK5-NT, GRK5-NTPB did not modify PE-induced NFAT and GATA-4 activation. In conclusion, this study identifies a double effect of GRK5-NT in the inhibition of LVH that is based on the regulation of multiple transcription factors through means of different mechanisms and proposes the amino-terminal sequence of GRK5 as a useful prototype for therapeutic purposes.

  10. The Amino-Terminal Domain of GRK5 Inhibits Cardiac Hypertrophy through the Regulation of Calcium-Calmodulin Dependent Transcription Factors

    Directory of Open Access Journals (Sweden)

    Daniela Sorriento

    2018-03-01

    Full Text Available We have recently demonstrated that the amino-terminal domain of G protein coupled receptor kinase (GRK type 5, (GRK5-NT inhibits NFκB activity in cardiac cells leading to a significant amelioration of LVH. Since GRK5-NT is known to bind calmodulin, this study aimed to evaluate the functional role of GRK5-NT in the regulation of calcium-calmodulin-dependent transcription factors. We found that the overexpression of GRK5-NT in cardiomyoblasts significantly reduced the activation and the nuclear translocation of NFAT and its cofactor GATA-4 in response to phenylephrine (PE. These results were confirmed in vivo in spontaneously hypertensive rats (SHR, in which intramyocardial adenovirus-mediated gene transfer of GRK5-NT reduced both wall thickness and ventricular mass by modulating NFAT and GATA-4 activity. To further verify in vitro the contribution of calmodulin in linking GRK5-NT to the NFAT/GATA-4 pathway, we examined the effects of a mutant of GRK5 (GRK5-NTPB, which is not able to bind calmodulin. When compared to GRK5-NT, GRK5-NTPB did not modify PE-induced NFAT and GATA-4 activation. In conclusion, this study identifies a double effect of GRK5-NT in the inhibition of LVH that is based on the regulation of multiple transcription factors through means of different mechanisms and proposes the amino-terminal sequence of GRK5 as a useful prototype for therapeutic purposes.

  11. Dietary Omega-3 Fatty Acids Prevented Adipocyte Hypertrophy by Downregulating DGAT-2 and FABP-4 in a Sex-Dependent Fashion.

    Science.gov (United States)

    Balogun, Kayode A; Cheema, Sukhinder K

    2016-01-01

    Obesity is characterized by an increase in fat mass primarily as a result of adipocyte hypertrophy. Diets enriched in omega (n)-3 polyunsaturated fatty acids (PUFA) are suggested to reduce obesity, however, the mechanisms are not well understood. We investigated the effect of n-3 PUFA on adipocyte hypertrophy and the key genes involved in adipocyte hypertrophy. Female C57BL/6 mice were fed semi-purified diets (20 % w/w fat) containing high n-3 PUFA before mating, during pregnancy, and until weaning. Male and female offspring were continued on high n-3 PUFA (10 % w/w), medium n-3 PUFA (4 % w/w), or low n-3 PUFA (2 % w/w) diet for 16 weeks postweaning. Adipocyte area was quantified using microscopy, and gonadal mRNA expression of acyl CoA:diacylglycerol acyltransferase-2 (DGAT-2), fatty acid binding protein-4 (FABP-4) and leptin were measured. The high n-3 PUFA group showed higher levels of total n-3 PUFA in gonadal TAG compared to the medium and low n-3 PUFA groups (P hypertrophy by downregulating FABP-4, DGAT-2 and leptin; the effects are however sex-specific.

  12. Carvedilol for prevention of atrial fibrillation after cardiac surgery: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Hui-Shan Wang

    Full Text Available BACKGROUND: Postoperative atrial fibrillation (POAF remains the most common complication after cardiac surgery. Current guidelines recommend β-blockers to prevent POAF. Carvedilol is a non-selective β-adrenergic blocker with anti-inflammatory, antioxidant, and multiple cationic channel blocking properties. These unique properties of carvedilol have generated interest in its use as a prophylaxis for POAF. OBJECTIVE: To investigate the efficacy of carvedilol in preventing POAF. METHODS: PubMed from the inception to September 2013 was searched for studies assessing the effect of carvedilol on POAF occurrence. Pooled relative risk (RR with 95% confidence interval (CI was calculated using random- or fixed-effect models when appropriate. Six comparative trials (three randomized controlled trials and three nonrandomized controlled trials including 765 participants met the inclusion criteria. RESULTS: Carvedilol was associated with a significant reduction in POAF (relative risk [RR] 0.49, 95% confidence interval [CI] 0.37 to 0.64, p<0.001. Subgroup analyses yielded similar results. In a subgroup analysis, carvedilol appeared to be superior to metoprolol for the prevention of POAF (RR 0.51, 95% CI 0.37 to 0.70, p<0.001. No evidence of heterogeneity was observed. CONCLUSIONS: In conclusion, carvedilol may effectively reduce the incidence of POAF in patients undergoing cardiac surgery. It appeared to be superior to metoprolol. A large-scale, well-designed randomized controlled trial is needed to conclusively answer the question regarding the utility of carvedilol in the prevention of POAF.

  13. Secondary prevention through cardiac rehabilitation: physical activity counselling and exercise training: key components of the position paper from the Cardiac Rehabilitation Section of the European Association of Cardiovascular Prevention and Rehabilitation

    DEFF Research Database (Denmark)

    Corrà, Ugo; Piepoli, Massimo F; Carré, François

    2010-01-01

    and global long-term care of cardiac patients. The CR approach is delivered in tandem with a flexible follow-up strategy and easy access to a specialized team. To promote implementation of cardiac prevention and rehabilitation, the CR Section of the EACPR (European Association of Cardiovascular Prevention......, exercise training, diet/nutritional counselling, weight control management, lipid management, blood pressure monitoring, smoking cessation, and psychosocial management. Cardiac rehabilitation services are by definition multi-factorial and comprehensive, with physical activity counselling and exercise...... training as central components in all rehabilitation and preventive interventions. Many of the risk factor improvements occurring in CR can be mediated through exercise training programmes. This call-for-action paper presents the key components of a CR programme: physical activity counselling and exercise...

  14. Awareness levels of prevention of cardiac diseases in general population of rawalpindi and requirement of health education.

    Science.gov (United States)

    Tanvir, S; Sajjad, S; Roshan, R

    2018-03-02

    To assess the level of awareness in population about cardiac diseases prevention and suggestion of recommendations. Descriptive cross-sectional survey was carried out in Rawalpindi Cantonment in Oct 2016. 100 respondents were selected through convenience sampling. Data was collected through questionnaire. Results indicated low levels of awareness as only 30% of the population knew that cardiac diseases can be prevented to certain extent by lifestyle changes. 46% population knew about importance of physical activity and 34% knew that excess of fried and salty food can cause cardiac diseases. Only 22% population knew that red meat use in excess can cause cardiac diseases. 20% population were aware that lack of sleep can cause cardiac disease. 13% (for sodas), 15% (for sweets) 13% (for consuming egg yolk daily) and 28% (for stress) were the statistics for remaining modifiable risk factors. 80% of the population was aware of smoking hazards which shows the success of anti-smoking campaigns. These levels of awareness indicate that there is dire need of policy making for health education to make people aware of lifestyle modifications necessary to prevent cardiac diseases. Copyright © 2018 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

  15. Canopy 2 attenuates the transition from compensatory hypertrophy to dilated heart failure in hypertrophic cardiomyopathy.

    Science.gov (United States)

    Guo, Jian; Mihic, Anton; Wu, Jun; Zhang, Yuemei; Singh, Kaustabh; Dhingra, Sanjiv; Weisel, Richard D; Li, Ren-Ke

    2015-10-01

    A mismatch between adequate angiogenesis and overgrowth of myocytes may be a critical mechanism controlling the transition from adaptive hypertrophy to heart failure. Canopy 2 (CNPY2) was recently identified as a secreted, HIF-1α-regulated angiogenic growth factor. As angiogenic factors play important roles in the development of myocardial hypertrophy, we investigated the role of CNPY2 in molecular and functional changes during development of chronic heart failure using cardiac-specific transgenic (TG) mice that overexpress human CNPY2. We generated TG mice that constitutively express CNPY2 in the myocardium. Cardiomyopathy was induced in TG and wild-type (WT) mice by transverse aortic constriction (TAC). WT mice developed significant ventricular hypertrophy at 4 weeks and severe dilatation and heart failure at 12 weeks after TAC. However, TG mice preserved much better cardiac structure and function, with less severe ventricular dilatation and markedly reduced cardiac apoptosis and fibrosis following TAC. Excess CNPY2 in TG mice prevented significant loss of vasculature up to 12 weeks after TAC injury, resulting in a better local myocardial environment that facilitated myocyte survival and prevented excessive matrix remodelling compared with WT mice. TG mice had less accumulation of endogenous tumor suppressor p53 after TAC, indicating intrinsic activation of the p53-mediated repression of HIF-1α, and Cnpy2 was diminished in TG mice compared with WT controls. Our study showed a correlation between downregulation of endogenous mouse Cnpy2 and p53-mediated HIF-1α inhibition during late-stage hypertrophic development. Additional CNPY2 attenuated the transition from compensatory hypertrophic response to maladaptive ventricular dilatation and heart failure. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

  16. Chronic administration of aqueous extract of Hibiscus sabdariffa attenuates hypertension and reverses cardiac hypertrophy in 2K-1C hypertensive rats.

    Science.gov (United States)

    Odigie, I P; Ettarh, R R; Adigun, S A

    2003-06-01

    The effect of aqueous extract of petals of Hibiscus sabdariffa (HS) on the established stages of 2-Kidney, 1-Clip renovascular hypertension was investigated in Sprague-Dawley rats. Renovascular hypertension was induced by subjecting the animals to left renal artery clamping using a 0.2mm silver clip under ether anesthesia. Sham-operated (Sh-Op) rats served as controls. Six weeks after renal artery clamping, one group of hypertensive rats (blood pressure (BP) >140 mmHg) received HS (250 mg/kg/day) in drinking water (2K-1C+HS). The second group (2K-1C) and the sham-operated (Sh-Op) controls, received drinking water. BP was monitored weekly using rat-tail plethysmography. After 8 weeks, 2K-1C+HS had a reduction in systolic BP (139.6+/-1.6 mmHg) compared to 2K-1C (174+/-2.4 mmHg, n=5; P<0.001). No significant difference was found in BP of 2K-1C+HS and Sh-Op (139.6+/-1.6 mmHg versus 132+/-3.4 mmHg). A reduction in heart rate in 2K-1C+HS was observed (388+/-3.7 bpm versus 444+/-6.8 bpm in 2K-1C and 416+/-9.3 in Sh-Op, n=5; P<0.001). The hearts of 2K-1C were heavier than those of 2K-1C+HS (0.74+/-0.03 g versus 0.66+/-0.03 g, n=5; P<0.05). Cardiac weight of 2K-1C+HS was comparable to those of Sh-Op (0.57+/-0.04 g). Serum creatinine and plasma electrolytes were not different from controls. This study suggests that HS exhibits antihypertensive and cardioprotective effects in vivo and supports the public belief that HS may be a useful antihypertensive agent.

  17. Meta-analysis of ascorbic acid for prevention of postoperative atrial fibrillation after cardiac surgery.

    Science.gov (United States)

    Baker, William L; Coleman, Craig I

    2016-12-15

    Results of a systematic review and meta-analysis of published data on use of ascorbic acid to prevent postoperative atrial fibrillation (POAF) after cardiac surgery are presented. MEDLINE and other sources were searched for reports on trials evaluating the effects of preoperative and/or postoperative use of ascorbic acid in patients undergoing cardiac surgery. For each study selected for meta-analysis, an assessment for risks of methodological bias was performed. Data on POAF frequency and length of stay (LOS) outcomes were pooled and analyzed via random-effects modeling. The 11 identified studies involved patients receiving coronary artery bypass grafts with or without valve replacement; both i.v. and oral ascorbic acid formulations were used. Analysis of pooled outcomes data on treatment and control groups indicated that ascorbic acid prophylaxis was associated with reductions in POAF frequency (odds ratio, 0.44; 95% confidence interval [CI], 0.32 to 0.61), intensive care unit (ICU) LOS (difference in means, -0.24 day; 95% CI, -0.45 to -0.03 day), and total hospital LOS (difference in means, -0.94 day; 95% CI, -1.65 to -0.23 day). Significant statistical, methodological, and clinical heterogeneity were observed. A meta-analysis revealed that, compared with use of a placebo or a nonplacebo control, perioperative administration of ascorbic acid to patients undergoing cardiac surgery was associated with a reduced frequency of POAF and a shorter ICU LOS and total hospital LOS. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

  18. Effect of Thymol on Serum Antioxidant Capacity of Rats Following Myocardial Hypertrophy

    Directory of Open Access Journals (Sweden)

    Mohabbat Jamhiri

    2017-07-01

    Full Text Available Abstract Background: Oxidative stress plays an important role in the pathogenesis of hypertension- induced cardiac hypertrophy. Plants are a rich source of antioxidant compounds. Thymol is a natural monoterpen phenol which is plentiful in some plants and shows many biological effects. The aim of the present study was to assess the effects of thymol on activity of antioxidant enzyme catalase, malondialdehyde (MDA level and the activity of the inhibition of free radical DPPH (2,2-Diphenyl-1-picryl-hydrazyl, following left ventricular hypertrophy in rats. Materials and Methods: In this experimental study, rats were divided into hypertrophied group without any treatment (H group and rats pretreated with 25 and 50 mg/kg/day of thymol (Thy25+H and Thy50+H groups, respectively. Intact animals were served as control (Ctl. Animal model of left ventricular hypertrophy was induced by abdominal aortic banding. Serum catalase (CAT activity, malondialdehyde (MDA level and the activity of inhibition of free radicals DPPH were determined by the biochemical methods. Results: In Thy25+H and Thy50+H groups, the CAT activity was increased significantly in serum (p<0.01, vs. Ctl. Also, serum level of MDA was decreased significantly compared to the group H in Thy25+H and Thy50+H groups (p<0.05 and p<0.001, respectively. The effect of inhibiting DPPH free radicals was increased significantly in Thy25+H and Thy50+H groups compared to the group H (p<0.001 and p<0.05, respectively. Conclusion: The findings of this study suggest that thymol as an antioxidant causes cardioprotective effects and as well as prevents left ventricular hypertrophy via augmentation of serum antioxidant capacity.

  19. The transcription factor MEF2C mediates cardiomyocyte hypertrophy induced by IGF-1 signaling

    Energy Technology Data Exchange (ETDEWEB)

    Munoz, Juan Pablo; Collao, Andres; Chiong, Mario; Maldonado, Carola; Adasme, Tatiana; Carrasco, Loreto; Ocaranza, Paula; Bravo, Roberto; Gonzalez, Leticia; Diaz-Araya, Guillermo [Centro FONDAP Estudios Moleculares de la Celula, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Facultad de Ciencias Quimicas y Farmaceuticas, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Hidalgo, Cecilia [Centro FONDAP Estudios Moleculares de la Celula, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Instituto de Ciencias Biomedicas, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Lavandero, Sergio, E-mail: slavander@uchile.cl [Centro FONDAP Estudios Moleculares de la Celula, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Facultad de Ciencias Quimicas y Farmaceuticas, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Instituto de Ciencias Biomedicas, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile)

    2009-10-09

    Myocyte enhancer factor 2C (MEF2C) plays an important role in cardiovascular development and is a key transcription factor for cardiac hypertrophy. Here, we describe MEF2C regulation by insulin-like growth factor-1 (IGF-1) and its role in IGF-1-induced cardiac hypertrophy. We found that IGF-1 addition to cultured rat cardiomyocytes activated MEF2C, as evidenced by its increased nuclear localization and DNA binding activity. IGF-1 stimulated MEF2 dependent-gene transcription in a time-dependent manner, as indicated by increased MEF2 promoter-driven reporter gene activity; IGF-1 also induced p38-MAPK phosphorylation, while an inhibitor of p38-MAPK decreased both effects. Additionally, inhibitors of phosphatidylinositol 3-kinase and calcineurin prevented IGF-1-induced MEF2 transcriptional activity. Via MEF2C-dependent signaling, IGF-1 also stimulated transcription of atrial natriuretic factor and skeletal {alpha}-actin but not of fos-lux reporter genes. These novel data suggest that MEF2C activation by IGF-1 mediates the pro-hypertrophic effects of IGF-1 on cardiac gene expression.

  20. The transcription factor MEF2C mediates cardiomyocyte hypertrophy induced by IGF-1 signaling

    International Nuclear Information System (INIS)

    Munoz, Juan Pablo; Collao, Andres; Chiong, Mario; Maldonado, Carola; Adasme, Tatiana; Carrasco, Loreto; Ocaranza, Paula; Bravo, Roberto; Gonzalez, Leticia; Diaz-Araya, Guillermo; Hidalgo, Cecilia; Lavandero, Sergio

    2009-01-01

    Myocyte enhancer factor 2C (MEF2C) plays an important role in cardiovascular development and is a key transcription factor for cardiac hypertrophy. Here, we describe MEF2C regulation by insulin-like growth factor-1 (IGF-1) and its role in IGF-1-induced cardiac hypertrophy. We found that IGF-1 addition to cultured rat cardiomyocytes activated MEF2C, as evidenced by its increased nuclear localization and DNA binding activity. IGF-1 stimulated MEF2 dependent-gene transcription in a time-dependent manner, as indicated by increased MEF2 promoter-driven reporter gene activity; IGF-1 also induced p38-MAPK phosphorylation, while an inhibitor of p38-MAPK decreased both effects. Additionally, inhibitors of phosphatidylinositol 3-kinase and calcineurin prevented IGF-1-induced MEF2 transcriptional activity. Via MEF2C-dependent signaling, IGF-1 also stimulated transcription of atrial natriuretic factor and skeletal α-actin but not of fos-lux reporter genes. These novel data suggest that MEF2C activation by IGF-1 mediates the pro-hypertrophic effects of IGF-1 on cardiac gene expression.

  1. Mechanical and non-mechanical functions of Dystrophin can prevent cardiac abnormalities in Drosophila.

    Science.gov (United States)

    Taghli-Lamallem, Ouarda; Jagla, Krzysztof; Chamberlain, Jeffrey S; Bodmer, Rolf

    2014-01-01

    Dystrophin-deficiency causes cardiomyopathies and shortens the life expectancy of Duchenne and Becker muscular dystrophy patients. Restoring Dystrophin expression in the heart by gene transfer is a promising avenue to explore as a therapy. Truncated Dystrophin gene constructs have been engineered and shown to alleviate dystrophic skeletal muscle disease, but their potential in preventing the development of cardiomyopathy is not fully understood. In the present study, we found that either the mechanical or the signaling functions of Dystrophin were able to reduce the dilated heart phenotype of Dystrophin mutants in a Drosophila model. Our data suggest that Dystrophin retains some function in fly cardiomyocytes in the absence of a predicted mechanical link to the cytoskeleton. Interestingly, cardiac-specific manipulation of nitric oxide synthase expression also modulates cardiac function, which can in part be reversed by loss of Dystrophin function, further implying a signaling role of Dystrophin in the heart. These findings suggest that the signaling functions of Dystrophin protein are able to ameliorate the dilated cardiomyopathy, and thus might help to improve heart muscle function in micro-Dystrophin-based gene therapy approaches. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Hypertension and cardiac arrhythmias

    DEFF Research Database (Denmark)

    Lip, Gregory Y H; Coca, Antonio; Kahan, Thomas

    2017-01-01

    Hypertension is a common cardiovascular risk factor leading to heart failure (HF), coronary artery disease, stroke, peripheral artery disease and chronic renal insufficiency. Hypertensive heart disease can manifest as many cardiac arrhythmias, most commonly being atrial fibrillation (AF). Both...... supraventricular and ventricular arrhythmias may occur in hypertensive patients, especially in those with left ventricular hypertrophy (LVH) or HF. Also, some of the antihypertensive drugs commonly used to reduce blood pressure, such as thiazide diuretics, may result in electrolyte abnormalities (e.g. hypokalaemia......, hypomagnesemia), further contributing to arrhythmias, whereas effective control of blood pressure may prevent the development of the arrhythmias such as AF. In recognizing this close relationship between hypertension and arrhythmias, the European Heart Rhythm Association (EHRA) and the European Society...

  3. Preventing tomorrow's sudden cardiac death in epilepsy today: what should physicians know about this?

    Directory of Open Access Journals (Sweden)

    Fulvio A. Scorza

    2008-01-01

    Full Text Available Approximately 1% of the population has epilepsy, the most common neurological disorder. Moreover, people with epilepsy are more likely to die prematurely than those without epilepsy, and the most common epilepsy-related category of death is sudden unexpected death in epilepsy (SUDEP. Information concerning risk factors for SUDEP is conflicting, but potential risk factors include: age, early onset of epilepsy, duration of epilepsy, uncontrolled seizures, seizure frequency, number of antiepileptic drugs and winter temperatures. Additionally, the cause of SUDEP is still unknown; however, the most commonly suggested mechanisms are cardiac abnormalities during and between seizures. This review discusses the epidemiology, risk factors, etiology, and preventative measures in the management of SUDEP.

  4. Myocardial hypertrophy in the recipient with twin-to-twin transfusion syndrome

    DEFF Research Database (Denmark)

    Jeppesen, D.L.; Jorgensen, F.S.; Pryds, O.A.

    2008-01-01

    In a set of monochorionic-diamniotic twins with twin-to-twin transfusion syndrome, systemic hypertension and biventricular myocardial hypertrophy were found in the recipient. The infant developed mild respiratory distress. A partial exchange transfusion was performed because of polycytaemia. Blood...... pressure measurements revealed persistent systemic hypertension. Biventricular hypertrophy was demonstrated by echocardiography. Blood pressure normalised after treatment with Nifedipine and the cardiac hypertrophy subsided over the following weeks. A potential contributing mechanism is intrauterine...

  5. Prevention of Pazopanib-Induced Prolonged Cardiac Repolarization and Proarrhythmic Effects.

    Science.gov (United States)

    Akman, Tulay; Erbas, Oytun; Akman, Levent; Yilmaz, Ahmet U

    2014-11-01

    Background: Pazopanib (PZP) may induce prolonged cardiac repolarization and proarrhythmic effects, similarly to other tyrosine kinase inhibitors. Objectives: To demonstrate PZP-induced prolonged cardiac repolarization and proarrhythmic electrophysiological effects and to investigate possible preventive effects of metoprolol and diltiazem on ECG changes (prolonged QT) in an experimental rat model. Methods: Twenty-four Sprague-Dawley adult male rats were randomly assigned to 4 groups (n = 6). The first group (normal group) received 4 mL of tap water and the other groups received 100 mg/kg of PZP (Votrient® tablet) perorally, via orogastric tubes. After 3 hours, the following solutions were intraperitoneally administered to the animals: physiological saline solution (SP), to the normal group and to the second group (control-PZP+SP group); 1 mg/kg metoprolol (Beloc, Ampule, AstraZeneca), to the third group (PZP+metoprolol group); and 1mg/kg diltiazem (Diltiazem, Mustafa Nevzat), to the fourth group (PZP+diltiazem group). One hour after, and under anesthesia, QTc was calculated by recording ECG on lead I. Results: The mean QTc interval values were as follows: normal group, 99.93 ± 3.62 ms; control-PZP+SP group, 131.23 ± 12.21 ms; PZP+metoprolol group, 89.36 ± 3.61 ms; and PZP+diltiazem group, 88.86 ± 4.04 ms. Both PZP+metoprolol and PZP+diltiazem groups had significantly shorter QTc intervals compared to the control-PZP+SP group (p < 0.001). Conclusion: Both metoprolol and diltiazem prevented PZP-induced QT interval prolongation. These drugs may provide a promising prophylactic strategy for the prolonged QTc interval associated with tyrosine kinase inhibitor use.

  6. Prevention of Pazopanib-Induced Prolonged Cardiac Repolarization and Proarrhythmic Effects

    Directory of Open Access Journals (Sweden)

    Tulay Akman

    2014-11-01

    Full Text Available Background: Pazopanib (PZP may induce prolonged cardiac repolarization and proarrhythmic effects, similarly to other tyrosine kinase inhibitors. Objectives: To demonstrate PZP-induced prolonged cardiac repolarization and proarrhythmic electrophysiological effects and to investigate possible preventive effects of metoprolol and diltiazem on ECG changes (prolonged QT in an experimental rat model. Methods: Twenty-four Sprague-Dawley adult male rats were randomly assigned to 4 groups (n = 6. The first group (normal group received 4 mL of tap water and the other groups received 100 mg/kg of PZP (Votrient® tablet perorally, via orogastric tubes. After 3 hours, the following solutions were intraperitoneally administered to the animals: physiological saline solution (SP, to the normal group and to the second group (control-PZP+SP group; 1 mg/kg metoprolol (Beloc, Ampule, AstraZeneca, to the third group (PZP+metoprolol group; and 1mg/kg diltiazem (Diltiazem, Mustafa Nevzat, to the fourth group (PZP+diltiazem group. One hour after, and under anesthesia, QTc was calculated by recording ECG on lead I. Results: The mean QTc interval values were as follows: normal group, 99.93 ± 3.62 ms; control-PZP+SP group, 131.23 ± 12.21 ms; PZP+metoprolol group, 89.36 ± 3.61 ms; and PZP+diltiazem group, 88.86 ± 4.04 ms. Both PZP+metoprolol and PZP+diltiazem groups had significantly shorter QTc intervals compared to the control-PZP+SP group (p < 0.001. Conclusion: Both metoprolol and diltiazem prevented PZP-induced QT interval prolongation. These drugs may provide a promising prophylactic strategy for the prolonged QTc interval associated with tyrosine kinase inhibitor use.

  7. Deletion of Interleukin-6 Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy and Dysfunction

    Science.gov (United States)

    Afzal, Muhammad R.; Samanta, Anweshan; Xuan, Yu-Ting; Girgis, Magdy; Elias, Harold K; Zhu, Yanqing; Davani, Arash; Yang, Yanjuan; Chen, Xing; Ye, Sheng; Wang, Ou-Li; Chen, Lei; Hauptman, Jeryl; Vincent, Robert J.; Dawn, Buddhadeb

    2016-01-01

    Rationale The role of interleukin (IL)-6 in the pathogenesis of cardiac myocyte hypertrophy remains controversial. Objective To conclusively determine whether IL-6 signaling is essential for the development of pressure overload-induced left ventricular (LV) hypertrophy, and to elucidate the underlying molecular pathways. Methods and Results Wild-type (WT) and IL-6 knockout (IL-6−/−) mice underwent sham surgery or transverse aortic constriction (TAC) to induce pressure overload. Serial echocardiograms and terminal hemodynamic studies revealed attenuated LV hypertrophy and superior preservation of LV function in IL-6−/− mice after TAC. The extents of LV remodeling, fibrosis, and apoptosis were reduced in IL-6−/− hearts after TAC. Transcriptional and protein assays of myocardial tissue identified CaMKII and STAT3 activation as important underlying mechanisms during cardiac hypertrophy induced by TAC. The involvement of these pathways in myocyte hypertrophy was verified in isolated cardiac myocytes from WT and IL-6−/− mice exposed to pro-hypertrophy agents. Furthermore, overexpression of CaMKII in H9c2 cells increased STAT3 phosphorylation, and exposure of H9c2 cells to IL-6 resulted in STAT3 activation that was attenuated by CaMKII inhibition. Together these results identify the importance of CaMKII-dependent activation of STAT3 during cardiac myocyte hypertrophy via IL-6 signaling. Conclusions Genetic deletion of IL-6 attenuates TAC-induced LV hypertrophy and dysfunction, indicating a critical role played by IL-6 in the pathogenesis of LV hypertrophy in response to pressure overload. CaMKII plays an important role in IL-6-induced STAT3 activation and consequent cardiac myocyte hypertrophy. These findings may have significant therapeutic implications for LV hypertrophy and failure in patients with hypertension. PMID:27126808

  8. Cardiac‐specific Hexokinase 2 Overexpression Attenuates Hypertrophy by Increasing Pentose Phosphate Pathway Flux

    Science.gov (United States)

    McCommis, Kyle S.; Douglas, Diana L.; Krenz, Maike; Baines, Christopher P.

    2013-01-01

    Background The enzyme hexokinase‐2 (HK2) phosphorylates glucose, which is the initiating step in virtually all glucose utilization pathways. Cardiac hypertrophy is associated with a switch towards increased glucose metabolism and decreased fatty acid metabolism. Recent evidence suggests that the increased glucose utilization is compensatory to the down‐regulated fatty acid metabolism during hypertrophy and is, in fact, beneficial. Therefore, we hypothesized that increasing glucose utilization by HK2 overexpression would decrease cardiac hypertrophy. Methods and Results Mice with cardiac‐specific HK2 overexpression displayed decreased hypertrophy in response to isoproterenol. Neonatal rat ventricular myocytes (NRVMs) infected with an HK2 adenovirus similarly displayed decreased hypertrophy in response to phenylephrine. Hypertrophy increased reactive oxygen species (ROS) levels, which were attenuated by HK2 overexpression, thereby decreasing NRVM hypertrophy and death. HK2 appears to modulate ROS via the pentose phosphate pathway, as inhibition of glucose‐6‐phosphate dehydrogenase with dehydroepiandrosterone decreased the ability of HK2 to diminish ROS and hypertrophy. Conclusions These results suggest that HK2 attenuates cardiac hypertrophy by decreasing ROS accumulation via increased pentose phosphate pathway flux. PMID:24190878

  9. Does a reduced glucose intake prevent hyperglycemia in children early after cardiac surgery? a randomized controlled crossover study

    NARCIS (Netherlands)

    de Betue, Carlijn T. I.; Verbruggen, Sascha C. A. T.; Schierbeek, Henk; Chacko, Shaji K.; Bogers, Ad J. J. C.; van Goudoever, Johannes B.; Joosten, Koen F. M.

    2012-01-01

    Introduction: Hyperglycemia in children after cardiac surgery can be treated with intensive insulin therapy, but hypoglycemia is a potential serious side effect. The aim of this study was to investigate the effects of reducing glucose intake below standard intakes to prevent hyperglycemia, on blood

  10. Does a reduced glucose intake prevent hyperglycemia in children early after cardiac surgery? A randomized controlled crossover study

    NARCIS (Netherlands)

    C.T. de Betue (Carlijn); S.C.A.T. Verbruggen (Sascha); H. Schierbeek (Henk); S. Chacko (Shaji); A.J.J.C. Bogers (Ad); J.B. van Goudoever (Hans); K.F.M. Joosten (Koen)

    2012-01-01

    textabstractIntroduction: Hyperglycemia in children after cardiac surgery can be treated with intensive insulin therapy, but hypoglycemia is a potential serious side effect. The aim of this study was to investigate the effects of reducing glucose intake below standard intakes to prevent

  11. Increased sarcolemmal Na+/H+ exchange activity in hypertrophied myocytes from dogs with chronic atrioventricular block

    NARCIS (Netherlands)

    van Borren, Marcel M. G. J.; Vos, Marc A.; Houtman, Marien J. C.; Antoons, Gudrun; Ravesloot, Jan H.

    2013-01-01

    Dogs with compensated biventricular hypertrophy due to chronic atrioventricular block (cAVB), are more susceptible to develop drug-induced Torsade-de-Pointes arrhythmias and sudden cardiac death. It has been suggested that the increased Na+ influx in hypertrophied cAVB ventricular myocytes

  12. [The discussion on relationship between adenoids hypertrophy and food intolerance].

    Science.gov (United States)

    Li, Yaqiong; Sun, Jie; Zhang, Hua

    2013-06-01

    To explore the relationship between food intolerance and adenoidal hypertrophy and accordingly to provide evidence for intolerance and adenoidal hypertrophy. Adenoidal hypertrophy in patients with a total of 111 cases as the experiment group, 30 cases of children with no history of allergies and allergy-related diseases and adenoidal hypertrophy symptoms as the control group, and compared the result of food intolerance between two groups. 1) Food intolerance detected positive rate of adenoidal hypertrophy group was higher than the control group. 2) The distribution of the two groups of children in the extent of food intolerance is different. 3) Adenoid hypertrophy and how many types of the food, which is high, moderate intolerance, are unrelated. 4) The daily consumption of 14 kinds of food, the top three foods of adenoidal hypertrophy group and control group are eggs, milk, cod. Food intolerance is the possible cause of adenoidal hypertrophy. The detection of specific IgG antibodies of food have positive significance in the prevention of adenoidal hypertrophy.

  13. ENerGetIcs in hypertrophic cardiomyopathy: traNslation between MRI, PET and cardiac myofilament function (ENGINE study).

    Science.gov (United States)

    Güçlü, A; Germans, T; Witjas-Paalberends, E R; Stienen, G J M; Brouwer, W P; Harms, H J; Marcus, J T; Vonk, A B A; Stooker, W; Yilmaz, A; Klein, P; Ten Berg, J M; Kluin, J; Asselbergs, F W; Lammertsma, A A; Knaapen, P; van Rossum, A C; van der Velden, J

    2013-12-01

    Hypertrophic cardiomyopathy (HCM) is an autosomal dominant heart disease mostly due to mutations in genes encoding sarcomeric proteins. HCM is characterised by asymmetric hypertrophy of the left ventricle (LV) in the absence of another cardiac or systemic disease. At present it lacks specific treatment to prevent or reverse cardiac dysfunction and hypertrophy in mutation carriers and HCM patients. Previous studies have indicated that sarcomere mutations increase energetic costs of cardiac contraction and cause myocardial dysfunction and hypertrophy. By using a translational approach, we aim to determine to what extent disturbances of myocardial energy metabolism underlie disease progression in HCM. Hypertrophic obstructive cardiomyopathy (HOCM) patients and aortic valve stenosis (AVS) patients will undergo a positron emission tomography (PET) with acetate and cardiovascular magnetic resonance imaging (CMR) with tissue tagging before and 4 months after myectomy surgery or aortic valve replacement + septal biopsy. Myectomy tissue or septal biopsy will be used to determine efficiency of sarcomere contraction in-vitro, and results will be compared with in-vivo cardiac performance. Healthy subjects and non-hypertrophic HCM mutation carriers will serve as a control group. Our study will reveal whether perturbations in cardiac energetics deteriorate during disease progression in HCM and whether these changes are attributed to cardiac remodelling or the presence of a sarcomere mutation per se. In-vitro studies in hypertrophied cardiac muscle from HOCM and AVS patients will establish whether sarcomere mutations increase ATP consumption of sarcomeres in human myocardium. Our follow-up imaging study in HOCM and AVS patients will reveal whether impaired cardiac energetics are restored by cardiac surgery.

  14. The Akt-mTOR axis is a pivotal regulator of eccentric hypertrophy during volume overload.

    Science.gov (United States)

    Ikeda, Masataka; Ide, Tomomi; Fujino, Takeo; Matsuo, Yuka; Arai, Shinobu; Saku, Keita; Kakino, Takamori; Oga, Yasuhiro; Nishizaki, Akiko; Sunagawa, Kenji

    2015-10-30

    The heart has two major modalities of hypertrophy in response to hemodynamic loads: concentric and eccentric hypertrophy caused by pressure and volume overload (VO), respectively. However, the molecular mechanism of eccentric hypertrophy remains poorly understood. Here we demonstrate that the Akt-mammalian target of rapamycin (mTOR) axis is a pivotal regulator of eccentric hypertrophy during VO. While mTOR in the heart was activated in a left ventricular end-diastolic pressure (LVEDP)-dependent manner, mTOR inhibition suppressed eccentric hypertrophy and induced cardiac atrophy even under VO. Notably, Akt was ubiquitinated and phosphorylated in response to VO, and blocking the recruitment of Akt to the membrane completely abolished mTOR activation. Various growth factors were upregulated during VO, suggesting that these might be involved in Akt-mTOR activation. Furthermore, the rate of eccentric hypertrophy progression was proportional to mTOR activity, which allowed accurate estimation of eccentric hypertrophy by time-integration of mTOR activity. These results suggested that the Akt-mTOR axis plays a pivotal role in eccentric hypertrophy, and mTOR activity quantitatively determines the rate of eccentric hypertrophy progression. As eccentric hypertrophy is an inherent system of the heart for regulating cardiac output and LVEDP, our findings provide a new mechanistic insight into the adaptive mechanism of the heart.

  15. Colchicine for prevention and treatment of cardiac diseases: A meta-analysis.

    Science.gov (United States)

    Papageorgiou, Nikolaos; Briasoulis, Alexandros; Lazaros, George; Imazio, Massimo; Tousoulis, Dimitris

    2017-02-01

    Colchicine has been suggested to be beneficial in preventing recurrent pericarditis. The goal of this study was to review all randomized controlled trials that assess the use of colchicine for the prevention and treatment of cardiac diseases. We performed a meta-analysis of the effects of colchicine on pericarditis, postpericardiotomy syndrome and postprocedural atrial fibrillation recurrence, in-stent restenosis, gastrointestinal adverse effects, and treatment discontinuation rates. We conducted an EMBASE and MEDLINE search for prospective controlled trials. We identified 17 prospective controlled randomized studies with 2082 patients that received colchicine and 1982 controls with an average follow-up duration of 12 months. Treatment with colchicine is associated with reduced risk of pericarditis recurrence/postpericardiotomy syndrome (OR: 0.37; 95% CI: 0.29-0.47; Pcolchicine (OR: 2.6; 95% CI: 1.82-3.72; Pcolchicine. Colchicine appears to be efficacious and well tolerated for recurrent pericarditis/postpericardiotomy syndrome and recurrence of postprocedural atrial fibrillation. However, its efficacy may be limited by its gastrointestinal adverse events and treatment discontinuation rates particularly in postoperative patients. © 2016 John Wiley & Sons Ltd.

  16. Parental Knowledge of Cardiovascular Screening and Prevention of Sudden Cardiac Arrest in Youth Athletes.

    Science.gov (United States)

    Wagener, Madison A; Diamond, Alex B; Karpinos, Ashley Rowatt

    2017-08-01

    Sudden cardiac arrest (SCA) is the leading cause of death in youth athletes. Survival from out- of-hospital SCA depends on prompt initiation of cardiopulmonary resuscitation (CPR) and use of an automated external defibrillator (AED). This study evaluated parental knowledge, experience, and attitudes related to cardiovascular screening, SCA, and CPR/AED use in youth athletes and made comparisons between parents who are employed in healthcare and parents who are not employed in healthcare. We conducted a cross-sectional survey to evaluate knowledge, experiences, and attitudes of 91 parents of youth athletes who attended a community-based cardiovascular screening event. Although cardiovascular screening can reduce the risk of SCA, we found that 36% of parents incorrectly thought cardiovascular screening could prevent SCA and there was no difference in knowledge between the two groups of parents. This initial evaluation of parental knowledge of cardiovascular screening issues in youth athletes should guide educational efforts to prevent and respond to SCA in youth athletes.

  17. Prior exercise training does not prevent acute cardiac alterations after myocardial infarction in female rats

    Directory of Open Access Journals (Sweden)

    Eduardo C. A. Veiga

    2011-01-01

    Full Text Available OBJECTIVE: This study aimed to investigate whether previous exercise training could prevent or attenuate acute cardiac alterations after myocardial infarction. METHODS: Female rats were submitted to swim training (1 h/day; 5 days/week or allowed to remain sedentary for 8 weeks. Afterwards, they were randomly assigned to left coronary artery occlusion or sham surgery. After this procedure, the rats remained sedentary for one week until euthanasia. Cardiac structural and functional analyses were performed using Doppler echocardiography. The rats that had a moderate or large infarct size were included in the evaluations. The data (mean + SEM were analyzed using a two-way ANOVA model followed byTukey's post-hoc test. RESULTS: After the surgery, no significant difference between the exercise and sedentary groups was observed in the left ventricular infarct sizes (34.58 + 3.04 vs. 37.59 + 3.07. In another group of rats evaluated with Evans blue 1 h after myocardial infarction, no siginificant difference in the area at risk was observed between the exercised and sedentary rats (49.73 + 1.52 vs. 45.48 + 3.49. The changes in the left ventricular fractional areas for the exercised and sedentary myocardial infarction groups (36 + 2% and 39 + 3%, respectively were smaller than those for the exercise sham surgery (ES, 67+1% and sedentary sham surgery (SS, 69 + 2% groups. The E/A was higher in the sedentary myocardial infarction (4.4 + 0.3 and exercised myocardial infarction (5.5 + 0.3 rats than in the SS (2.4 + 0.1 and ES (2.2 + 0.1 rats. CONCLUSION: Previous swim training of female rats does not attenuate systolic and diastolic function alterations after myocardial infarction induced by left coronary artery occlusion, suggesting that cardioprotection cannot be provided by exercise training in this experimental model.

  18. Tempol prevents cardiac oxidative damage and left ventricular dysfunction in the PPAR-α KO mouse.

    Science.gov (United States)

    Guellich, Aziz; Damy, Thibaud; Conti, Marc; Claes, Victor; Samuel, Jane-Lise; Pineau, Thierry; Lecarpentier, Yves; Coirault, Catherine

    2013-06-01

    Peroxisome proliferator-activated receptor (PPAR)-α deletion induces a profound decrease in MnSOD activity, leading to oxidative stress and left ventricular (LV) dysfunction. We tested the hypothesis that treatment of PPAR-α knockout (KO) mice with the SOD mimetic tempol prevents the heart from pathological remodelling and preserves LV function. Twenty PPAR-α KO mice and 20 age-matched wild-type mice were randomly treated for 8 wk with vehicle or tempol in the drinking water. LV contractile parameters were determined both in vivo using echocardiography and ex vivo using papillary muscle mechanics. Translational and posttranslational modifications of myosin heavy chain protein as well as the expression and activity of major antioxidant enzymes were measured. Tempol treatment did not affect LV function in wild-type mice; however, in PPAR-α KO mice, tempol prevented the decrease in LV ejection fraction and restored the contractile parameters of papillary muscle, including maximum shortening velocity, maximum extent of shortening, and total tension. Moreover, compared with untreated PPAR-α KO mice, myosin heavy chain tyrosine nitration and anion superoxide production were markedly reduced in PPAR-α KO mice after treatment. Tempol also significantly increased glutathione peroxidase and glutathione reductase activities (~ 50%) in PPAR-α KO mice. In conclusion, these findings demonstrate that treatment with the SOD mimetic tempol can prevent cardiac dysfunction in PPAR-α KO mice by reducing the oxidation of contractile proteins. In addition, we show that the beneficial effects of tempol in PPAR-α KO mice involve activation of the glutathione peroxidase/glutathione reductase system.

  19. Safety and efficacy of landiolol hydrochloride for prevention of atrial fibrillation after cardiac surgery in patients with left ventricular dysfunction: Prevention of Atrial Fibrillation After Cardiac Surgery With Landiolol Hydrochloride for Left Ventricular Dysfunction (PLATON) trial.

    Science.gov (United States)

    Sezai, Akira; Osaka, Shunji; Yaoita, Hiroko; Ishii, Yusuke; Arimoto, Munehito; Hata, Hiroaki; Shiono, Motomi

    2015-10-01

    We previously conducted a prospective study of landiolol hydrochloride (INN landiolol), an ultrashort-acting β-blocker, and reported that it could prevent atrial fibrillation after cardiac surgery. This trial was performed to investigate the safety and efficacy of landiolol hydrochloride in patients with left ventricular dysfunction undergoing cardiac surgery. Sixty patients with a preoperative left ventricular ejection fraction of less than 35% were randomly assigned to 2 groups before cardiac surgery and then received intravenous infusion with landiolol hydrochloride (landiolol group) or without landiolol (control group). The primary end point was occurrence of atrial fibrillation as much as 1 week postoperatively. The secondary end points were blood pressure, heart rate, intensive care unit and hospital stays, ventilation time, ejection fraction, biomarkers of ischemia, and brain natriuretic peptide. Atrial fibrillation occurred in 3 patients (10%) in the landiolol group versus 12 (40%) in the control group, and its frequency was significantly lower in the landiolol group (P = .002). During the early postoperative period, levels of brain natriuretic peptide and ischemic biomarkers were significantly lower in the landiolol group than the control group. The landiolol group also had a significantly shorter hospital stay (P = .019). Intravenous infusion was not discontinued for hypotension or bradycardia in either group. Low-dose infusion of landiolol hydrochloride prevented atrial fibrillation after cardiac surgery in patients with cardiac dysfunction and was safe, with no effect on blood pressure. This intravenous β-blocker seems useful for perioperative management of cardiac surgical patients with left ventricular dysfunction. Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

  20. Does Resistance Training Stimulate Cardiac Muscle Hypertrophy?

    Science.gov (United States)

    Bloomer, Richard J.

    2003-01-01

    Reviews the literature on the left ventricular structural adaptations induced by resistance/strength exercise, focusing on human work, particularly well-trained strength athletes engaged in regular, moderate- to high-intensity resistance training (RT). The article discusses both genders and examines the use of anabolic-androgenic steroids in…

  1. O bloqueio da síntese do óxido nítrico promove aumento da hipertrofia e da fibrose cardíaca em ratos submetidos a treinamento aeróbio Nitric oxide synthesis blockade increases hypertrophy and cardiac fibrosis in rats submitted to aerobic training

    Directory of Open Access Journals (Sweden)

    Hugo Celso Dutra de Souza

    2007-08-01

    induced hypertension but did not cause cardiac hypertrophy. In the trained animals, the inhibition of NO synthesis attenuated hypertension, induced cardiac hypertrophy and significantly increased myocardial fibrosis, indicating that NO plays an important role in cardiac tissue adaptations caused by aerobic exercise.

  2. Triheptanoin Alleviates Ventricular Hypertrophy and Improves Myocardial Glucose Oxidation in Rats With Pressure Overload.

    Science.gov (United States)

    Nguyen, T Dung; Shingu, Yasushige; Amorim, Paulo A; Schwarzer, Michael; Doenst, Torsten

    2015-11-01

    Cardiac hypertrophy is characterized by changes in substrate utilization and activity of the Krebs cycle. We assessed the effects of triheptanoin, an odd-chain fat that might support the Krebs cycle, on cardiac metabolism and function in a model of cardiac hypertrophy. Rats were subjected to aortic banding (AoB) to induce pressure overload (PO). Starting at 1 week after AoB, rats were blindly fed a control diet or a special diet containing triheptanoin at 7% (T7 group) or 30% (T30 group) of total energy value. Six weeks after AoB, echocardiography revealed attenuated hypertrophy and improved diastolic function of the left ventricle. Isolated working heart perfusion showed similar cardiac power, fatty acid oxidation, substrate preference, and insulin response among groups. However, cardiac glucose oxidation (GO) was increased in the T30 group compared with the T7 and control groups. Blood levels of the odd-chain ketone body beta-hydroxypentanoate confirmed adequate bioavailability of triheptanoin. Importantly, they were directly proportional to cardiac GO. Treatment with triheptanoin-enriched diet reduces ventricular hypertrophy and improves diastolic function in rats with PO, which is associated with enhanced cardiac GO. The results suggest targeting supplementation of the Krebs cycle to approach ventricular and metabolic remodeling in cardiac hypertrophy. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Evidence to service gap: cardiac rehabilitation and secondary prevention in rural and remote Western Australia.

    Science.gov (United States)

    Hamilton, Sandra; Mills, Belynda; McRae, Shelley; Thompson, Sandra

    2018-01-30

    Cardiovascular disease (CVD), a leading cause of morbidity and mortality, has similar incidence in metropolitan and rural areas but poorer cardiovascular outcomes for residents living in rural and remote Australia. Cardiac Rehabilitation (CR) is an evidence-based intervention that helps reduce subsequent cardiovascular events and rehospitalisation. Unfortunately CR attendance rates are as low as 10-30% with rural/remote populations under-represented. This in-depth assessment investigated the provision of CR and secondary prevention services in Western Australia (WA) with a focus on rural and remote populations. CR and Aboriginal Community Controlled Health Services were identified through the Directory of Western Australian Cardiac Rehabilitation and Secondary Prevention Services 2012. Structured interviews with CR coordinators included questions specific to program delivery, content, referral and attendance. Of the 38 CR services identified, 23 (61%) were located in rural (n = 11, 29%) and remote (n = 12, 32%) regions. Interviews with coordinators from 34 CR services (10 rural, 12 remote, 12 metropolitan) found 77% of rural/remote services were hospital-based, with no service providing a comprehensive home-based or alternative method of program delivery. The majority of rural (60%) and remote (80%) services provided CR through chronic condition exercise programs compared with 17% of metropolitan services; only 27% of rural/remote programs provided education classes. Rural/remote coordinators were overwhelmingly physiotherapists, and only 50% of rural and 33% of remote programs had face-to-face access to multidisciplinary support. Patient referral and attendance rates differed greatly across WA and referrals to rural/remote services generally numbered less than 5 per month. Program evaluation was reported by 33% of rural/remote coordinators. Geography, population density and service availability limits patient access to CR services in rural/remote WA. Current

  4. Role of hypoxia-inducible factor in diabetic myocardial hypertrophy ...

    African Journals Online (AJOL)

    Purpose: This study was carried out to investigate the role of hypoxia-inducible factor (HIF) in diabetic cardiomyopathy in vitro. Methods: Hypoxia was induced chemically in H9C2 cells (cardiac hypertrophy model), and the cells were treated with phenylephrine (PE), deferoxamine (DFO), PE + DFO, and HIF-1α siRNA under ...

  5. Role of hypoxia-inducible factor in diabetic myocardial hypertrophy

    African Journals Online (AJOL)

    Purpose: This study was carried out to investigate the role of hypoxia-inducible factor (HIF) in diabetic cardiomyopathy in vitro. Methods: Hypoxia was induced chemically in H9C2 cells (cardiac hypertrophy model), and the cells were treated with phenylephrine (PE), deferoxamine (DFO), PE + DFO, and HIF-1α siRNA under.

  6. Protective effect of Boerhaavia diffusa L. against mitochondrial dysfunction in angiotensin II induced hypertrophy in H9c2 cardiomyoblast cells.

    Directory of Open Access Journals (Sweden)

    Ayyappan Prathapan

    Full Text Available Mitochondrial dysfunction plays a critical role in the development of cardiac hypertrophy and heart failure. So mitochondria are emerging as one of the important druggable targets in the management of cardiac hypertrophy and other associated complications. In the present study, effects of ethanolic extract of Boerhaavia diffusa (BDE, a green leafy vegetable against mitochondrial dysfunction in angiotensin II (Ang II induced hypertrophy in H9c2 cardiomyoblasts was evaluated. H9c2 cells challenged with Ang II exhibited pathological hypertrophic responses and mitochondrial dysfunction which was evident from increment in cell volume (49.09±1.13%, protein content (55.17±1.19%, LDH leakage (58.74±1.87%, increased intracellular ROS production (26.25±0.91%, mitochondrial superoxide generation (65.06±2.27%, alteration in mitochondrial transmembrane potential (ΔΨm, opening of mitochondrial permeability transition pore (mPTP and mitochondrial swelling. In addition, activities of mitochondrial respiratory chain complexes (I-IV, aconitase, NADPH oxidase, thioredoxin reductase, oxygen consumption rate and calcium homeostasis were evaluated. Treatment with BDE significantly prevented the generation of intracellular ROS and mitochondrial superoxide radicals and protected the mitochondria by preventing dissipation of ΔΨm, opening of mPTP, mitochondrial swelling and enhanced the activities of respiratory chain complexes and oxygen consumption rate in H9c2 cells. Activities of aconitase and thioredoxin reductase which was lowered (33.77±0.68% & 45.81±0.71% respectively due to hypertrophy, were increased in BDE treated cells (P≤0.05. Moreover, BDE also reduced the intracellular calcium overload in Ang II treated cells. Overall results revealed the protective effects of B. diffusa against mitochondrial dysfunction in hypertrophy in H9c2 cells and the present findings may shed new light on the therapeutic potential of B. diffusa in addition to its

  7. Empagliflozin Prevents Worsening of Cardiac Function in an Experimental Model of Pressure Overload-Induced Heart Failure

    Directory of Open Access Journals (Sweden)

    Nikole J. Byrne, BSc

    2017-08-01

    Full Text Available This study sought to determine whether the sodium/glucose cotransporter 2 (SGLT2 inhibitor empagliflozin improved heart failure (HF outcomes in nondiabetic mice. The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients trial demonstrated that empagliflozin markedly prevented HF and cardiovascular death in subjects with diabetes. However, despite ongoing clinical trials in HF patients without type 2 diabetes, there are no objective and translational data to support an effect of SGLT2 inhibitors on cardiac structure and function, particularly in the absence of diabetes and in the setting of established HF. Male C57Bl/6 mice were subjected to either sham or transverse aortic constriction surgery to induce HF. Following surgery, mice that progressed to HF received either vehicle or empagliflozin for 2 weeks. Cardiac function was then assessed in vivo using echocardiography and ex vivo using isolated working hearts. Although vehicle-treated HF mice experienced a progressive worsening of cardiac function over the 2-week treatment period, this decline was blunted in empagliflozin-treated HF mice. Treatment allocation to empagliflozin resulted in an improvement in cardiac systolic function, with no significant changes in cardiac remodeling or diastolic dysfunction. Moreover, isolated hearts from HF mice treated with empagliflozin displayed significantly improved ex vivo cardiac function compared to those in vehicle-treated controls. Empagliflozin treatment of nondiabetic mice with established HF blunts the decline in cardiac function both in vivo and ex vivo, independent of diabetes. These data provide important basic and translational clues to support the evaluation of SGLT2 inhibitors as a treatment strategy in a broad range of patients with established HF.

  8. Secondary prevention through cardiac rehabilitation: physical activity counselling and exercise training: key components of the position paper from the Cardiac Rehabilitation Section of the European Association of Cardiovascular Prevention and Rehabilitation

    DEFF Research Database (Denmark)

    Corrà, Ugo; Piepoli, Massimo F; Carré, François

    2010-01-01

    , exercise training, diet/nutritional counselling, weight control management, lipid management, blood pressure monitoring, smoking cessation, and psychosocial management. Cardiac rehabilitation services are by definition multi-factorial and comprehensive, with physical activity counselling and exercise...... and Rehabilitation) has recently completed a Position Paper, entitled 'Secondary prevention through cardiac rehabilitation: A condition-oriented approach'. Components of multidisciplinary CR for seven clinical presentations have been addressed. Components include patient assessment, physical activity counselling...... training as central components in all rehabilitation and preventive interventions. Many of the risk factor improvements occurring in CR can be mediated through exercise training programmes. This call-for-action paper presents the key components of a CR programme: physical activity counselling and exercise...

  9. Role of statins in delirium prevention in critical ill and cardiac surgery patients: A systematic review and meta-analysis.

    Science.gov (United States)

    Vallabhajosyula, Saraschandra; Kanmanthareddy, Arun; Erwin, Patricia J; Esterbrooks, Dennis J; Morrow, Lee E

    2017-02-01

    The data evaluating the role of statins in delirium prevention in the intensive care unit are conflicting and limited. We performed a systematic review and meta-analysis of literature from 1975 to 2015. All English-language adult studies evaluating delirium incidence in statin and statin nonusers were included and studies without a control group were excluded. Mantel-Haenszel model was used to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs). Statistical significance was defined as CI not including unity and P value less than .05. Of a total 57 identified studies, 6 were included. The studies showed high heterogeneity (I 2 = 73%) for all and moderate for cardiac surgery studies (I 2 = 55%). Of 289 773 patients, statins were used in 22 292 (7.7%). Cardiac surgery was performed in 4382 (1.5%) patients and 2321 (53.0%) used statins. Delirium was noted in 710 (3.2%) and 3478 (1.3%) of the patients in the statin and nonstatin groups, respectively, with no difference between groups in the total cohort (RR, 1.05 [95% CI, 0.85-1.29]; P = .56) or in cardiac surgery patients (RR, 1.03 [95% CI, 0.68-1.56]; P = .89). In critically ill and cardiac surgery patients, this meta-analysis did not show a benefit with statin therapy in the prevention of delirium. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. [Hypertrophy and coronary reserve].

    Science.gov (United States)

    Motz, W; Scheler, S

    2008-12-01

    Left ventricular hypertrophy represents the structural mechanism of adaptation of the left ventricle as the answer of a chronic pressure overload in arterial hypertension. Initially an increment in left ventricular wall thickness occurs. In this stadium of "concentric hypertrophy" LV systolic wall stress, LV ejection fraction and myocardial oxygen consumption per weight unit myocardium remain unchanged. In the further time course of disease LV dilatation will be present. In this phase of "excentric hypertrophy" LV systolic wall stress and myocardial oxygen consumption per weight unit myocardium rise and LV ejection fraction decreases. Patients with arterial hypertension frequently complain of angina pectoris. Angina pectoris and the positive exercise tolerance test or the positive myocardial scintigraphy are the consequence of the impaired coronary flow reserve. The coronary flow reserve is diminished due to structural and functional changes of the coronary circulation. ACE-inhibitors and AT1-receptor blockers cause a significant improvement of coronary flow reserve and regression of both left ventricular hypertrophy and myocardial fibrosis.

  11. Multi-Strain Probiotics Inhibit Cardiac Myopathies and Autophagy to Prevent Heart Injury in High-Fat Diet-Fed Rats.

    Science.gov (United States)

    Lai, Chao-Hung; Tsai, Cheng-Chih; Kuo, Wei-Wen; Ho, Tsung-Jung; Day, Cecilia-Hsuan; Pai, Pei-ying; Chung, Li-Chin; Huang, Chun-Chih; Wang, Hsueh-Fang; Liao, Po-Hsiang; Huang, Chih-Yang

    2016-01-01

    High-fat diets induce obesity, leading to cardiomyocyte fibrosis and autophagy imbalance. In addition, no previous studies have indicated that probiotics have potential health effects associated with cardiac fibrosis and autophagy in obese rats. This study investigates the effects of probiotics on high-fat (HF) diet-induced obesity and cardiac fibrosis and autophagy in rat hearts. Eight-week-old male Wistar rats were separated randomly into five equally sized experimental groups: Normal diet (control) and high-fat (HF) diet groups and groups fed a high-fat diet supplemented with low (HL), medium (HM) or high (HH) doses of multi-strain probiotic powders. These experiments were designed for an 8-week trial period. The myocardial architecture of the left ventricle was evaluated using Masson's trichrome staining and immunohistochemistry staining. Key probiotics-related pathway molecules were analyzed using western blotting. Abnormal myocardial architecture and enlarged interstitial spaces were observed in HF hearts. These interstitial spaces were significantly decreased in groups provided with multi-strain probiotics compared with HF hearts. Western blot analysis demonstrated that key components of the TGF/MMP2/MMP9 fibrosis pathways and ERK5/uPA/ANP cardiac hypertrophy pathways were significantly suppressed in probiotic groups compared to the HF group. Autophagy balance is very important in cardiomyocytes. In this study, we observed that the beclin-1/LC3B/Atg7 autophagy pathway in HF was increased after probiotic supplementation was significantly decreased. Together, these results suggest that oral administration of probiotics may attenuate cardiomyocyte fibrosis and cardiac hypertrophy and the autophagy-signaling pathway in obese rats.

  12. The role of transient receptor potential vanilloid 2 channel in cardiac aging.

    Science.gov (United States)

    Jones, Shannon; Mann, Adrien; Worley, Mariah C; Fulford, Logan; Hall, David; Karani, Rajiv; Jiang, Min; Robbins, Nathan; Rubinstein, Jack; Koch, Sheryl E

    2017-10-01

    The aging heart is characterized by cellular and molecular changes leading to a decline in physiologic function and cardiac remodeling, specifically the development of myocyte hypertrophy and fibrosis. Transient receptor potential vanilloid 2 (TRPV2), a stretch-mediated channel and regulator of calcium homeostasis, plays a key role in the function and structure of the heart. TRPV2 also plays an important role in the adaptive and maladaptive compensatory mechanisms of the heart in response to pathologic and exercise-induced stress. Our current study seeks to elucidate the potential role of TRPV2 channels in the regulation of cardiac function in aging. Wild-type (WT) and TRPV2 functional knockout (FKO) mice were aged out to various time points, and their cardiac function was measured using advanced echocardiography. Furthermore, we histologically analyzed the heart morphology to determine myocyte hypertrophy, the development of fibrosis and the relative expression of TRPV2. Our results demonstrate that even though TRPV2-FKO mice have impaired function at baseline, their cardiac function as measured via standard and advanced echocardiographic parameters (ejection fraction, cardiac output and circumferential strain) decreased less with aging in comparison with the WT group. Furthermore, there was less fibrosis and hypertrophy in the TRPV2-FKO group with aging in comparison with the WT. The expression of TRPV2 in the WT group did not significantly change with aging. TRPV2 functional deletion is compatible with aging and associated with a decreased development of myocyte hypertrophy and fibrosis. It may be an important target for prevention of age-induced cardiac remodeling.

  13. Cardio-oncology: a multidisciplinary approach for detection, prevention and management of cardiac dysfunction in cancer patients.

    Science.gov (United States)

    Tajiri, Kazuko; Aonuma, Kazutaka; Sekine, Ikuo

    2017-08-01

    Cardiac dysfunction that develops during or after completion of cancer therapy is a growing health concern that should be addressed in a multidisciplinary setting. Cardio-oncology is a new discipline that focuses on screening, monitoring and treating cardiovascular disease during and after cancer treatment. A baseline cardiovascular risk assessment is essential. For high-risk patients, a tailored and detailed plan for cardiovascular management throughout treatment and beyond should also be established. Anthracycline and/or trastuzumab-containing chemotherapy and chest-directed radiation therapy are well known cardiotoxic cancer therapies. Monitoring for the development of subclinical cardiotoxicity is crucial for the prevention of clinical heart failure. Detecting a decreased left ventricular ejection fraction after cancer therapy might be a late finding; therefore, earlier markers of cardiac injury are being actively explored. Abnormal myocardial strain and increased serum cardiac biomarkers (e.g. troponins and natriuretic peptides) are possible candidates for this purpose. An important method for preventing heart failure is the avoidance or minimization of the use of cardiotoxic therapies. Decisions must balance the anti-tumor efficacy of the treatment with its potential cardiotoxicity. If patients develop cardiac dysfunction or heart failure, they should be treated in accordance with established guidelines for heart failure. Cancer survivors who have been exposed to cardiotoxic cancer therapies are at high risk of developing heart failure. The management of cardiovascular risk factors and periodic screening with cardiac imaging and biomarkers should be considered in high-risk survivors. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  14. The role of long-term antibiotics in the prevention of infection in postoperative cardiac surgeries

    International Nuclear Information System (INIS)

    Shahid, U.; Arain, M.A.; Dar, M.I.; Khan, A.B.; Aftab, S.; Manan, A.U.

    2007-01-01

    To compare the effect of long-term (7 days) versus short-term (2 days) postoperative antibiotics in preventing postoperative infective complications in patients who have undergone open-heart surgeries. Cardiac patients (n=42), operated for valvular disease (36%), coronary artery bypass grafting (50%), or septal repair (14%), were included in our study. Patients were prospectively randomized into two groups. Group A (n=21) patients received oral antibiotics for 7 days, whereas group B (n=21) patients were given the same for 2 days postoperative. Pre-operative and intraoperative variables were equal in both groups. Total leukocyte count and temperature were monitored daily until the patients were discharged. The chest and leg wounds were inspected daily for any signs of infection. Sputum and urine cultures were sent for selected patients in case of respiratory tract infection or urinary tract infection, respectively. Each patient was followed until the next routine visit in outpatient department. In group A, 3 patients (14%), developed infection postoperatively, whereas in group B, 13 patients (62%) (p =0.001) had to be started on oral or intravenous antibiotics as a result of developing either wound infection, a positive sputum culture, a positive urine culture or a localized infection elsewhere. Mean ward stay in group A was 4.8 +- 4.5 days and in group B 6.5 +- 4.1 days (p =0.011). In this series, there was a significantly higher frequency of infection and longer hospital stay in patients who received antibiotics for 2 days postoperatively as compared to those who received antibiotics for 7 days. (author)

  15. Prevention of nosocomial infection in cardiac surgery by decontamination of the nasopharynx and oropharynx with chlorhexidine gluconate: a randomized controlled trial

    NARCIS (Netherlands)

    Segers, Patrique; Speekenbrink, Ron G. H.; Ubbink, Dirk T.; van Ogtrop, Marc L.; de Mol, Bas A.

    2006-01-01

    CONTEXT: Nosocomial infections are an important cause of morbidity and mortality after cardiac surgery. Decolonization of endogenous potential pathogenic microorganisms is important in the prevention of nosocomial infections. OBJECTIVE: To determine the efficacy of perioperative decontamination of

  16. Secondary Prevention Recommendation Attainment with Cardiac Rehabilitation: Is There a Gender Disparity?

    Science.gov (United States)

    Turk-Adawi, Karam I; Oldridge, Neil B; Vitcenda, Mark J; Tarima, Sergey S; Grace, Sherry L

    2016-01-01

    Achievement of secondary prevention guideline recommendations (i.e., goals) with cardiac rehabilitation (CR) is not well-documented, especially for women. This study examined achievement of the American Heart Association/American College of Cardiology (AHA/ACC) goals before and after CR by gender. Of 12,976 patients enrolled in the Wisconsin CR Outcomes Registry, 8,929 (68.8%) completed CR and were included in the sample. Attainment of 15 AHA/ACC goals before and after CR was examined by extracting corresponding data points in the registry as entered by CR program staff. Gender differences in achievement of these goals after CR were examined via generalized estimating equations technique. Attainment of AHA/ACC goals before CR ranged from 15.3% of patients (physical activity) to 98.1% (aspirin), and by 17.6% (physical activity) to 98.4% (diastolic blood pressure) by CR completion. Significant improvements were achieved for 8 goals (53.3%), ranging from 0.7% for body mass index (BMI) to 50.8% for physical activity. Women were significantly less likely than men to achieve the following goals by CR completion: triglycerides (adjusted odds ratio [AOR], 0.54; 95% confidence interval [CI], 0.45-0.66), physical activity (AOR, 0.66; 95% CI, 0.59-0.74), and hemoglobin A1C (AOR, 0.50; 95% CI, 0.32-0.78). Women were significantly more likely than men to achieve the high-density lipoprotein goal (AOR, 1.39; 95% CI, 1.05-1.86). There were no gender differences in goal achievement for blood pressure, total cholesterol, low-density lipoprotein, BMI, smoking cessation, or medication use. More than 94% of patients were taking three of four recommended secondary prevention medications both before and after the program. Men and women generally improved similarly in terms of AHA/ACC goal achievement. Quality improvement strategies need to focus on physical activity and blood glucose control in women. Copyright © 2016 Jacobs Institute of Women's Health. Published by Elsevier Inc. All

  17. Preadmission interventions to prevent postoperative complications in older cardiac surgery patients : A systematic review

    NARCIS (Netherlands)

    Ettema, Roelof G A; Van Koeven, Heleen; Peelen, Linda M.; Kalkman, Cor J.; Schuurmans, Marieke J.

    Objective(s): The literature on postoperative complications in cardiac surgery patients shows high incidences of postoperative complications such as delirium, depression, pressure ulcer, infection, pulmonary complications and atrial fibrillation. These complications are associated with functional

  18. Dual chamber stent prevents organ malperfusion in a model of donation after cardiac death.

    Science.gov (United States)

    Tillman, Bryan W; Chun, Youngjae; Cho, Sung Kwon; Chen, Yanfei; Liang, Nathan; Maul, Timothy; Demetris, Anthony; Gu, Xinzhu; Wagner, William R; Tevar, Amit D

    2016-10-01

    The paradigm for donation after cardiac death subjects donor organs to ischemic injury. A dual-chamber organ perfusion stent would maintain organ perfusion without affecting natural cardiac death. A center lumen allows uninterrupted cardiac blood flow, while an external chamber delivers oxygenated blood to the visceral vessels. A prototype organ perfusion stent was constructed from commercial stents. In a porcine model, the organ perfusion stent was deployed, followed by a simulated agonal period. Oxygenated blood perfused the external stent chamber. Organ perfusion was compared between controls (n = 3) and organ perfusion stent (n = 6). Finally, a custom, nitinol, dual chamber organ perfusion stent was fabricated using a retrievable "petal and stem" design. Endovascular organ perfusion stent deployment achieved visceral isolation without adverse impact on cardiac parameters. Visceral oxygen delivery was 4.8-fold greater compared with controls. During the agonal period, organs in organ perfusion stent-treated animals appeared well perfused in contrast with the malperfused controls. A custom nitinol and polyurethane organ perfusion stent was recaptured easily with simple sheath advancement. An organ perfusion stent maintained organ perfusion during the agonal phase in a porcine model of donation after cardiac death organ donation without adversely affecting cardiac function. Ultimately, the custom retrievable design of this study may help resolve the critical shortage of donor organs for transplant. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Inhibition of Receptor Interacting Protein Kinases Attenuates Cardiomyocyte Hypertrophy Induced by Palmitic Acid.

    Science.gov (United States)

    Zhao, Mingyue; Lu, Lihui; Lei, Song; Chai, Hua; Wu, Siyuan; Tang, Xiaoju; Bao, Qinxue; Chen, Li; Wu, Wenchao; Liu, Xiaojing

    2016-01-01

    Palmitic acid (PA) is known to cause cardiomyocyte dysfunction. Cardiac hypertrophy is one of the important pathological features of PA-induced lipotoxicity, but the mechanism by which PA induces cardiomyocyte hypertrophy is still unclear. Therefore, our study was to test whether necroptosis, a receptor interacting protein kinase 1 and 3 (RIPK1 and RIPK3-) dependent programmed necrosis, was involved in the PA-induced cardiomyocyte hypertrophy. We used the PA-treated primary neonatal rat cardiac myocytes (NCMs) or H9c2 cells to study lipotoxicity. Our results demonstrated that cardiomyocyte hypertrophy was induced by PA treatment, determined by upregulation of hypertrophic marker genes and cell surface area enlargement. Upon PA treatment, the expression of RIPK1 and RIPK3 was increased. Pretreatment with the RIPK1 inhibitor necrostatin-1 (Nec-1), the PA-induced cardiomyocyte hypertrophy, was attenuated. Knockdown of RIPK1 or RIPK3 by siRNA suppressed the PA-induced myocardial hypertrophy. Moreover, a crosstalk between necroptosis and endoplasmic reticulum (ER) stress was observed in PA-treated cardiomyocytes. Inhibition of RIPK1 with Nec-1, phosphorylation level of AKT (Ser473), and mTOR (Ser2481) was significantly reduced in PA-treated cardiomyocytes. In conclusion, RIPKs-dependent necroptosis might be crucial in PA-induced myocardial hypertrophy. Activation of mTOR may mediate the effect of necroptosis in cardiomyocyte hypertrophy induced by PA.

  20. Lactosylceramide promotes hypertrophy through ROS generation and activation of ERK1/2 in cardiomyocytes

    Science.gov (United States)

    Mishra, Sumita; Chatterjee, Subroto

    2014-01-01

    Hypertrophy is central to several heart diseases; however, not much is known about the role of glycosphingolipids (GSLs) in this phenotype. Since GSLs have been accorded several physiological functions, we sought to determine whether these compounds affect cardiac hypertrophy. By using a rat cardiomyoblast cell line, H9c2 cells and cultured primary neonatal rat cardiomyocytes, we have determined the effects of GSLs on hypertrophy. Our study comprises (a) measurement of [3H]-leucine incorporation into protein, (b) measurement of cell size and morphology by immunofluorescence microscopy and (c) real-time quantitative mRNA expression assay for atrial natriuretic peptide and brain natriuretic peptide. Phenylephrine (PE), a well-established agonist of cardiac hypertrophy, served as a positive control in these studies. Subsequently, mechanistic studies were performed to explore the involvement of various signaling transduction pathways that may contribute to hypertrophy in these cardiomyocytes. We observed that lactosylceramide specifically exerted a concentration- (50–100 µM) and time (48 h)-dependent increase in hypertrophy in cardiomyocytes but not a library of other structurally related GSLs. Further, in cardiomyocytes, LacCer generated reactive oxygen species, stimulated the phosphorylation of p44 mitogen activated protein kinase and protein kinase-C, and enhanced c-jun and c-fos expression, ultimately leading to hypertrophy. In summary, we report here that LacCer specifically induces hypertrophy in cardiomyocytes via an “oxygen-sensitive signal transduction pathway.” PMID:24658420

  1. The role of satellite cells in muscle hypertrophy.

    Science.gov (United States)

    Blaauw, Bert; Reggiani, Carlo

    2014-02-01

    The role of satellite cells in muscle hypertrophy has long been a debated issue. In the late 1980s it was shown that proteins remain close to the myonucleus responsible for its synthesis, giving rise to the idea of a nuclear domain. This, together with the observation that during various models of muscle hypertrophy there is an activation of the muscle stem cells, i.e. satellite cells, lead to the idea that satellite cell activation is required for muscle hypertrophy. Thus, satellite cells are not only responsible for muscle repair and regeneration, but also for hypertrophic growth. Further support for this line of thinking was obtained after studies showing that irradiation of skeletal muscle, and therefore elimination of all satellite cells, completely prevented overload-induced hypertrophy. Recently however, using different transgenic approaches, it has become clear that muscle hypertrophy can occur without a contribution of satellite cells, even though in most situations of muscle hypertrophy satellite cells are activated. In this review we will discuss the contribution of satellite cells, and other muscle-resident stem cells, to muscle hypertrophy both in mice as well as in humans.

  2. Hypoxia preconditioned mesenchymal stem cells prevent cardiac fibroblast activation and collagen production via leptin.

    Directory of Open Access Journals (Sweden)

    Panpan Chen

    Full Text Available Activation of cardiac fibroblasts into myofibroblasts constitutes a key step in cardiac remodeling after myocardial infarction (MI, due to interstitial fibrosis. Mesenchymal stem cells (MSCs have been shown to improve post-MI remodeling an effect that is enhanced by hypoxia preconditioning (HPC. Leptin has been shown to promote cardiac fibrosis. The expression of leptin is significantly increased in MSCs after HPC but it is unknown whether leptin contributes to MSC therapy or the fibrosis process. The objective of this study was to determine whether leptin secreted from MSCs modulates cardiac fibrosis.Cardiac fibroblast (CF activation was induced by hypoxia (0.5% O2. The effects of MSCs on fibroblast activation were analyzed by co-culturing MSCs with CFs, and detecting the expression of α-SMA, SM22α, and collagen IαI in CFs by western blot, immunofluorescence and Sirius red staining. In vivo MSCs antifibrotic effects on left ventricular remodeling were investigated using an acute MI model involving permanent ligation of the left anterior descending coronary artery.Co-cultured MSCs decreased fibroblast activation and HPC enhanced the effects. Leptin deficit MSCs from Ob/Ob mice did not decrease fibroblast activation. Consistent with this, H-MSCs significantly inhibited cardiac fibrosis after MI and mediated decreased expression of TGF-β/Smad2 and MRTF-A in CFs. These effects were again absent in leptin-deficient MSCs.Our data demonstrate that activation of cardiac fibroblast was inhibited by MSCs in a manner that was leptin-dependent. The mechanism may involve blocking TGF-β/Smad2 and MRTF-A signal pathways.

  3. Copper reverses cardiomyocyte hypertrophy through vascular endothelial growth factor-mediated reduction in the cell size.

    Science.gov (United States)

    Zhou, Yang; Jiang, Youchun; Kang, Y James

    2008-07-01

    Previous studies have shown that dietary copper supplementation reversed heart hypertrophy induced by pressure overload in a mouse model. The present study was undertaken to understand the cellular basis of copper-induced regression of cardiac hypertrophy. Primary cultures of neonatal rat cardiomyocytes were treated with phenylephrine (PE) at a final concentration of 100 microM in cultures for 48 h to induce cellular hypertrophy. The hypertrophied cardiomyocytes were exposed to copper sulfate at a final concentration of 5 microM in cultures for additional 24 h. This copper treatment reduced the size of the hypertrophied cardiomyocytes, as measured by flow cytometry, protein content in cells, cell volume and cardiomyocyte hypertrophy markers including beta-myosin heavy chain protein, skeletal alpha-actin, and atrial natriuretic peptide. Cell cycle analysis and cell sorting of p-histone-3 labeled cardiomyocytes indicated that cell division was not involved in the copper-induced regression of cardiomyocyte hypertrophy. Copper also inhibited PE-induced apoptosis, determined by a TUNEL assay. Because copper stimulates vascular endothelial growth factor (VEGF) production through activation of hypoxia-inducible transcription factor, an anti-VEGF antibody at a final concentration of 2 ng/ml in cultures was used and shown to blunt copper-induced regression of cell hypertrophy. Conversely, VEGF alone at a final concentration of 0.2 microg/ml reversed cell hypertrophy as the same as copper did. This study demonstrates that both copper and VEGF reduce the size of hypertrophied cardiomyocytes, and copper regression of cardiac hypertrophy is VEGF-dependent.

  4. Sulforaphane protects H9c2 cardiomyocytes from angiotensin II-induced hypertrophy.

    Science.gov (United States)

    Wu, Q-Q; Zong, J; Gao, L; Dai, J; Yang, Z; Xu, M; Fang, Y; Ma, Z-G; Tang, Q-Z

    2014-05-01

    Cardiac hypertrophy is an adaptive process of the heart in response to various stimuli, but sustained cardiac hypertrophy will finally lead to heart failure. Sulforaphane-extracted from cruciferous vegetables of the genus Brassica such as broccoli, brussels sprouts, and cabbage-has been evaluated for its anticarcinogenic and antioxidant effects. To investigate the effect of sulforaphane on angiotensin II (Ang II)-induced cardiac hypertrophy in vitro. Embryonic rat heart-derived H9c2 cells were co-incubated with sulforaphane and Ang II. The cell surface area and mRNA levels of hypertrophic markers were measured to clarify the effect of sulforaphane on cardiac hypertrophy. The underlying mechanism was further investigated by detecting the activation of Akt and NF-κB signaling pathways. We found that H9c2 cells pretreated with sulforaphane were protected from Ang II-induced hypertrophy. The increasing mRNA levels of ANP, BNP, and β-MHC in Ang II-stimulated cells were also down-regulated after sulforaphane treatment. Moreover, sulforaphane repressed the Ang II-induced phosphorylation of Akt, GSK3β, mTOR, eIF4e, as well as of IκBα and NF-κB. Based on our results, sulforaphane attenuates Ang II-induced hypertrophy of H9c2 cardiomyocytes mediated by the inhibition of intracellular signaling pathways including Akt and NF-κB.

  5. A Dual Chamber Stent Prevents Organ Malperfusion in a Model of Donation after Cardiac Death

    Science.gov (United States)

    Tillman, Bryan W.; Chun, Youngjae; Cho, Sung Kwon; Chen, Yanfei; Liang, Nathan; Maul, Timothy; Demetris, Anthony; Gu, Xinzhu; Wagner, William R.; Tevar, Amit D.

    2016-01-01

    Background The paradigm for Donation after Cardiac Death (DCD) subjects donor organs to significant ischemic injury. A dual-chamber Organ Perfusion Stent (OPS) would maintain organ perfusion without impacting natural cardiac death. A center lumen allows uninterrupted cardiac blood flow, while an external chamber delivers oxygenated blood to the visceral vessels. Methods A prototype OPS was constructed from commercial stents. In a porcine model, the OPS was deployed, followed by a simulated agonal period. Oxygenated blood perfused the external stent chamber. Organ perfusion was compared between controls (n=3) and OPS (n=6). Finally, a custom nitinol dual chamber OPS was fabricated using a retrievable “petal and stem” design. Results Endovascular OPS deployment achieved visceral isolation without adverse impact on cardiac parameters. Visceral oxygen delivery was 4.8 fold higher as compared to controls. During the agonal period, organs in OPS treated animals appeared well perfused, contrasting to malperfused controls. A custom nitinol and polyurethane OPS was easily recaptured with simple sheath advancement. Conclusions An OPS maintained organ perfusion during the agonal phase in a model of DCD organ donation without adversely impacting cardiac function. Ultimately, the custom retrievable design of this study may help resolve the critical shortage of donor organs for transplant. PMID:27524434

  6. Telomere dynamics during aging in polygenic left ventricular hypertrophy.

    Science.gov (United States)

    Marques, Francine Z; Booth, Scott A; Prestes, Priscilla R; Curl, Claire L; Delbridge, Lea M D; Lewandowski, Paul; Harrap, Stephen B; Charchar, Fadi J

    2016-01-01

    Short telomeres are associated with increased risk of cardiovascular disease. Here we studied cardiomyocyte telomere length at key ages during the ontogeny of cardiac hypertrophy and failure in the hypertrophic heart rat (HHR) and compared these with the normal heart rat (NHR) control strain. Key ages corresponded with the pathophysiological sequence beginning with fewer cardiomyocytes (2 days), leading to left ventricular hypertrophy (LVH) (13 wk) and subsequently progression to heart failure (38 wk). We measured telomere length, tissue activity of telomerase, mRNA levels of telomerase reverse transcriptase (Tert) and telomerase RNA component (Terc), and expression of the telomeric regulator microRNA miR-34a. Cardiac telomere length was longer in the HHR compared with the control strain at 2 days and 38 wk, but shorter at 13 wk. Neonatal HHR had higher cardiac telomerase activity and expression of Tert and miR-34a. Telomerase activity was not different at 13 or 38 wk. Tert mRNA and Terc RNA were overexpressed at 38 wk, while miR-34a was overexpressed at 13 wk but downregulated at 38 wk. Circulating leukocytes were strongly correlated with cardiac telomere length in the HHR only. The longer neonatal telomeres in HHR are likely to reflect fewer fetal and early postnatal cardiomyocyte cell divisions and explain the reduced total cardiomyocyte complement that predisposes to later hypertrophy and failure. Although shorter telomeres were a feature of cardiac hypertrophy at 13 wk, they were not present at the progression to heart failure at 38 wk. Copyright © 2016 the American Physiological Society.

  7. Preventing Long-Term Cardiac Damage in Pediatric Patients With Kawasaki Disease.

    Science.gov (United States)

    Williams, Kelly

    Kawasaki disease is currently the leading cause of long-term cardiac damage in pediatric patients in the United States. Kawasaki disease is diagnosed based on symptomatology and by ruling out other etiology. There is a significant need for an improved, standardized treatment protocol for patients diagnosed with Kawasaki disease and a more rapid initiation of treatment for these patients. Decreasing the cardiac damage caused by Kawasaki disease with timely diagnosis and treatment needs be a principal goal. Copyright © 2016 National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.

  8. Autophagy Plays an Essential Role in Mediating Regression of Hypertrophy during Unloading of the Heart

    Science.gov (United States)

    Hariharan, Nirmala; Ikeda, Yoshiyuki; Hong, Chull; Alcendor, Ralph R.; Usui, Soichiro; Gao, Shumin; Maejima, Yasuhiro; Sadoshima, Junichi

    2013-01-01

    Autophagy is a bulk degradation mechanism for cytosolic proteins and organelles. The heart undergoes hypertrophy in response to mechanical load but hypertrophy can regress upon unloading. We hypothesize that autophagy plays an important role in mediating regression of cardiac hypertrophy during unloading. Mice were subjected to transverse aortic constriction (TAC) for 1 week, after which the constriction was removed (DeTAC). Regression of cardiac hypertrophy was observed after DeTAC, as indicated by reduction of LVW/BW and cardiomyocyte cross-sectional area. Indicators of autophagy, including LC3-II expression, p62 degradation and GFP-LC3 dots/cell, were significantly increased after DeTAC, suggesting that autophagy is induced. Stimulation of autophagy during DeTAC was accompanied by upregulation of FoxO1. Upregulation of FoxO1 and autophagy was also observed in vitro when cultured cardiomyocytes were subjected to mechanical stretch followed by incubation without stretch (de-stretch). Transgenic mice with cardiac-specific overexpression of FoxO1 exhibited smaller hearts and upregulation of autophagy. Overexpression of FoxO1 in cultured cardiomyocytes significantly reduced cell size, an effect which was attenuated when autophagy was inhibited. To further examine the role of autophagy and FoxO1 in mediating the regression of cardiac hypertrophy, beclin1+/− mice and cultured cardiomyocytes transduced with adenoviruses harboring shRNA-beclin1 or shRNA-FoxO1 were subjected to TAC/stretch followed by DeTAC/de-stretch. Regression of cardiac hypertrophy achieved after DeTAC/de-stretch was significantly attenuated when autophagy was suppressed through downregulation of beclin1 or FoxO1. These results suggest that autophagy and FoxO1 play an essential role in mediating regression of cardiac hypertrophy during mechanical unloading. PMID:23308102

  9. Pregnancy as a cardiac stress model

    Science.gov (United States)

    Chung, Eunhee; Leinwand, Leslie A.

    2014-01-01

    Cardiac hypertrophy occurs during pregnancy as a consequence of both volume overload and hormonal changes. Both pregnancy- and exercise-induced cardiac hypertrophy are generally thought to be similar and physiological. Despite the fact that there are shared transcriptional responses in both forms of cardiac adaptation, pregnancy results in a distinct signature of gene expression in the heart. In some cases, however, pregnancy can induce adverse cardiac events in previously healthy women without any known cardiovascular disease. Peripartum cardiomyopathy is the leading cause of non-obstetric mortality during pregnancy. To understand how pregnancy can cause heart disease, it is first important to understand cardiac adaptation during normal pregnancy. This review provides an overview of the cardiac consequences of pregnancy, including haemodynamic, functional, structural, and morphological adaptations, as well as molecular phenotypes. In addition, this review describes the signalling pathways responsible for pregnancy-induced cardiac hypertrophy and angiogenesis. We also compare and contrast cardiac adaptation in response to disease, exercise, and pregnancy. The comparisons of these settings of cardiac hypertrophy provide insight into pregnancy-associated cardiac adaptation. PMID:24448313

  10. Similar arrhythmicity in hypertrophic and fibrotic cardiac cultures caused by distinct substrate-specific mechanisms.

    Science.gov (United States)

    Askar, Saïd F A; Bingen, Brian O; Schalij, Martin J; Swildens, Jim; Atsma, Douwe E; Schutte, Cindy I; de Vries, Antoine A F; Zeppenfeld, Katja; Ypey, Dirk L; Pijnappels, Daniël A

    2013-01-01

    Cardiac hypertrophy and fibrosis are associated with potentially lethal arrhythmias. As these substrates often occur simultaneously in one patient, distinguishing between pro-arrhythmic mechanisms is difficult. This hampers understanding of underlying pro-arrhythmic mechanisms and optimal treatment. This study investigates and compares arrhythmogeneity and underlying pro-arrhythmic mechanisms of either cardiac hypertrophy or fibrosis in in vitro models. Fibrosis was mimicked by free myofibroblast (MFB) proliferation in neonatal rat ventricular monolayers. Cultures with inhibited MFB proliferation were used as control or exposed to phenylephrine to induce hypertrophy. At Day 9, cultures were studied with patch-clamp and optical-mapping techniques and assessed for protein expression. In hypertrophic (n = 111) and fibrotic cultures (n = 107), conduction and repolarization were slowed. Triggered activity was commonly found in these substrates and led to high incidences of spontaneous re-entrant arrhythmias [67.5% hypertrophic, 78.5% fibrotic vs. 2.9% in controls (n = 102)] or focal arrhythmias (39.1, 51.7 vs. 8.8%, respectively). Kv4.3 and Cx43 protein expression levels were decreased in hypertrophy but unaffected in fibrosis. Depolarization of cardiomyocytes (CMCs) was only found in fibrotic cultures (-48 ± 7 vs. -66 ± 7 mV in control, P arrhythmias in hypertrophy, but caused conduction block in fibrosis. Targeting heterocellular coupling by low doses of gap-junction uncouplers prevented arrhythmias by accelerating repolarization only in fibrotic cultures. Cultured hypertrophic or fibrotic myocardial tissues generated similar focal and re-entrant arrhythmias. These models revealed electrical remodelling of CMCs as a pro-arrhythmic mechanism of hypertrophy and MFB-induced depolarization of CMCs as a pro-arrhythmic mechanism of fibrosis. These findings provide novel mechanistic insight into substrate-specific arrhythmicity.

  11. Syncope and the risk of sudden cardiac death: Evaluation, management, and prevention

    Directory of Open Access Journals (Sweden)

    Ryan J. Koene, MD

    2017-12-01

    Full Text Available Syncope is a clinical syndrome defined as a relatively brief self-limited transient loss of consciousness (TLOC caused by a period of inadequate cerebral nutrient flow. Most often the trigger is an abrupt drop of systemic blood pressure. True syncope must be distinguished from other common non-syncope conditions in which real or apparent TLOC may occur such as seizures, concussions, or accidental falls. The causes of syncope are diverse, but in most instances, are relatively benign (e.g., reflex and orthostatic faints with the main risks being accidents and/or injury. However, in some instances, syncope may be due to more worrisome conditions (particularly those associated with cardiac structural disease or channelopathies; in such circumstances, syncope may be an indicator of increased morbidity and mortality risk, including sudden cardiac death (SCD. Establishing an accurate basis for the etiology of syncope is crucial in order to initiate effective therapy. In this review, we focus primarily on the causes of syncope that are associated with increased SCD risk (i.e., sudden arrhythmic cardiac death, and the management of these patients. In addition, we discuss the limitations of our understanding of SCD in relation to syncope, and propose future studies that may ultimately address how to improve outcomes of syncope patients and reduce SCD risk. Keywords: Syncope, Sudden cardiac death, Risk assessment

  12. Dexamethasone for the prevention of postpericardiotomy syndrome: A DExamethasone for Cardiac Surgery substudy

    NARCIS (Netherlands)

    Bunge, Jeroen J. H.; van Osch, Dirk; Dieleman, Jan M.; Jacob, Kirolos A.; Kluin, Jolanda; van Dijk, Diederik; Nathoe, Hendrik M.; Bredée, Jaap J.; Buhre, Wolfgang F.; van Herwerden, Lex A.; Kalkman, Cor J.; van Klarenbosch, Jan; Moons, Karel G.; Numan, Sandra C.; Ottens, Thomas H.; Roes, Kit C.; Sauer, Anne-Mette C.; Slooter, Arjen J.; Nierich, Arno P.; Ennema, Jacob J.; Rosseel, Peter M.; van der Meer, Nardo J.; van der Maaten, Joost M.; Cernak, Vlado; Hofland, Jan; van Thiel, Robert J.; Diephuis, Jan C.; Schepp, Ronald M.; Haenen, Jo; de Lange, Fellery; Boer, Christa; de Jong, Jan R.; Tijssen, Jan G.

    2014-01-01

    The postpericardiotomy syndrome (PPS) is a common complication following cardiac surgery. The pathophysiology remains unclear, although evidence exists that surgical trauma and the use of cardiopulmonary bypass provoke an immune response leading to PPS. We hypothesized that an intraoperative dose of

  13. Tissue characteristics in left ventricular hypertrophy using magnetic resonance imaging

    International Nuclear Information System (INIS)

    Yoshida, Shigeru; Ueno, Yuji; Arita, Mikio; Nishio, Ichiro; Masuyama, Yoshiaki

    1988-01-01

    For 15 normotensive patients with asymmetric septal hypertrophy (ASH), 10 hypertensive patients with concentric hypertrophy (CH), and five normal subjects (N), we examined changes in myocardial T 1 and T 2 values related to the cardiac cycle. The usefulness of those values in differentiating diseases with left ventricular hypertrophy was evaluated. Left ventricular (LV) short-axis spin echo images and inversion recovery images were obtained at endsystolic and diastolic cardiac phases, and T 1 and T 2 images were calculated. The regional wall thickness (WT) and T 1 and T 2 values were measured in the anterior septum, anterior wall, lateral wall, posterior wall and posterior septum. Myocardial T 1 and T 2 values were significantly decreased in systole (T 1 : 185.6±37.9 msec, T 2 : 24.4±6.3 msec, mean±SD) compared to those in diastole (T 1 : 249.2±56.7 msec, T 2 : 31.7±9.4 msec). In both the ASH and CH groups, significant correlations were observed between diastolic T 1 values and WT (ASH: r = 0.80, p 2 values and WT (ASH: r = 0.58, p 1 values in the ASH group (343.4±40.5 msec) were significantly higher than those of the CH group (247.3±21.4 msec), although the mean wall thickness values were similar in both groups. The T 1 /WT and T 2 /WT were significantly lower in the CH group than those in the ASH and N groups. In conclusion, myocardial T 1 and T 2 values were related not only to the cardiac cycle, but to wall thickness and to types of hypertrophy. The T 1 and T 2 values may be useful for distinguishing hypertrophic cardiomyopathy from hypertrophy due to hypertension. (author)

  14. Long-term exercise and risk of metabolic and cardiac diseases: the erlangen fitness and prevention study.

    Science.gov (United States)

    Kemmler, Wolfgang; von Stengel, Simon; Bebenek, Michael; Kalender, Willi A

    2013-01-01

    In female subjects, ageing and the menopausal transition contribute to a rapid increase of metabolic and cardiac risk factors. Exercise may be an option to positively impact various risk factors prone to severe metabolic and cardiac diseases and events. This study was conducted to determine the long-term effect of a multipurpose exercise program on metabolic and cardiac risk scores in postmenopausal women. 137 osteopenic Caucasian females (55.4 ± 3.2 yrs), 1-8 years postmenopausal, were included in the study. Eighty-six subjects joined the exercise group (EG) and performed an intense multipurpose exercise program which was carefully supervised during the 12-year period, while 51 females maintained their habitual physical activity (CG). Main outcome measures were 10-year coronary heart disease risk (10 y CHD risk), metabolic syndrome Z-score (MetS Index), and 10-year myocardial infarction risk (10 y hard CHD risk). Significant between-group differences all in favor of the EG were determined for 10 y-CHD risk (EG: 2.65 ± 2.09% versus CG: 5.40 ± 3.30%; P = 0.001), MetS-Index (EG: -0.42 ± 1.03% versus CG: 1.61 ± 1.88; P = 0.001), and 10 y-hard-CHD risk (EG: 2.06 ± 1.17% versus CG: 3.26 ± 1.31%; P = 0.001). Although the nonrandomized design may prevent definite evidence, the intense multi-purpose exercise program determined the long-term efficacy and feasibility of an exercise program to significantly impact metabolic and cardiac risk scores in postmenopausal women. This trial is registered with ClinicalTrials.gov NCT01177761.

  15. Long-Term Exercise and Risk of Metabolic and Cardiac Diseases: The Erlangen Fitness and Prevention Study

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    Wolfgang Kemmler

    2013-01-01

    Full Text Available In female subjects, ageing and the menopausal transition contribute to a rapid increase of metabolic and cardiac risk factors. Exercise may be an option to positively impact various risk factors prone to severe metabolic and cardiac diseases and events. This study was conducted to determine the long-term effect of a multipurpose exercise program on metabolic and cardiac risk scores in postmenopausal women. 137 osteopenic Caucasian females (55.4 ± 3.2 yrs, 1–8 years postmenopausal, were included in the study. Eighty-six subjects joined the exercise group (EG and performed an intense multipurpose exercise program which was carefully supervised during the 12-year period, while 51 females maintained their habitual physical activity (CG. Main outcome measures were 10-year coronary heart disease risk (10 y CHD risk, metabolic syndrome Z-score (MetS Index, and 10-year myocardial infarction risk (10 y hard CHD risk. Significant between-group differences all in favor of the EG were determined for 10 y-CHD risk (EG: 2.65±2.09% versus CG: 5.40±3.30%; P=0.001, MetS-Index (EG: −0.42±1.03% versus CG: 1.61±1.88; P=0.001, and 10 y-hard-CHD risk (EG: 2.06±1.17% versus CG: 3.26±1.31%; P=0.001. Although the nonrandomized design may prevent definite evidence, the intense multi-purpose exercise program determined the long-term efficacy and feasibility of an exercise program to significantly impact metabolic and cardiac risk scores in postmenopausal women. This trial is registered with ClinicalTrials.gov NCT01177761.

  16. MiR-30-Regulated Autophagy Mediates Angiotensin II-Induced Myocardial Hypertrophy

    Science.gov (United States)

    Pan, Wei; Zhong, Yun; Cheng, Chuanfang; Liu, Benrong; Wang, Li; Li, Aiqun; Xiong, Longgen; Liu, Shiming

    2013-01-01

    Dysregulated autophagy may lead to the development of disease. Role of autophagy and the diagnostic potential of microRNAs that regulate the autophagy in cardiac hypertrophy have not been evaluated. A rat model of cardiac hypertrophy was established using transverse abdominal aortic constriction (operation group). Cardiomyocyte autophagy was enhanced in rats from the operation group, compared with those in the sham operation group. Moreover, the operation group showed up-regulation of beclin-1 (an autophagy-related gene), and down-regulation of miR-30 in cardiac tissue. The effects of inhibition and over-expression of the beclin-1 gene on the expression of hypertrophy-related genes and on autophagy were assessed. Angiotensin II-induced myocardial hypertrophy was found to be mediated by over-expression of the beclin-1 gene. A dual luciferase reporter assay confirmed that beclin-1 was a target gene of miR-30a. miR-30a induced alterations in beclin-1 gene expression and autophagy in cardiomyocytes. Treatment of cardiomyocytes with miR-30a mimic attenuated the Angiotensin II-induced up-regulation of hypertrophy-related genes and decreased in the cardiomyocyte surface area. Conversely, treatment with miR-30a inhibitor enhanced the up-regulation of hypertrophy-related genes and increased the surface area of cardiomyocytes induced by Angiotensin II. In addition, circulating miR-30 was elevated in patients with left ventricular hypertrophy, and circulating miR-30 was positively associated with left ventricular wall thickness. Collectively, these above-mentioned results suggest that Angiotensin II induces down-regulation of miR-30 in cardiomyocytes, which in turn promotes myocardial hypertrophy through excessive autophagy. Circulating miR-30 may be an important marker for the diagnosis of left ventricular hypertrophy. PMID:23326547

  17. Correlation of Electrocardiographic Changes with Cardiac Magnetic Resonance Findings in Patients with Hypertrophic Cardiomyopathy

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    Gabriela Miana de Mattos Paixão

    Full Text Available Abstract Background: Electrocardiogram is the initial test in the investigation of heart disease. Electrocardiographic changes in hypertrophic cardiomyopathy have no set pattern, and correlates poorly with echocardiographic findings. Cardiac magnetic resonance imaging has been gaining momentum for better assessment of hypertrophy, as well as the detection of myocardial fibrosis. Objectives: To correlate the electrocardiographic changes with the location of hypertrophy in hypertrophic cardiomyopathy by cardiac magnetic resonance. Methods: This descriptive cross-sectional study evaluated 68 patients with confirmed diagnosis of hypertrophic cardiomyopathy by cardiac magnetic resonance. The patients’ electrocardiogram was compared with the location of the greatest myocardial hypertrophy by cardiac magnetic resonance. Statistical significance level of 5% and 95% confidence interval were adopted. Results: Of 68 patients, 69% had septal hypertrophy, 21% concentric and 10% apical hypertrophies. Concentric hypertrophy showed the greatest myocardial fibrosis mass (p < 0.001 and the greatest R wave size in D1 (p = 0.0280. The amplitudes of R waves in V5 and V6 (p = 0.0391, p = 0.0148 were higher in apical hypertrophy, with statistical significance. Apical hypertrophy was also associated with higher T wave negativity in D1, V5 and V6 (p < 0.001. Strain pattern was found in 100% of the patients with apical hypertrophy (p < 0.001. Conclusion: The location of myocardial hypertrophy by cardiac magnetic resonance can be correlated with electrocardiographic changes, especially for apical hypertrophy.

  18. Cardiac-Specific SOCS3 Deletion Prevents In Vivo Myocardial Ischemia Reperfusion Injury through Sustained Activation of Cardioprotective Signaling Molecules.

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    Takanobu Nagata

    Full Text Available Myocardial ischemia reperfusion injury (IRI adversely affects cardiac performance and the prognosis of patients with acute myocardial infarction. Although myocardial signal transducer and activator of transcription (STAT 3 is potently cardioprotective during IRI, the inhibitory mechanism responsible for its activation is largely unknown. The present study aimed to investigate the role of the myocardial suppressor of cytokine signaling (SOCS-3, an intrinsic negative feedback regulator of the Janus kinase (JAK-STAT signaling pathway, in the development of myocardial IRI. Myocardial IRI was induced in mice by ligating the left anterior descending coronary artery for 1 h, followed by different reperfusion times. One hour after reperfusion, the rapid expression of JAK-STAT-activating cytokines was observed. We precisely evaluated the phosphorylation of cardioprotective signaling molecules and the expression of SOCS3 during IRI and then induced myocardial IRI in wild-type and cardiac-specific SOCS3 knockout mice (SOCS3-CKO. The activation of STAT3, AKT, and ERK1/2 rapidly peaked and promptly decreased during IRI. This decrease correlated with the induction of SOCS3 expression up to 24 h after IRI in wild-type mice. The infarct size 24 h after reperfusion was significantly reduced in SOCS3-CKO compared with wild-type mice. In SOCS3-CKO mice, STAT3, AKT, and ERK1/2 phosphorylation was sustained, myocardial apoptosis was prevented, and the expression of anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1 was augmented. Cardiac-specific SOCS3 deletion led to the sustained activation of cardioprotective signaling molecules including and prevented myocardial apoptosis and injury during IRI. Our findings suggest that SOCS3 may represent a key factor that exacerbates the development of myocardial IRI.

  19. Use of magnesium orotate in children with myocardial hypertrophy in the presence of arterial hypertension

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    V. V. Linyaeva

    2014-01-01

    Full Text Available The article provides a comparative analysis of the antihypertensive and cardioprotective effects of magnerot® on pathological cardiac remodeling and repolarization in children with sustained hypertension complicated by left ventricular hypertrophy. Stress testing before and after combined therapy with angiotensin-converting enzyme inhibitors and magnerot® revealed higher exercise tolerance and a normalized blood pressure response in hypertensive children with left ventricular hypertrophy. Moreover, there was a reduction in the spatial dispersion of repolarization. These results substantiate the need to incorporate magnerot® in combination with angiotensin-converting enzyme inhibitors into therapy for patients with hypertension complicated with left ventricular hypertrophy.

  20. Prevention of sudden cardiac death in athletes, sportspersons and marathoners in India

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    Amit Vora

    2018-01-01

    Full Text Available The annual incidence of sudden cardiac death (SCD in athletes is significantly lower than the general population. However, when SCD occurs in an athlete during sporting event or training, it sends shockwaves in the society and raises questions about cardiovascular effects of sports and exercise. This document reviews the causes and mechanism of SCD in sports and exercise in young and older athletes. In the Indian context, we suggest a ‘pre-participation screening’ of young and older athletes and consider a ‘supervised, graded exercise regime’ for the uninitiated, older sports participant. Finally, the document proposes medical infrastructure required to successfully revive a victim of sudden cardiac arrest during a sporting event.

  1. CDK6 mediates the effect of attenuation of miR-1 on provoking cardiomyocyte hypertrophy.

    Science.gov (United States)

    Yuan, Weiwei; Tang, Chunmei; Zhu, Wensi; Zhu, Jiening; Lin, Qiuxiong; Fu, Yongheng; Deng, Chunyu; Xue, Yumei; Yang, Min; Wu, Shulin; Shan, Zhixin

    2016-01-01

    MicroRNA-1 (miR-1) is approved involved in cardiac hypertrophy, but the underlying molecular mechanisms of miR-1 in cardiac hypertrophy are not well elucidated. The present study aimed to investigate the potential role of miR-1 in modulating CDKs-Rb pathway during cardiomyocyte hypertrophy. A rat model of hypertrophy was established with abdominal aortic constriction, and a cell model of hypertrophy was also achieved based on PE-promoted neonatal rat ventricular cardiomyocytes (NRVCs). We demonstrated that miR-1 expression was markedly decreased in hypertrophic myocardium and hypertrophic cardiomyocytes. Dual luciferase reporter assays revealed that miR-1 interacted with the 3'UTR of CDK6, and miR-1 was verified to inhibit CDK6 expression at the posttranscriptional level. CDK6 protein expression was observed increased in hypertrophic myocardium and hypertrophic cardiomyocytes. Morover, miR-1 mimic, in parallel to CDK6 siRNA, could inhibit PE-induced hypertrophy of NRVCs, with decreases in cell size, newly transcribed RNA, expressions of ANF and β-MHC, and the phosphorylated pRb. Taken together, our results reveal that derepression of CDK6 and activation of Rb pathway contributes to the effect of attenuation of miR-1 on provoking cardiomyocyte hypertrophy.

  2. Preventing Sudden Cardiac Death: Automated External Defibrillators in Ohio High Schools.

    Science.gov (United States)

    Lear, Aaron; Hoang, Minh-Ha; Zyzanski, Stephen J

    2015-10-01

    Ohio passed legislation in 2004 for optional public funding of automated external defibrillators (AEDs) in all Ohio high schools. To report occurrences of sudden cardiac arrest in which AEDs were used in Ohio high schools and to evaluate the adherence of Ohio high schools with AEDs to state law and published guidelines on AEDs and emergency action plans (EAPs) in schools. Cross-sectional survey. Web-based survey. A total of 264 of 827 schools that were members of the Ohio High School Athletic Association. We surveyed schools on AED use, AED maintenance, and EAPs. Twenty-five episodes of AED deployment at 22 schools over an 11-year period were reported; 8 (32%) involved students and 17 (68%) involved adults. The reported survival rate was 60% (n = 15). Most events (n = 20, 80%) in both students and adults occurred at or near athletic facilities. The annual use rate of AEDs was 0.7%. Fifty-three percent (n = 140) of schools reported having an EAP in place for episodes of cardiac arrest. Of the schools with EAPs, 57% (n = 80) reported having rehearsed them. Our data supported the placement of AEDs in high schools given the frequency of use for sudden cardiac arrest and the survival rate reported. They also suggested the need for increased awareness of recommendations for EAPs and the need to formulate and practice EAPs. School EAPs should emphasize planning for events in the vicinity of athletic facilities.

  3. C-Myc regulates substrate oxidation patterns during early pressure-overload hypertrophy

    Energy Technology Data Exchange (ETDEWEB)

    Ledee, Dolena R. [Seattle Children' s Research Inst., Seattle, WA (United States); Smith, Lincoln [Seattle Children' s Hospital, Seattle, WA (United States); Kajimoto, Masaki [Seattle Children' s Research Inst., Seattle, WA (United States); Bruce, Margaret [Seattle Children' s Research Inst., Seattle, WA (United States); Isern, Nancy G. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Environmental Molecular Sciences Lab. (EMSL); Xu, Chun [Seattle Children' s Research Inst., Seattle, WA (United States); Portman, Michael A. [Seattle Children' s Research Inst., Seattle, WA (United States); Olson, Aaron [Seattle Children' s Research Inst., Seattle, WA (United States)

    2013-11-26

    Pressure overload cardiac hypertrophy alters substrate metabolism. Prior work showed that myocardial inactivation of c-Myc (Myc) attenuated hypertrophy and decreased expression of glycolytic genes after aortic constriction. Accordingly, we hypothesize that Myc regulates substrate preferences for the citric acid cycle during pressure overload hypertrophy from transverse aortic constriction (TAC) and that these metabolic changes impact cardiac function and growth. To test this hypothesis, we subjected FVB mice with cardiac specific, inducible Myc inactivation (MycKO-TAC) and non-transgenic littermates (Cont-TAC) to transverse aortic constriction (n=7/group). A separate group underwent sham surgery (Sham, n=5). After two weeks, function was measured in isolated working hearts along with substrate fractional contributions to the citric acid cycle by using perfusate with 13C labeled mixed fatty acids, lactate, ketones and unlabeled glucose and insulin. Western blots were used to evaluate metabolic enzymes. Cardiac function was similar between groups after TAC although +dP/dT and -dP/dT trended towards improvement in MycKO-TAC versus Cont-TAC. Compared to Sham, Cont-TAC had increased free fatty acid fractional contribution with a concurrent decrease in unlabeled (presumably glucose) contribution. Myc inactivation (MycKO-TAC) inhibited these metabolic changes. Hypertrophy in general increased protein levels of PKM2; however this change was not linked to Myc status. Protein post-translation modification by O-GlcNAc was significantly greater in Cont-TAC versus both Sham and MycKO-TAC. In conclusion, Myc regulates substrate utilization during early pressure overload hypertrophy. Our results show that the metabolic switch during hypertrophy is not necessary to maintain cardiac function, but it may be important mechanism to promote cardiomyocyte growth. Myc also regulates protein O-GlcNAcylation during hypertrophy.

  4. Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease.

    Science.gov (United States)

    Oakley, Robert H; Ren, Rongqin; Cruz-Topete, Diana; Bird, Gary S; Myers, Page H; Boyle, Michael C; Schneider, Michael D; Willis, Monte S; Cidlowski, John A

    2013-10-15

    Heart failure is a leading cause of death in humans, and stress is increasingly associated with adverse cardiac outcomes. Glucocorticoids are primary stress hormones, but their direct role in cardiovascular health and disease is poorly understood. To determine the in vivo function of glucocorticoid signaling in the heart, we generated mice with cardiomyocyte-specific deletion of the glucocorticoid receptor (GR). These mice are born at the expected Mendelian ratio, but die prematurely from spontaneous cardiovascular disease. By 3 mo of age, mice deficient in cardiomyocyte GR display a marked reduction in left ventricular systolic function, as evidenced by decreases in ejection fraction and fractional shortening. Heart weight and left ventricular mass are elevated, and histology revealed cardiac hypertrophy without fibrosis. Removal of endogenous glucocorticoids and mineralocorticoids neither augmented nor lessened the hypertrophic response. Global gene expression analysis of knockout hearts before pathology onset revealed aberrant regulation of a large cohort of genes associated with cardiovascular disease as well as unique disease genes associated with inflammatory processes. Genes important for maintaining cardiac contractility, repressing cardiac hypertrophy, promoting cardiomyocyte survival, and inhibiting inflammation had decreased expression in the GR-deficient hearts. These findings demonstrate that a deficiency in cardiomyocyte glucocorticoid signaling leads to spontaneous cardiac hypertrophy, heart failure, and death, revealing an obligate role for GR in maintaining normal cardiovascular function. Moreover, our findings suggest that selective activation of cardiomyocyte GR may represent an approach for the prevention of heart disease.

  5. MEK1 inhibits cardiac PPARα activity by direct interaction and prevents its nuclear localization.

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    Hamid el Azzouzi

    Full Text Available BACKGROUND: The response of the postnatal heart to growth and stress stimuli includes activation of a network of signal transduction cascades, including the stress activated protein kinases such as p38 mitogen-activated protein kinase (MAPK, c-Jun NH2-terminal kinase (JNK and the extracellular signal-regulated kinase (ERK1/2 pathways. In response to increased workload, the mitogen-activated protein kinase kinase (MAPKK MEK1 has been shown to be active. Studies embarking on mitogen-activated protein kinase (MAPK signaling cascades in the heart have indicated peroxisome-proliferators activated-receptors (PPARs as downstream effectors that can be regulated by this signaling cascade. Despite the importance of PPARα in controlling cardiac metabolism, little is known about the relationship between MAPK signaling and cardiac PPARα signaling. METHODOLOGY/PRINCIPAL FINDING: Using co-immunoprecipitation and immunofluorescence approaches we show a complex formation of PPARα with MEK1 and not with ERK1/2. Binding of PPARα to MEK1 is mediated via a LXXLL motif and results in translocation from the nucleus towards the cytoplasm, hereby disabling the transcriptional activity of PPARα. Mice subjected to voluntary running-wheel exercise showed increased cardiac MEK1 activation and complex formation with PPARα, subsequently resulting in reduced PPARα activity. Inhibition of MEK1, using U0126, blunted this effect. CONCLUSION: Here we show that activation of the MEK1-ERK1/2 pathway leads to specific inhibition of PPARα transcriptional activity. Furthermore we show that this inhibitory effect is mediated by MEK1, and not by its downstream effector kinase ERK1/2, through a mechanism involving direct binding to PPARα and subsequent stimulation of PPARα export from the nucleus.

  6. Preventing Postoperative Atrial Fibrillation after Non-Cardiac Surgery: a Meta-Analysis.

    Science.gov (United States)

    Oesterle, Adam; Weber, Benjamin; Tung, Roderick; Choudhry, Niteesh K; Singh, Jagmeet P; Upadhyay, Gaurav A

    2018-02-21

    Although post-operative atrial fibrillation is common after non-cardiac surgery, there is a paucity of data regarding prophylaxis. We sought to determine if pharmacologic prophylaxis reduces the incidence of post-operative atrial fibrillation after non-cardiac surgery. We performed an electronic search of Ovid MEDLINE, the Cochrane central register of controlled trials database, and SCOPUS from inception to 9/7/2016 and included prospective randomized studies in which patients in sinus rhythm underwent non-cardiac surgery and examined the incidence of post-operative atrial fibrillation as well as secondary safety outcomes. 21 studies including 11,608 patients were included. Types of surgery included vascular surgery (3,465 patients), thoracic surgery (2,757 patients), general surgery (2,292 patients), orthopedic surgery (1,756 patients), and other surgery (1,338 patients). Beta-blockers (RR 0.32; 95% CI 0.11 to 0.87), amiodarone (RR 0.42; 95% CI 0.26 to 0.67), and statins (RR 0.43; 95% CI 0.27 to 0.68) reduced post-operative atrial fibrillation compared to placebo or active controls. Calcium channel blockers (RR 0.55; 95% CI 0.30 to 1.01), digoxin (RR 1.62; 95% CI 0.95 to 2.76), and magnesium (RR 0.73; 95% CI 0.23 to 2.33) had no statistically significant effect on post-operative atrial fibrillation incidence. The incidence of adverse events was comparable across agents, except for increased mortality (RR 1.33; 95% CI 1.03 to 1.37) and bradycardia (RR 2.74; 95% CI 2.19 to 3.43) in patients receiving beta-blockers. Pharmacologic prophylaxis with amiodarone, beta-blockers, or statins reduces the incidence of postoperative atrial fibrillation after non-cardiac surgery. Amiodarone and statins have a relatively low overall-risk of short-term adverse events. Copyright © 2018. Published by Elsevier Inc.

  7. Possibly preventable cardiac arrest in a morbidly obese patient - a comment on the 2015 ERC guidelines.

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    Hans, Felix Patricius; Hoeren, Claudia Johanna Maria; Kellmeyer, Phillipp; Hohloch, Lisa; Busch, Hans-Jörg; Bayer, Jörg

    2016-10-04

    The incidence of overweight and obesity has been steadily on the rise and has reached epidemic proportions in various countries and this represents a well-known major health problem. Nevertheless, current guidelines for resuscitation do not include special sequences of action in this subset of patients. The aim of this letter is to bring this controversy into focus and to suggest alterations of the known standard cardiopulmonary resuscitation in the obese. An obese patient weighing 272 kg fell to the floor, afterwards being unable to get up again. Thus, emergency services were called for assistance. There were no signs or symptoms signifying that the person had been harmed in consequence of the fall. Only when brought into a supine position the patient suffered an immediate cardiac arrest. Cardiopulmonary resuscitation was performed but there was no return of a stable spontaneous circulation until the patient was brought into a full lateral position. In spite of immediate emergency care the patient ultimately suffered a lethal hypoxic brain damage. A full lateral position should be considered in obese patients having a cardiac arrest as it might help to re-establish stable circulatory conditions.

  8. Apical left ventricular hypertrophy and mid-ventricular obstruction in fabry disease.

    Science.gov (United States)

    Cianciulli, Tomás F; Saccheri, María C; Fernández, Segundo P; Fernández, Cinthia C; Rozenfeld, Paula A; Kisinovsky, Isaac

    2015-05-01

    We report the case of a rare cardiac presentation of Fabry disease. Although concentric left ventricular hypertrophy is a major cardiac finding in Fabry disease, there is no case report of dynamic obstruction at mid-left ventricular level. We describe a 59-year-old-woman suffering from a severe form of Fabry disease, mimicking an apical hypertrophic cardiomyopathy with mid-ventricular obstruction. Differentiation of Fabry disease from hypertrophic cardiomyopathy is crucial given the therapeutic and prognostic differences. Fabry disease should always be suspected in an adult, independently of the pattern of left ventricular hypertrophy. © 2015, Wiley Periodicals, Inc.

  9. Tapping the brake on cardiac growth-endogenous repressors of hypertrophic signaling

    NARCIS (Netherlands)

    Leenders, Joost J.; Pinto, Yigal M.; Creemers, Esther E.

    2011-01-01

    Cardiac hypertrophy is considered an early hallmark during the clinical course of heart failure and an important risk factor for cardiac morbidity and mortality. Although hypertrophy of individual cardiomyocytes in response to pathological stimuli has traditionally been considered as an adaptive

  10. Phosphorylation of ribosomal protein S6 mediates compensatory renal hypertrophy

    Science.gov (United States)

    Xu, Jinxian; Chen, Jianchun; Dong, Zheng; Meyuhas, Oded; Chen, Jian-Kang

    2014-01-01

    The molecular mechanism underlying renal hypertrophy and progressive nephron damage remains poorly understood. Here we generated congenic ribosomal protein S6 (rpS6) knockin mice expressing non-phosphorylatable rpS6 and found that uninephrectomy-induced renal hypertrophy was significantly blunted in these knockin mice. Uninephrectomy-induced increases in cyclin D1 and decreases in cyclin E in the remaining kidney were attenuated in the knockin mice compared to their wild-type littermates. Uninephrectomy induced rpS6 phosphorylation in the wild type mice; however, no rpS6 phosphorylation was detected in uninephrectomized or sham-operated knockin mice. Nonetheless, uninephrectomy stimulated comparable 4E-BP1 phosphorylation in both knockin and wild type mice, indicating that mTORC1 was still activated in the knockin mice. Moreover, the mTORC1 inhibitor rapamycin prevented both rpS6 and 4E-BP1 phosphorylation, significantly blunted uninephrectomy-induced renal hypertrophy in wild type mice, but did not prevent residual renal hypertrophy despite inhibiting 4E-BP1 phosphorylation in uninephrectomized knockin mice. Thus, both genetic and pharmacological approaches unequivocally demonstrate that phosphorylated rpS6 is a downstream effector of the mTORC1-S6K1 signaling pathway mediating renal hypertrophy. Hence, rpS6 phosphorylation facilitates the increase in cyclin D1 and decrease in cyclin E1 that underlie the hypertrophic nature of uninephrectomy-induced kidney growth. PMID:25229342

  11. Compensative hypertrophy of the kidney

    International Nuclear Information System (INIS)

    Raynaud, C.

    1976-01-01

    Several measurement methods are available to practitioners to reveal a compensative hypertrophy. Mensuration of the kidney has the advantage of simplicity but is in fact an unreliable and inaccurate method. Separate clearances in their traditional form have never entered into routine use because of the disadvantages of ureteral catheterism. The use of radioactive tracers avoids this drawback, but clearances calculated in this way are only valid in the absence of obstructive urinary disorders. Solutions have been proposed, but the values obtained are no longer identical with the clearances. The Hg uptake test quantifies quite accurately the function of each kidney. From the results obtained a complete compensative hypertrophy developed on a healthy kidney and an incomplete compensative hypertrophy developed on the diseased kidney have been described. In each of these situations the degree to which compensative hypertrophy develops seems to be fixed at a given level peculiar to each patient [fr

  12. N-acetylcysteine versus Dopamine to Prevent Acute Kidney Injury after Cardiac Surgery in Patients with Preexisting Moderate Renal Insufficiency.

    Science.gov (United States)

    Savluk, Omer Faruk; Guzelmeric, Fusun; Yavuz, Yasemin; Cevirme, Deniz; Gurcu, Emre; Ogus, Halide; Orki, Tulay; Kocak, Tuncer

    2017-01-01

    Acute kidney injury after cardiac surgery is associated with mortality and morbidity. Therefore, strategies to prevent acute kidney injury are very important. The aim of this placebo-controlled randomized double-blind study was to compare the prophylactic efficacy of N-Acetylcysteine and dopamine administration in patients with pre-existing moderate renal insufficiency who were undergoing cardiopulmonary bypass. This study included 135 patients with pre-existing moderate renal insufficiency who were scheduled for coronary artery bypass grafting surgery. Serum creatinine and GFR were recorded preoperatively and on the first and second postoperative days. On the first and second postoperative days, the drugs used showed statistically significant differences among the creatinine groups (Prenal function, whereas the application of renal dose dopamine did not have a protective effect in patients with pre-existing moderate renal failure.

  13. Therapeutic Inhibition of miR-208a Improves Cardiac Function and Survival During Heart Failure

    Science.gov (United States)

    Montgomery, Rusty L.; Hullinger, Thomas G.; Semus, Hillary M.; Dickinson, Brent A.; Seto, Anita G.; Lynch, Joshua M.; Stack, Christianna; Latimer, Paul A.; Olson, Eric N.; van Rooij, Eva

    2012-01-01

    Background Diastolic dysfunction in response to hypertrophy is a major clinical syndrome with few therapeutic options. MicroRNAs act as negative regulators of gene expression by inhibiting translation or promoting degradation of target mRNAs. Previously, we reported that genetic deletion of the cardiac-specific miR-208a prevents pathological cardiac remodeling and upregulation of Myh7 in response to pressure overload. Whether this miRNA might contribute to diastolic dysfunction or other forms of heart disease is currently unknown. Methods and Results Here, we show that systemic delivery of an antisense oligonucleotide induces potent and sustained silencing of miR-208a in the heart. Therapeutic inhibition of miR-208a by subcutaneous delivery of antimiR-208a during hypertension-induced heart failure in Dahl hypertensive rats dose-dependently prevents pathological myosin switching and cardiac remodeling while improving cardiac function, overall health, and survival. Transcriptional profiling indicates that antimiR-208a evokes prominent effects on cardiac gene expression; plasma analysis indicates significant changes in circulating levels of miRNAs on antimiR-208a treatment. Conclusions These studies indicate the potential of oligonucleotide-based therapies for modulating cardiac miRNAs and validate miR-208 as a potent therapeutic target for the modulation of cardiac function and remodeling during heart disease progression. PMID:21900086

  14. Azelnidipine prevents cardiac dysfunction in streptozotocin-diabetic rats by reducing intracellular calcium accumulation, oxidative stress and apoptosis

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    Kain Vasundhara

    2011-11-01

    Full Text Available Abstract Background Numerous evidences suggest that diabetic heart is characterized by compromised ventricular contraction and prolonged relaxation attributable to multiple causative factors including calcium accumulation, oxidative stress and apoptosis. Therapeutic interventions to prevent calcium accumulation and oxidative stress could be therefore helpful in improving the cardiac function under diabetic condition. Methods This study was designed to examine the effect of long-acting calcium channel blocker (CCB, Azelnidipine (AZL on contractile dysfunction, intracellular calcium (Ca2+ cycling proteins, stress-activated signaling molecules and apoptosis on cardiomyocytes in diabetes. Adult male Wistar rats were made diabetic by a single intraperitoneal (IP injection of streptozotocin (STZ. Contractile functions were traced from live diabetic rats to isolated individual cardiomyocytes including peak shortening (PS, time-to-PS (TPS, time-to-relengthening (TR90, maximal velocity of shortening/relengthening (± dL/dt and intracellular Ca2+ fluorescence. Results Diabetic heart showed significantly depressed PS, ± dL/dt, prolonged TPS, TR90 and intracellular Ca2+ clearing and showed an elevated resting intracellular Ca2+. AZL itself exhibited little effect on myocyte mechanics but it significantly alleviated STZ-induced myocyte contractile dysfunction. Diabetes increased the levels of superoxide, enhanced expression of the cardiac damage markers like troponin I, p67phox NADPH oxidase subunit, restored the levels of the mitochondrial superoxide dismutase (Mn-SOD, calcium regulatory proteins RyR2 and SERCA2a, and suppressed the levels of the anti-apoptotic Bcl-2 protein. All of these STZ-induced alterations were reconciled by AZL treatment. Conclusion Collectively, the data suggest beneficial effect of AZL in diabetic cardiomyopathy via altering intracellular Ca2+ handling proteins and preventing apoptosis by its antioxidant property.

  15. Serum Natriuretic Peptides as Differential Biomarkers Allowing for the Distinction between Physiologic and Pathologic Left Ventricular Hypertrophy.

    Science.gov (United States)

    Dunn, Michael E; Manfredi, Thomas G; Agostinucci, Kevin; Engle, Steven K; Powe, Josh; King, Nicholas M P; Rodriguez, Luis A; Gropp, Kathryn E; Gallacher, Matthew; Vetter, Frederick J; More, Vijay; Shimpi, Prajakta; Serra, David; Colton, Heidi M

    2017-02-01

    Given the proven utility of natriuretic peptides as serum biomarkers of cardiovascular maladaptation and dysfunction in humans and the high cross-species sequence conservation of atrial natriuretic peptides, natriuretic peptides have the potential to serve as translational biomarkers for the identification of cardiotoxic compounds during multiple phases of drug development. This work evaluated and compared the response of N-terminal proatrial natriuretic peptide (NT-proANP) and N-terminal probrain natriuretic peptide (NT-proBNP) in rats during exercise-induced and drug-induced increases in cardiac mass after chronic swimming or daily oral dosing with a peroxisome proliferator-activated receptor γ agonist. Male Sprague-Dawley rats aged 8 to 10 weeks were assigned to control, active control, swimming, or drug-induced cardiac hypertrophy groups. While the relative heart weights from both the swimming and drug-induced cardiac hypertrophy groups were increased 15% after 28 days of dosing, the serum NT-proANP and NT-proBNP values were only increased in association with cardiac hypertrophy caused by compound administration. Serum natriuretic peptide concentrations did not change in response to adaptive physiologic cardiac hypertrophy induced by a 28-day swimming protocol. These data support the use of natriuretic peptides as fluid biomarkers for the distinction between physiological and drug-induced cardiac hypertrophy.

  16. Epoxyeicosatrienoic acids regulate macrophage polarization and prevent LPS-induced cardiac dysfunction.

    Science.gov (United States)

    Dai, Meiyan; Wu, Lujin; He, Zuowen; Zhang, Shasha; Chen, Chen; Xu, Xizhen; Wang, Peihua; Gruzdev, Artiom; Zeldin, Darryl C; Wang, Dao Wen

    2015-09-01

    Macrophages, owning tremendous phenotypic plasticity and diverse functions, were becoming the target cells in various inflammatory, metabolic and immune diseases. Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acid to form epoxyeicosatrienoic acids (EETs), which possess various beneficial effects on cardiovascular system. In the present study, we evaluated the effects of EETs treatment on macrophage polarization and recombinant adeno-associated virus (rAAV)-mediated CYP2J2 expression on lipopolysaccharide (LPS)-induced cardiac dysfunction, and sought to investigate the underlying mechanisms. In vitro studies showed that EETs (1µmol/L) significantly inhibited LPS-induced M1 macrophage polarization and diminished the proinflammatory cytokines at transcriptional and post-transcriptional level; meanwhile it preserved M2 macrophage related molecules expression and upregulated anti-inflammatory cytokine IL-10. Furthermore, EETs down-regulated NF-κB activation and up-regulated peroxisome proliferator-activated receptors (PPARα/γ) and heme oxygenase 1 (HO-1) expression, which play important roles in regulating M1 and M2 polarization. In addition, LPS treatment in mice induced cardiac dysfunction, heart tissue damage and infiltration of M1 macrophages, as well as the increase of inflammatory cytokines in serum and heart tissue, but rAAV-mediated CYP2J2 expression increased EETs generation in heart and significantly attenuated the LPS-induced harmful effects, which mechanisms were similar as the in vitro study. Taken together, the results indicate that CYP2J2/EETs regulates macrophage polarization by attenuating NF-κB signaling pathway via PPARα/γ and HO-1 activation and its potential use in treatment of inflammatory diseases. © 2015 Wiley Periodicals, Inc.

  17. Cardiac Resynchronization Therapy prevents progression of renal failure in heart failure patients.

    Science.gov (United States)

    Jeevanantham, Vinodh; Turagam, Mohit; Shanberg, David; Reddy, Madhu; Atoui, Moustapha; Daubert, James P; Dawn, Buddhadeb; Lakkireddy, Dhanunjaya

    The goal of this study is to assess the effect of cardiac resynchronization therapy (CRT) over time on renal function and its impact on mortality. The effect of CRT on renal function in patients with heart failure is not well understood. All patients who underwent CRT implantation at University of Kansas between year 2000 and 2009 were reviewed and patients who had pre and post CRT renal function studied were included in our study. Stages of chronic kidney disease (CKD) were defined based on Kidney Disease Outcome Quality Initiative (KDOQI) guidelines. The effect of CRT on renal and cardiac function were studied at short term (≤6 months post implantation) and long term (>6 months). A total of 588 patients with mean age of 67 ± 12 yrs were included in the study. CRT responders (defined by increase in LVEF ≥ 5%) were 54% during short term follow-up and 65% on long term follow-up. When compared to baseline, there was no significant deterioration in mean Glomerular Filtration Rate (GFR) during follow up. When analyzed based on the stages of CKD, there was significant improvement of renal function in patients with advanced kidney disease. Multivariate logistic regression analysis showed that stable GFR or an improvement in GFR independently predicted mortality after adjusting for co-morbidities. CRT was associated with stabilization of renal function in patients with severe LV dysfunction and improvement in stage 4 and 5 CKD. Improved renal function was associated with a lower mortality. Copyright © 2016 Indian Heart Rhythm Society. Production and hosting by Elsevier B.V. All rights reserved.

  18. The Natural History of Soft Tissue Hypertrophy, Bony Hypertrophy, and Nodule Formation in Patients With Untreated Head and Neck Capillary Malformations.

    Science.gov (United States)

    Lee, Jeong Woo; Chung, Ho Yun; Cerrati, Eric W; O, Teresa M; Waner, Milton

    2015-11-01

    A percentage of patients with capillary malformation (CM) develop soft tissue hypertrophy, bony hypertrophy, and/or nodule formation. To determine the incidence, age of onset, anatomic distribution of soft tissue/bony hypertrophy, and nodule formation in patients with untreated CM. A retrospective medical records review of head and neck CM patients presenting to a tertiary referral center over a 7-year period (2004-2011) was performed. Of the 160 patients with CM, 96 demonstrated progression of disease to include either soft tissue/bony hypertrophy or nodule formation. Of these, 87 patients had not received previous treatment and met the inclusion criteria for analysis. On average, soft tissue hypertrophy began at 9 years of age. The V2/maxillary segment was most commonly involved with upper lip hypertrophy being the most prominent. Fourteen percent of the patients also presented with bony hypertrophy, which began at an average age of 15 years. Nodules were present in 38/87 (44%) of patients with an average age of onset of 22 years. This study demonstrates the nature progression of CM and quantifies the clinical characteristics of hypertrophy and nodule formation with untreated head and neck CM. Early and continuous treatment is recommended in hopes of preventing CM progression.

  19. The effect of 12 weeks of aerobic exercise on plasma levels of fibroblast growth factor 23, Angiotensin converting enzyme and left ventricular hypertrophy in hypertensive elderly women

    Directory of Open Access Journals (Sweden)

    Z Keshavarzi

    2017-06-01

    Conclusion: The results of this study demonstrated that aerobic exercise has a positive effect on heart function and serum levels of ACE, and can potentially reverse cardiac dysfunction associated with left ventricular hypertrophy.

  20. Aggravated Cardiac Remodeling post Aortocaval Fistula in Unilateral Nephrectomized Rats.

    Directory of Open Access Journals (Sweden)

    Jie Wu

    Full Text Available Aortocaval fistula (AV in rat is a unique model of volume-overload congestive heart failure and cardiac hypertrophy. Living donor kidney transplantation is regarded as beneficial to allograft recipients and not particularly detrimental to the donors. Impact of AV on animals with mild renal dysfunction is not fully understood. In this study, we explored the effects of AV in unilateral ne