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Sample records for hypertrophied rat hearts

  1. 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

  2. Prevention of anemia alleviates heart hypertrophy in copper deficient rats

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    Lure, M.D.; Fields, M.; Lewis, C.G. (Dept. of Agriculture, Beltsville, MD (United States) Univ. of Maryland, College Park (United States) Georgetown Univ., Washington, DC (United States))

    1991-03-11

    The present investigation was designed to examine the role of anemia in the cardiomegaly and myocardial pathology of copper deficiency. Weanling rats were fed a copper deficient diet containing either starch (ST) or fructose (FRU) for five weeks. Six rats consuming the FRU diet were intraperitoneally injected once a week with 1.0 ml/100g bw of packed red blood cells (RBC) obtained from copper deficient rats fed ST. FRU rats injected with RBC did not develop anemia. Additionally, none of the injected rats exhibited heart hypertrophy or gross pathology and all survived. In contrast, non-injected FRU rats were anemic, exhibited severe signs of copper deficiency which include heart hypertrophy with gross pathology, and 44% died. Maintaining the hematocrit with RBC injections resulted in normal heart histology and prevented the mortality associated with the fructose x copper interaction. The finding suggest that the anemia associated with copper deficiency contributes to heart pathology.

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

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    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.

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

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    Nagai-Okatani, Chiaki; Minamino, Naoto

    2016-01-01

    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.

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

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    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); Phypertrophy of neurons in cardiac ganglia compared with controls. Western blot analysis shows that nerve growth factor levels in the explanted, failing human 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.

  6. Heart-bound adiponectin, not serum adiponectin, inversely correlates with cardiac hypertrophy in stroke-prone spontaneously hypertensive rats.

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    Inoue, Takao; Takemori, Kumiko; Mizuguchi, Nobuyuki; Kimura, Masatomo; Chikugo, Takaaki; Hagiyama, Man; Yoneshige, Azusa; Mori, Tatsufumi; Maenishi, Osamu; Kometani, Takashi; Itoh, Tatsuki; Satou, Takao; Ito, Akihiko

    2017-11-01

    What is the central question of this study? An inverse correlation between circulating adiponectin and many diseases has been reported, but some studies have found no correlation. To evaluate this controversy, we investigated the relationship between heart-bound adiponectin and hypertension or cardiac hypertrophy, compared with serum adiponectin. What is the main finding and its importance? Using hypertensive and normotensive rats, we found that heart-bound adiponectin was inversely correlated with cardiac hypertrophy, suggesting that heart-bound adiponectin has a more important function in preventing cardiac hypertrophy than circulating adiponectin. Our study provides new insights regarding the role of adiponectin in diseases. The inverse correlation between circulating adiponectin concentration and hypertension or cardiac hypertrophy is still controversial. In addition to circulating adiponectin, adiponectin is also bound to tissues such as the heart and skeletal muscle. In this study, we investigated the relationship of serum adiponectin and heart-bound adiponectin with hypertension and cardiac hypertrophy. Four types of hypertensive rats presenting different blood pressure levels were used at different ages, as follows: normotensive Wistar-Kyoto rats (WKYs); two sub-strains (strains C and B2, having low and high blood pressure, respectively) of spontaneously hypertensive rats (SHRs); and stroke-prone SHRs (SHRSPs). Blood pressure, heart-to-body weight ratio, serum adiponectin and heart-bound adiponectin were determined. Histopathological analysis of the heart was carried out to evaluate the relationship with heart-bound adiponectin. Serum adiponectin concentration was not inversely correlated with blood pressure or heart-to-body weight ratio. In contrast, heart-bound adiponectin levels were significantly lower in SHRSPs than in other strains at respective ages. This resulted from a decrease in T-cadherin expression, which induced adiponectin binding to tissues

  7. Telmisartan reduces mortality and left ventricular hypertrophy with sympathoinhibition in rats with hypertension and heart failure.

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    Kishi, Takuya; Hirooka, Yoshitaka; Sunagawa, Kenji

    2014-02-01

    Angiotensin II type 1 receptor (AT1R) blockers have various benefits on hypertension and/or heart failure. We demonstrated that telmisartan (TLM), an AT1R blocker, causes sympathoinhibition by reduction of reactive oxygen species (ROS) in the rostral ventrolateral medulla (RVLM) of stroke-prone spontaneously hypertensive rats (SHRSPs). The aim of this study was to determine whether TLM improves survival in rats with hypertension and heart failure. Angiotensin II-infused and salt-loaded SHRSPs were divided into TLM-treated, candesartan cilexetil (CAN)-treated, and control groups. We determined the dose of TLM or CAN with similar depressor effects. We examined survival, urinary norepinephrine excretion (uNE) as a parameter of sympathoexcitation, ROS in the RVLM, and left ventricular (LV) end-diastolic pressure (LVEDP). LV hypertrophy (LVH) was assessed by echocardiography and heart/body weight. Compared with the control group, TLM improved survival to a greater extent than CAN. At 4 weeks after treatment, ROS in the RVLM and uNE were significantly lower in the TLM-treated group than in the CAN-treated group, despite the similar depressor effects. At 8 weeks after the treatments, LVH and LVEDP were attenuated in the TLM-treated group compared with the CAN-treated group. Our results suggest that TLM has the potential to reduce mortality, LVH, and LVEDP and that enhanced sympathoinhibition by reduction of ROS in the RVLM might be one of the mechanisms contributing to the beneficial actions of TLM in a model of rats with severe hypertension and heart failure.

  8. Aortocaval Fistula in Rat: A Unique Model of Volume-Overload Congestive Heart Failure and Cardiac Hypertrophy

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    Zaid Abassi

    2011-01-01

    Full Text Available Despite continuous progress in our understanding of the pathogenesis of congestive heart failure (CHF and its management, mortality remains high. Therefore, development of reliable experimental models of CHF and cardiac hypertrophy is essential to better understand disease progression and allow new therapy developement. The aortocaval fistula (ACF model, first described in dogs almost a century ago, has been adopted in rodents by several groups including ours. Although considered to be a model of high-output heart failure, its long-term renal and cardiac manifestations are similar to those seen in patients with low-output CHF. These include Na+-retention, cardiac hypertrophy and increased activity of both vasoconstrictor/antinatriureticneurohormonal systems and compensatory vasodilating/natriuretic systems. Previous data from our group and others suggest that progression of cardiorenal pathophysiology in this model is largely determined by balance between opposing hormonal forces, as reflected in states of CHF decompensation that are characterized by overactivation of vasoconstrictive/Na+-retaining systems. Thus, ACF serves as a simple, cheap, and reproducible platform to investigate the pathogenesis of CHF and to examine efficacy of new therapeutic approaches. Hereby, we will focus on the neurohormonal, renal, and cardiac manifestations of the ACF model in rats, with special emphasis on our own experience.

  9. Diets containing corn oil, coconut oil and cholesterol alter ventricular hypertrophy, dilatation and function in hearts of rats fed copper-deficient diets.

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    Jenkins, J E; Medeiros, D M

    1993-06-01

    Cardiac hypertrophy and function were evaluated in rats fed diets containing deficient, marginal or adequate levels of copper. The fat concentration of the diets was either 10 g/100 g corn oil, 10 g/100 g coconut oil or 10 g/100 g coconut oil + 1 g/100 g added cholesterol. Left ventricular (LV) wall thickening of hearts in rats fed copper-deficient diets was characterized by greater (P oil. Rats fed the copper-deficient diet with coconut oil + cholesterol had LV chamber volumes that were twofold larger than those of rats fed the copper-deficient diet with coconut oil or corn oil. Copper deficiency reduced LV chamber volume only in rats fed coconut oil + cholesterol. Cardiac LV end diastolic pressure in rats fed copper-deficient diets was twofold larger than in copper-adequate and copper-marginal groups fed corn oil or coconut oil. Hearts from rats fed the copper-deficient diet with corn oil compared with those from rats fed the copper-deficient diet with coconut oil + cholesterol had greater right ventricular (RV) and LV end diastolic pressures, LV pressures and LV and RV maximal rates of positive pressure development. Our data suggest that cardiac adaptations in rats fed copper-deficient diets are influenced by dietary fat type: 1) hearts of rats fed the copper-deficient diet with corn oil were concentrically hypertrophied, whereas cardiac contractility was maintained in the presence of high preload; 2) preload and contractility in hearts of coconut oil-fed rats was greater than cardiac response to cholesterol addition to the coconut oil diet; 3) hearts in copper-deficient rats fed coconut oil + cholesterol exhibited eccentric hypertrophy and ventricular dysfunction.

  10. Direct implication of carbon monoxide in the development of heart failure in rats with cardiac hypertrophy subjected to air pollution.

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    Melin, Alexandre; Bonnet, Pierre; Eder, Veronique; Antier, Daniel; Obert, Philippe; Fauchier, Laurent

    2005-01-01

    Pollution is known to particularly affect patients with respiratory insufficiency and right ventricle abnormalities. We therefore hypothesized that carbon monoxide (CO) at low dose could be involved in cardiovascular disorders in patients with chronic hypoxic pulmonary hypertension secondary to chronic hypoxia. Ten-week-old male and female healthy Dark Agouti rats were randomly divided into two series--untrained (U) and trained (T)--of four groups of 18 animals each. Both U and T series were continuously exposed to ambient air (U(AIR), and T(AIR); n = 16) or air plus 50 ppm CO (U(AIR+CO) and T(AIR+CO); n = 18). Similarly, rats initially subjected to right ventricle hypertrophy secondary to chronic hypoxia (H) were continuously exposed to ambient air (TH(AIR), and UH(AIR); n = 18) or air plus 50 ppm CO (UH(AIR+CO), and TH(AIR+CO); n = 18). Doppler-echocardiography and hemodynamic studies performed at rest both indi-cated that CO had no significant effect on cardiac morphology or functions in control rats (U(AIR+CO) vs U(AIR)). In contrast, cardiac dilation and large decreases in left ventricular ejection fraction, mitral early diastolic rapid inflow (E) deceleration, E/atrial contraction filling (A) ratio, +dP/dt, and -dP/dt were found in TH(AIR+CO) compared with TH(AIR). After exposure, heart rate variability was unaffected in U(AIR+CO), whereas total power spectra were markedly decreased and low frequency/high frequency power ratio was increased in TH(AIR+CO) rats. CO pollution could be directly involved in cardiac disorders of patients with pre-existent hypertrophic cardiomyopathies.

  11. Aortocaval Fistula in Rat: A Unique Model of Volume-Overload Congestive Heart Failure and Cardiac Hypertrophy

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    Abassi, Zaid; Goltsman, Ilia; Karram, Tony; Winaver, Joseph; Hoffman, Aaron

    2011-01-01

    Despite continuous progress in our understanding of the pathogenesis of congestive heart failure (CHF) and its management, mortality remains high. Therefore, development of reliable experimental models of CHF and cardiac hypertrophy is essential to better understand disease progression and allow new therapy developement. The aortocaval fistula (ACF) model, first described in dogs almost a century ago, has been adopted in rodents by several groups including ours. Although considered to be a mo...

  12. Mitochondria in cardiac hypertrophy and heart failure

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    Rosca, Mariana G.; Tandler, Bernard; Hoppel, Charles L.

    2013-01-01

    Heart failure (HF) frequently is the unfavorable outcome of pathological heart hypertrophy. In contrast to physiological cardiac hypertrophy, which occurs in response to exercise and leads to full adaptation of contractility to the increased wall stress, pathological hypertrophy occurs in response to volume or pressure overload, ultimately leading to contractile dysfunction and HF. Because cardiac hypertrophy impairs the relationship between ATP demand and production, mitochondrial bioenergetics must keep up with the cardiac hypertrophic phenotype. We review data regarding the mitochondrial proteomic and energetic remodeling in cardiac hypertrophy, as well as the temporal and causal relationship between mitochondrial failure to match the increased energy demand and progression to cardiac decompensation. We suggest that the maladaptive effect of sustained neuroendocrine signals on mitochondria leads to bioenergetic fading which contributes to the progression from cardiac hypertrophy to failure. PMID:22982369

  13. Reduced expression of adherens and gap junction proteins can have a fundamental role in the development of heart failure following cardiac hypertrophy in rats.

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    dos Santos, Daniele O; Blefari, Valdecir; Prado, Fernanda P; Silva, Carlos A; Fazan, Rubens; Salgado, Helio C; Ramos, Simone G; Prado, Cibele M

    2016-02-01

    Hypertension causes cardiac hypertrophy, cardiac dysfunction and heart failure (HF). The mechanisms implicated in the transition from compensated to decompensated cardiac hypertrophy are not fully understood. This study was aimed to investigate whether alterations in the expression of intercalated disk proteins could contribute to the transition of compensated cardiac hypertrophy to dilated heart development that culminates in HF. Male rats were submitted to abdominal aortic constriction and at 90 days post surgery (dps), three groups were observed: sham-operated animals (controls), animals with hypertrophic hearts (HH) and animals with hypertrophic + dilated hearts (HD). Blood pressure was evaluated. The hearts were collected and Western blot and immunofluorescence were performed to desmoglein-2, desmocollin-2, N-cadherin, plakoglobin, Bcatenin, and connexin-43. Cardiac systolic function was evaluated using the Vevo 2100 ultrasound system. Data were considered significant when p b 0.05. Seventy percent of the animals presented with HH and 30% were HD at 90 dps. The blood pressure increased in both groups. The amount of desmoglein-2 and desmocollin-2 expression was increased in both groups and no difference was observed in either group. The expression of N-cadherin, plakoglobin and B-catenin increased in the HHgroup and decreased in the HDgroup; and connexin-43 decreased only in theHDgroup. Therewas no difference between the ejection fraction and fractional shortening at 30 and 60 dps; however, they were decreased in the HD group at 90 dps. We found that while some proteins have increased expression accompanied by the increase in the cell volume associated with preserved systolic cardiac function in theHHgroup, these same proteins had decreased expression evenwithout significant reduction in the cell volume associated with decreased systolic cardiac function in HD group. The increased expression of desmoglein-2 and desmocollin-2 in both the HH and HD groups could

  14. Hypertrophied hearts: what of sevoflurane cardioprotection?

    DEFF Research Database (Denmark)

    Larsen, Jens Kjærgaard Rolighed; Smerup, Morten Holdgaard; Hasenkam, John Michael

    2009-01-01

    of cardioprotection with anaesthetics remain controversial--in contrast to solid experimental evidence. Concomitant left ventricular hypertrophy is found in some cardiac surgery patients and could change cardioprotection efficacy. Hypertrophy could potentially render the heart less susceptible to sevoflurane...... pigs (n=7-12/group) were subjected to 45 min distal coronary artery balloon occlusion, followed by 120 min of reperfusion. Controls were given pentobarbital, while sevoflurane cardioprotection was achieved by 3.2% inhalation throughout the experiment. Chronic banding of the ascending aorta resulted......-at-risk) was reduced from mean 55.0 (13.6%) (+/-SD) in controls to 17.5 (13.2%) by sevoflurane (P=0.001). Sevoflurane reduced the infarct size in hypertrophied hearts to 14.6 (10.4%) (P=0.001); however, in hypertrophic controls, infarcts were reduced to 34.2 (10.2%) (P=0.001). CONCLUSION: Sevoflurane abrogated...

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

    NARCIS (Netherlands)

    Hoffmann, S; van Geel, PP; Willenbrock, R; Pagel, [No Value; Pinto, YM; Buikema, H; van Gilst, WH; 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 AT(1) receptors. However, the role of myocardial AT(1) receptors in cardiac hypertrophy and contractility is still rarely defined. To address the hypothesis that

  16. The PPARbeta/delta agonist GW0742 relaxes pulmonary vessels and limits right heart hypertrophy in rats with hypoxia-induced pulmonary hypertension.

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    Louise S Harrington

    2010-03-01

    Full Text Available Pulmonary vascular diseases are increasingly recognised as important clinical conditions. Pulmonary hypertension associated with a range of aetiologies is difficult to treat and associated with progressive morbidity and mortality. Current therapies for pulmonary hypertension include phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, or prostacyclin mimetics. However, none of these provide a cure and the clinical benefits of these drugs individually decline over time. There is, therefore, an urgent need to identify new treatment strategies for pulmonary hypertension.Here we show that the PPARbeta/delta agonist GW0742 induces vasorelaxation in systemic and pulmonary vessels. Using tissue from genetically modified mice, we show that the dilator effects of GW0742 are independent of the target receptor PPARbeta/delta or cell surface prostacyclin (IP receptors. In aortic tissue, vascular relaxant effects of GW0742 were not associated with increases in cGMP, cAMP or hyperpolarisation, but were attributed to inhibition of RhoA activity. In a rat model of hypoxia-induced pulmonary hypertension, daily oral dosing of animals with GW0742 (30 mg/kg for 3 weeks significantly reduced the associated right heart hypertrophy and right ventricular systolic pressure. GW0742 had no effect on vascular remodelling induced by hypoxia in this model.These observations are the first to show a therapeutic benefit of 'PPARbeta/delta' agonists in experimental pulmonary arterial hypertension and provide pre-clinical evidence to favour clinical trials in man.

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

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    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 pcardiac 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.

  18. Effects of chronic treprostinil treatment on experimental right heart hypertrophy and failure.

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    Axelgaard, Sofie; Holmboe, Sarah; Ringgaard, Steffen; Hillgaard, Thomas K; Andersen, Stine; Hansen, Mona S; Andersen, Asger; Nielsen-Kudsk, Jens E

    2017-01-01

    Right heart function is an important predictor of morbidity and mortality in pulmonary arterial hypertension and many CHD. We investigated whether treatment with the prostacyclin analogue treprostinil could prevent pressure overload-induced right ventricular hypertrophy and failure. Male Wistar rats were randomised to severe pulmonary trunk banding with a 0.5-mm banding clip (n=41), moderate pulmonary trunk banding with a 0.6-mm banding clip (n=36), or sham procedure (n=10). The banded rats were randomised to 6 weeks of treatment with a moderate dose of treprostinil (300 ng/kg/minute), a high dose of treprostinil (900 ng/kg/minute), or vehicle. Pulmonary trunk banding effectively induced hypertrophy, dilatation, and decreased right ventricular function. The severely banded animals presented with decompensated heart failure with extracardial manifestations. Treatment with treprostinil neither reduced right ventricular hypertrophy nor improved right ventricular function. In the pulmonary trunk banding model of pressure overload-induced right ventricular hypertrophy and failure, moderate- and high-dose treatment with treprostinil did not improve right ventricular function neither in compensated nor in decompensated right heart failure.

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

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    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.

  20. Transthoracic echocardiography in rats. Evalution of commonly used indices of left ventricular dimensions, contractile performance, and hypertrophy in a genetic model of hypertrophic heart failure (SHHF-Mcc-facp-Rats) in comparison with Wistar rats during aging.

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    Reffelmann, Thorsten; Kloner, Robert A

    2003-09-01

    Two-weekly echocardiographic examinations were conducted in nine SHHF-Mc-fa(cp) rats in comparison with eight age-matched Wistar rats. In the SHHF-rats, characterized by progressive LV-dilation and decreasing contractile function between 77-87 weeks of age, left ventricular (LV) hypertrophy was most sensitively demonstrated by increased LV-mass-index (p < 0.001). LV-areas and area-ejection fraction (EF) (2D-images) discriminated more sensitively in the early stages than M-mode-derived diameters and fractional shortening (FS); midwall shortening was the most sensitive parameter of reduced systolic function. Post-mortem measurements showed an excellent correlation with calculated LV-mass (r = 0.91). Post-mortem LV-volumes correlated significantly with diastolic LV-diameters, LV-areas, and calculated LV-volumes (r = 0.56-0.59). Mean within-subject standard deviations in controls were 0.5-0.6 mm (LV-diameters), 3.1-4.6 mm(2) (LV-areas), approximately 10% of the mean for FS, area-EF and midwall shortening, and approximately 20% for wall thickness and LV-mass. The data might be used to choose the most sensitive parameters, and to estimate sample size for echocardiographic investigations in rats.

  1. Regional ischemia in hypertrophic Langendorff-perfused rat hearts

    NARCIS (Netherlands)

    J.F. Ashruf; C. Ince (Can); H.A. Bruining (Hajo)

    1999-01-01

    textabstractMyocardial hypertrophy decreases the muscle mass-to-vascularization ratio, thereby changing myocardial perfusion. The effect of these changes on myocardial oxygenation in hypertrophic Langendorff-perfused rat hearts was measured using epimyocardial NADH

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

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    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

    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. Growth hormone-releasing hormone attenuates cardiac hypertrophy and improves heart function in pressure overload-induced heart failure.

    Science.gov (United States)

    Gesmundo, Iacopo; Miragoli, Michele; Carullo, Pierluigi; Trovato, Letizia; Larcher, Veronica; Di Pasquale, Elisa; Brancaccio, Mara; Mazzola, Marta; Villanova, Tania; Sorge, Matteo; Taliano, Marina; Gallo, Maria Pia; Alloatti, Giuseppe; Penna, Claudia; Hare, Joshua M; Ghigo, Ezio; Schally, Andrew V; Condorelli, Gianluigi; Granata, Riccarda

    2017-11-07

    It has been shown that growth hormone-releasing hormone (GHRH) reduces cardiomyocyte (CM) apoptosis, prevents ischemia/reperfusion injury, and improves cardiac function in ischemic rat hearts. However, it is still not known whether GHRH would be beneficial for life-threatening pathological conditions, like cardiac hypertrophy and heart failure (HF). Thus, we tested the myocardial therapeutic potential of GHRH stimulation in vitro and in vivo, using GHRH or its agonistic analog MR-409. We show that in vitro, GHRH(1-44)NH 2 attenuates phenylephrine-induced hypertrophy in H9c2 cardiac cells, adult rat ventricular myocytes, and human induced pluripotent stem cell-derived CMs, decreasing expression of hypertrophic genes and regulating hypertrophic pathways. Underlying mechanisms included blockade of Gq signaling and its downstream components phospholipase Cβ, protein kinase Cε, calcineurin, and phospholamban. The receptor-dependent effects of GHRH also involved activation of Gα s and cAMP/PKA, and inhibition of increase in exchange protein directly activated by cAMP1 (Epac1). In vivo, MR-409 mitigated cardiac hypertrophy in mice subjected to transverse aortic constriction and improved cardiac function. Moreover, CMs isolated from transverse aortic constriction mice treated with MR-409 showed improved contractility and reversal of sarcolemmal structure. Overall, these results identify GHRH as an antihypertrophic regulator, underlying its therapeutic potential for HF, and suggest possible beneficial use of its analogs for treatment of pathological cardiac hypertrophy. Copyright © 2017 the Author(s). Published by PNAS.

  4. Effect of hepatocyte growth factor and angiotensin II on rat cardiomyocyte hypertrophy

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Ai-Lan [Department of Cardiology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou (China); Ou, Cai-Wen [The Fourth Affiliated Hospital of Guangzhou Medical University, Guangzhou (China); He, Zhao-Chu [Department of Cardiology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou (China); Liu, Qi-Cai [Experimental Medical Research Center, Guangzhou Medical University, Guangzhou (China); Dong, Qi [Department of Physiology, Guangzhou Medical University, Guangzhou (China); Chen, Min-Sheng [Guangzhou Key Laboratory of Cardiovascular Disease, Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou (China)

    2012-10-15

    Angiotensin II (Ang II) plays an important role in cardiomyocyte hypertrophy. The combined effect of hepatocyte growth factor (HGF) and Ang II on cardiomyocytes is unknown. The present study was designed to determine the effect of HGF on cardiomyocyte hypertrophy and to explore the combined effect of HGF and Ang II on cardiomyocyte hypertrophy. Primary cardiomyocytes were isolated from neonatal rat hearts and cultured in vitro. Cells were treated with Ang II (1 µM) alone, HGF (10 ng/mL) alone, and Ang II (1 µM) plus HGF (10 ng/mL) for 24, 48, and 72 h. The amount of [{sup 3}H]-leucine incorporation was then measured to evaluate protein synthesis. The mRNA levels of β-myosin heavy chain and atrial natriuretic factor were determined by real-time PCR to evaluate the presence of fetal phenotypes of gene expression. The cell size of cardiomyocytes was also studied. Ang II (1 µM) increased cardiomyocyte hypertrophy. Similar to Ang II, treatment with 1 µM HGF promoted cardiomyocyte hypertrophy. Moreover, the combination of 1 µM Ang II and 10 ng/mL HGF clearly induced a combined pro-hypertrophy effect on cardiomyocytes. The present study demonstrates for the first time a novel, combined effect of HGF and Ang II in promoting cardiomyocyte hypertrophy.

  5. 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.

  6. Cardiac nuclear high mobility group box 1 prevents the development of cardiac hypertrophy and heart failure.

    Science.gov (United States)

    Funayama, Akira; Shishido, Tetsuro; Netsu, Shunsuke; Narumi, Taro; Kadowaki, Shinpei; Takahashi, Hiroki; Miyamoto, Takuya; Watanabe, Tetsu; Woo, Chang-Hoon; Abe, Jun-ichi; Kuwahara, Koichiro; Nakao, Kazuwa; Takeishi, Yasuchika; Kubota, Isao

    2013-09-01

    High mobility group box 1 (HMGB1) is an abundant and ubiquitous nuclear DNA-binding protein that has multiple functions dependent on its cellular location. HMGB1 binds to DNA, facilitating numerous nuclear functions including maintenance of genome stability, transcription, and repair. However, little is known about the effects of nuclear HMGB1 on cardiac hypertrophy and heart failure. The aim of this study was to examine whether nuclear HMGB1 plays a role in the development of cardiac hypertrophy induced by pressure overload. Analysis of human biopsy samples by immunohistochemistry showed decreased nuclear HMGB1 expression in failing hearts compared with normal hearts. Nuclear HMGB1 decreased in response to both endothelin-1 (ET-1) and angiotensin II (Ang II) stimulation in neonatal rat cardiomyocytes, where nuclear HMGB1 was acetylated and translocated to the cytoplasm. Overexpression of nuclear HMGB1 attenuated ET-1 induced cardiomyocyte hypertrophy. Thoracic transverse aortic constriction (TAC) was performed in transgenic mice with cardiac-specific overexpression of HMGB1 (HMGB1-Tg) and wild-type (WT) mice. Cardiac hypertrophy after TAC was attenuated in HMGB1-Tg mice and the survival rate after TAC was higher in HMGB1-Tg mice than in WT mice. Induction of foetal cardiac genes was decreased in HMGB1-Tg mice compared with WT mice. Nuclear HMGB1 expression was preserved in HMGB1-Tg mice compared with WT mice and significantly attenuated DNA damage after TAC was attenuated in HMGB1-TG mice. These results suggest that the maintenance of stable nuclear HMGB1 levels prevents hypertrophy and heart failure by inhibiting DNA damage.

  7. Deciphering the microRNA signature of pathological cardiac hypertrophy by engineered heart tissue- and sequencing-technology.

    Science.gov (United States)

    Hirt, Marc N; Werner, Tessa; Indenbirken, Daniela; Alawi, Malik; Demin, Paul; Kunze, Ann-Cathrin; Stenzig, Justus; Starbatty, Jutta; Hansen, Arne; Fiedler, Jan; Thum, Thomas; Eschenhagen, Thomas

    2015-04-01

    Pathological cardiac hypertrophy and fibrosis are modulated by a set of microRNAs, most of which have been detected in biologically complex animal models of hypertrophy by arrays with moderate sensitivity and disregard of passenger strand (previously "star") microRNAs. Here, we aimed at precisely analyzing the microRNA signature of cardiac hypertrophy and fibrosis by RNA sequencing in a standardized in vitro hypertrophy model based on engineered heart tissue (EHT). Spontaneously beating, force-generating fibrin EHTs from neonatal rat heart cells were subjected to afterload enhancement for 7days (AE-EHT), and EHTs without intervention served as controls. AE resulted in reduced contractile force and relaxation velocity, fibrotic changes and reactivation of the fetal gene program. Small RNAs were extracted from control and AE-EHTs and sequencing yielded almost 750 different mature microRNAs, many of which have never been described before in rats. The detection of both arms of the precursor stem-loop (pre-miRNA), namely -3p and -5p miRs, was frequent. 22 abundantly sequenced microRNAs were >1.3× upregulated and 15 abundantly sequenced microRNAs downregulated to hypertrophy and fibrotic response, recapitulating prior results in whole animals. Taken together, AE-induced pathological hypertrophy in EHTs is associated with 37 differentially regulated microRNAs, including many passenger strands. Antagonizing miR-21-5p ameliorates dysfunction in this model. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. 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...... also affects cardiac hypertrophy and fibrosis. In this study we examined the expression of genes for the NPRs in rats with pressure-overload cardiac hypertrophy. The ANG II type 1 receptor was blocked with losartan (10 mg.kg(-1).day(-1)) to investigate a possible role of the renin-angiotensin system...

  9. Cardiac O-GlcNAc signaling is increased in hypertrophy and heart failure.

    Science.gov (United States)

    Lunde, Ida G; Aronsen, Jan Magnus; Kvaløy, Heidi; Qvigstad, Eirik; Sjaastad, Ivar; Tønnessen, Theis; Christensen, Geir; Grønning-Wang, Line M; Carlson, Cathrine R

    2012-02-01

    Reversible protein O-GlcNAc modification has emerged as an essential intracellular signaling system in several tissues, including cardiovascular pathophysiology related to diabetes and acute ischemic stress. We tested the hypothesis that cardiac O-GlcNAc signaling is altered in chronic cardiac hypertrophy and failure of different etiologies. Global protein O-GlcNAcylation and the main enzymes regulating O-GlcNAc, O-GlcNAc transferase (OGT), O-GlcNAcase (OGA), and glutamine-fructose-6-phosphate amidotransferase (GFAT) were measured by immunoblot and/or real-time RT-PCR analyses of left ventricular tissue from aortic stenosis (AS) patients and rat models of hypertension, myocardial infarction (MI), and aortic banding (AB), with and without failure. We show here that global O-GlcNAcylation was increased by 65% in AS patients, by 47% in hypertensive rats, by 81 and 58% post-AB, and 37 and 60% post-MI in hypertrophic and failing hearts, respectively (P cardiac contractility in post-MI failing hearts, demonstrating a possible role of O-GlcNAcylation in development of chronic cardiac dysfunction. Our data support the novel concept that O-GlcNAc signaling is altered in various etiologies of cardiac hypertrophy and failure, including human aortic stenosis. This not only provides an exciting basis for discovery of new mechanisms underlying pathological cardiac remodeling but also implies protein O-GlcNAcylation as a possible new therapeutic target in heart failure.

  10. 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.

  11. Netrin-1 prevents the development of cardiac hypertrophy and heart failure.

    Science.gov (United States)

    Wang, Nan; Cao, Yunshan; Zhu, Yan

    2016-03-01

    The aim of the present study was to examine whether netrin-1 is involved in the development of cardiac hypertrophy, induced by pressure overload. For this investigation, thoracic transverse aortic constriction (TAC) was performed in mice. A total of 18 mice were divided into three groups (n=6 per group): Sham, TAC and TAC + recombinant netrin-1. Neonatal rat cardiomyocytes were stimulated with endothelin-1 (ET-1), and samples were collected to examine the expression levels of netrin‑1 by western blot analysis and the mRNA expression of A‑type natriuretic peptide by reverse transcription‑quantitative polymerase chain reaction. It was found that the expression of netrin‑1 was decreased in the TAC mice and in the neonatal rat cardiomyocytes in response to ET‑1 stimulation. Netrin‑1 eliminated ventricular remodeling, cardiac dysfunction and DNA damage during pressure overload. Furthermore, analysis of the signaling events indicated that netrin‑1‑mediated protection against cardiac hypertrophy was attributed to interruption of the activation of mitogen‑activated protein kinase kinase (MEK) kinase‑1 (K1)‑dependent MEK‑extracellular signal‑regulated protein kinase 1/2 (ERK1/2) and c‑Jun N‑terminal kinase 1/2 (JNK1/2). Therefore, netrin‑1 prevented cardiac hypertrophy and heart failure through the negative regulation of the MEKK1-dependent MEK‑ERK1/2 and JNK1/2 signaling pathways.

  12. 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...

  13. 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.

  14. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  16. PERIOPERATIVE PERIOD FOLLOWING HEART TRANSPLANTATION WITH SEVERE LEFT VENTRICULAR HYPERTROPHY

    Directory of Open Access Journals (Sweden)

    V. N. Poptsov

    2012-01-01

    Full Text Available Use donor hearts with left ventricular hypertrophy (LVH is controversial. This category of heart recipients has increasing risk of early graft failure. We proposed that heart transplantation (HT with LVH ≥1.5 cm may be successful if performed in selective category patients from alternate transplant list. This study included 10 pati- ents (2 female and 8 male at the age 26–62 (44 ± 3, who needed urgent HT. This study showed that recipients with LVH ≥1.5 cm demanded more high and long inotropic support with adrenalin and dopamine, more fre- quent use of levosimendan infusion (in 40% of cases and intraaortic balloon conterpulsation (in 50% of cases. However we didn’t observed any difference in survival rate (90.0% vs 89.0% and ICU time (4.8 ± 0.6 days vs 4.1 ± 0.4 days between HT recipients with and without LVH. Our study showed that HT from donor with LVH ≥1.5 cm may be performed in patients, demanding urgent HT, with acceptable early posttransplant results. 

  17. Inhalation of diesel exhaust does not exacerbate cardiac hypertrophy or heart failure in two mouse models of cardiac hypertrophy.

    Science.gov (United States)

    Liu, Yonggang; Chien, Wei-Ming; Medvedev, Ivan O; Weldy, Chad S; Luchtel, Daniel L; Rosenfeld, Michael E; Chin, Michael T

    2013-10-05

    Strong associations have been observed between exposure to fine ambient particulate matter (PM2.5) and adverse cardiovascular outcomes. In particular, exposure to traffic related PM2.5 has been associated with increases in left ventricular hypertrophy, a strong risk factor for cardiovascular mortality. As much of traffic related PM2.5 is derived from diesel exhaust (DE), we investigated the effects of chronic DE exposure on cardiac hypertrophy and heart failure in the adult mouse by exposing mice to DE combined with either of two mouse models of cardiac hypertrophy: angiotensin II infusion or pressure overload induced by transverse aortic banding. Wild type male C57BL/6 J mice were either infused with angiotensin II (800 ng/kg/min) via osmotic minipump implanted subcutaneously for 1 month, or underwent transverse aortic banding (27 gauge needle 1 week for observing acute reactions, 26 gauge needle 3 months or 6 months for observing chronic reactions). Vehicle (saline) infusion or sham surgery was used as a control. Shortly after surgery, mice were transferred to our exposure facility and randomly assigned to either diesel exhaust (300 or 400 μg/m(3)) or filtered air exposures. After reaching the end of designated time points, echocardiography was performed to measure heart structure and function. Gravimetric analysis was used to measure the ventricular weight to body weight ratio. We also measured heart rate by telemetry using implanted ambulatory ECG monitors. Both angiotensin II and transverse aortic banding promoted cardiac hypertrophy compared to vehicle or sham controls. Transverse aortic banding for six months also promoted heart failure in addition to cardiac hypertrophy. In all cases, DE failed to exacerbate the development of hypertrophy or heart failure when compared to filtered air controls. Prolonged DE exposure also led to a decrease in average heart rate. Up to 6-months of DE exposure had no effect on cardiac hypertrophy and heart function induced by

  18. An EP4 Receptor Agonist Inhibits Cardiac Fibrosis Through Activation of PKA Signaling in Hypertrophied Heart.

    Science.gov (United States)

    Wang, Qi; Oka, Toru; Yamagami, Kiyoshi; Lee, Jong-Kook; Akazawa, Hiroshi; Naito, Atsuhiko T; Yasui, Taku; Ishizu, Takamaru; Nakaoka, Yoshikazu; Sakata, Yasushi; Komuro, Issei

    2017-02-07

    Cardiac fibrosis is a pathological feature of myocardium of failing heart and plays causative roles in arrhythmia and cardiac dysfunction, but its regulatory mechanisms remain largely elusive. In this study, we investigated the effects of the novel EP4 receptor agonist ONO-0260164 on cardiac fibrosis in hypertrophied heart and explored the regulatory mechanisms in cardiac fibroblasts.In a mouse model of cardiac hypertrophy generated by transverse aortic constriction (TAC), ONO-0260164 treatment significantly prevented systolic dysfunction and progression of myocardial fibrosis at 5 weeks after TAC. In cultured neonatal rat cardiac fibroblasts, transforming growth factor-β1 (TGF-β1) induced upregulation of collagen type 1, alpha 1 (Col1a1) and type 3, alpha 1 (Col3a1), which was inhibited by ONO-0260164 treatment. ONO-0260164 activated protein kinase A (PKA) in the presence of TGF-β1 in the cardiac fibroblasts. PKA activation suppressed an increase in collagen expression induced by TGF-β1, indicating the important inhibitory roles of PKA activation in TGF-β1mediated collagen induction.We have demonstrated for the first time the antifibrotic effects of the novel EP4 agonist ONO-0260164 in vivo and in vitro, and the important role of PKA activation in the effects.

  19. Quantitative phosphoproteomic study of pressure-overloaded mouse heart reveals dynamin-related protein 1 as a modulator of cardiac hypertrophy.

    Science.gov (United States)

    Chang, Yu-Wang; Chang, Ya-Ting; Wang, Qinchuan; Lin, Jim Jung-Ching; Chen, Yu-Ju; Chen, Chien-Chang

    2013-11-01

    Pressure-overload stress to the heart causes pathological cardiac hypertrophy, which increases the risk of cardiac morbidity and mortality. However, the detailed signaling pathways induced by pressure overload remain unclear. Here we used phosphoproteomics to delineate signaling pathways in the myocardium responding to acute pressure overload and chronic hypertrophy in mice. Myocardial samples at 4 time points (10, 30, 60 min and 2 weeks) after transverse aortic banding (TAB) in mice underwent quantitative phosphoproteomics assay. Temporal phosphoproteomics profiles showed 360 phosphorylation sites with significant regulation after TAB. Multiple mechanical stress sensors were activated after acute pressure overload. Gene ontology analysis revealed differential phosphorylation between hearts with acute pressure overload and chronic hypertrophy. Most interestingly, analysis of the cardiac hypertrophy pathway revealed phosphorylation of the mitochondrial fission protein dynamin-related protein 1 (DRP1) by prohypertrophic kinases. Phosphorylation of DRP1 S622 was confirmed in TAB-treated mouse hearts and phenylephrine (PE)-treated rat neonatal cardiomyocytes. TAB-treated mouse hearts showed phosphorylation-mediated mitochondrial translocation of DRP1. Inhibition of DRP1 with the small-molecule inhibitor mdivi-1 reduced the TAB-induced hypertrophic responses. Mdivi-1 also prevented PE-induced hypertrophic growth and oxygen consumption in rat neonatal cardiomyocytes. We reveal the signaling responses of the heart to pressure stress in vivo and in vitro. DRP1 may be important in the development of cardiac hypertrophy.

  20. Polyphenol rich ethanolic extract from Boerhavia diffusa L. mitigates angiotensin II induced cardiac hypertrophy and fibrosis in rats.

    Science.gov (United States)

    A, Prathapan; Varghese, Mathews V; S, Abhilash; P, Salin Raj; Mathew, Anil K; Nair, Anupama; Nair, R Harikumaran; K G, Raghu

    2017-03-01

    Boerhavia diffusa is a renowned edible medicinal plant extensively used against different ailments including heart diseases in the traditional system of medicine in several countries. The present study aims to evaluate the therapeutic efficacy of ethanolic extract of Boerhavia diffusa (BDE) on cardiac hypertrophy and fibrosis induced by angiotensin II (Ang II) in male wistar rats and to identify the active components present in it. A substantial increase of hypertrophy markers such as cardiac mass index, concentration of ANP and BNP, cardiac injury markers like CK-MB, LDH and SGOT, has been observed in hypertrophied groups whereas BDE treatment attenuated these changes when compared to hypertrophied rats. Moreover, Ang II induced myocardial oxidative stress was reduced by BDE which was apparent from diminished level of lipid and protein oxidation products, increased activities of membrane bound ATPases and endogenous antioxidant enzymes along with enhanced translocation of Nrf2 from the cytosol to nucleus. It appears that BDE evokes its antioxidant effects by attenuating lipid peroxidation, enhancing the translocation of Nrf2 from the cytoplasm to nucleus as well as by regulating the metabolism of glutathione. The extent of fibrosis during cardiac hypertrophy was determined by histopathology analysis and the results revealed that BDE treatment considerably reduced the fibrosis in the heart. HPLC analysis of BDE leads to the identification of four compounds viz., quercetin, kaempferol, boeravinone B and caffeic acid. The study substantiate the effect of B. diffusa in protecting the heart from pathological hypertrophy and the attenuation of cardiac abnormalities may be partly attributed through the reduction of oxidative stress and cardiac fibrosis. Since the plant is widely used as a green leafy vegetable, incorporation of this plant in diet may be an alternative way for the prevention and better management of heart diseases and associated complications. Copyright

  1. Calcineurin as a marker of myocardial hypertrophy in children with valvular congenital heart diseases

    Directory of Open Access Journals (Sweden)

    A. V. Kamenshchyk

    2015-06-01

    Full Text Available Aim. To identify interrelations between the calcineurin levels in children with valvular congenital heart diseases without heart failure and the echocardiography parameters of myocardial hypertrophy. Results: It was established the significantly decreased calcineurin level in congenial valvular heart diseases in children as well as an absence of correlations of the left ventricle myocardial mass and index with negative ones to the dimensions of right ventricle in comparison to healthy children of corresponding age. Conclusion: The obtained data testifies the importance of calcineurin system activity in the formation of pathologic myocardial hypertrophy in children with valvular congenital heart diseases and without manifestation of heart failure.

  2. DNA methylation in an engineered heart tissue model of cardiac hypertrophy: common signatures and effects of DNA methylation inhibitors.

    Science.gov (United States)

    Stenzig, Justus; Hirt, Marc N; Löser, Alexandra; Bartholdt, Lena M; Hensel, Jan-Tobias; Werner, Tessa R; Riemenschneider, Mona; Indenbirken, Daniela; Guenther, Thomas; Müller, Christian; Hübner, Norbert; Stoll, Monika; Eschenhagen, Thomas

    2016-01-01

    DNA methylation affects transcriptional regulation and constitutes a drug target in cancer biology. In cardiac hypertrophy, DNA methylation may control the fetal gene program. We therefore investigated DNA methylation signatures and their dynamics in an in vitro model of cardiac hypertrophy based on engineered heart tissue (EHT). We exposed EHTs from neonatal rat cardiomyocytes to a 12-fold increased afterload (AE) or to phenylephrine (PE 20 µM) and compared DNA methylation signatures to control EHT by pull-down assay and DNA methylation microarray. A 7-day intervention sufficed to induce contractile dysfunction and significantly decrease promoter methylation of hypertrophy-associated upregulated genes such as Nppa (encoding ANP) and Acta1 (α-skeletal actin) in both intervention groups. To evaluate whether pathological consequences of AE are affected by inhibiting de novo DNA methylation we applied AE in the absence and presence of DNA methyltransferase (DNMT) inhibitors: 5-aza-2'-deoxycytidine (aza, 100 µM, nucleosidic inhibitor), RG108 (60 µM, non-nucleosidic) or methylene disalicylic acid (MDSA, 25 µM, non-nucleosidic). Aza had no effect on EHT function, but RG108 and MDSA partially prevented the detrimental consequences of AE on force, contraction and relaxation velocity. RG108 reduced AE-induced Atp2a2 (SERCA2a) promoter methylation. The results provide evidence for dynamic DNA methylation in cardiac hypertrophy and warrant further investigation of the potential of DNA methylation in the treatment of cardiac hypertrophy.

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

    Science.gov (United States)

    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...

  4. Overexpression of mitofilin in the mouse heart promotes cardiac hypertrophy in response to hypertrophic stimuli.

    Science.gov (United States)

    Zhang, Yuan; Xu, Jing; Luo, Yu-Xuan; An, Xi-Zhou; Zhang, Ran; Liu, Guang; Li, Hongliang; Chen, Hou-Zao; Liu, De-Pei

    2014-10-20

    Mitofilin was originally described as a heart muscle protein because of its abundance in the heart tissue; however, its function in the heart is still to be elucidated. Thus, this study aims at investigating the role of mitofilin in the heart in response to hypertrophic stimuli. In this study, a significant increase in mitofilin expression was observed in the hearts of patients with hypertrophic cardiomyopathy. Transgenic (TG) mice with cardiomyocyte-specific overexpression of mitofilin were generated, and cardiac hypertrophy was introduced by transverse aortic constriction (TAC) or chronic infusion of isoproterenol (ISO). In TG mice overexpressing mitofilin, the level of cardiac hypertrophy was significantly greater than that in wild-type (WT) mice after TAC and ISO stimulation. A detailed analysis showed that compared with WT mice, the level of reactive oxygen species was increased after TAC and ISO induction and mitochondrial oxidative phosphorylation (OXPHOS) activity in the TG hearts was lower. These alterations may contribute to the aggravated cardiac hypertrophy observed in response to TAC and ISO stimulation. Over-expression of mitofilin promotes cardiac hypertrophy under pathological conditions both in vivo and in vitro. Mitofilin, a mitochondria protein, is shown to be related to cardiac hypertrophy for the first time, which enhances our understanding of the role of mitochondria in cardiac hypertrophy.

  5. A RAT MODEL OF HEART FAILURE INDUCED BY ISOPROTERENOL AND A HIGH SALT DIET

    Science.gov (United States)

    Rat models of heart failure (HF) show varied pathology and time to disease outcome, dependent on induction method. We found that subchronic (4wk) isoproterenol (ISO) infusion in Spontaneously Hypertensive Heart Failure (SHHF) rats caused cardiac injury with minimal hypertrophy. O...

  6. An increased TREK-1-like potassium current in ventricular myocytes during rat cardiac hypertrophy.

    Science.gov (United States)

    Wang, Weiping; Zhang, Man; Li, Pingping; Yuan, Hui; Feng, Nan; Peng, Ying; Wang, Ling; Wang, Xiaoliang

    2013-04-01

    To elucidate the expression and identify the functional changes of 2 pore domain potassium channel TREK-1 during cardiac hypertrophy in rats, left ventricular hypertrophy was induced by subcutaneous injection with isoproterenol. Western blot was used to detect the expression of TREK-1 channel protein, and inside-out and whole-cell recordings were used to record TREK-1 currents. The results showed that TREK-1 protein expression in endocardium was slightly higher than that in epicardium in control left ventricles. However, it was obviously upregulated by 89.8% during hypertrophy, 2.3-fold higher than in epicardium. Mechanical stretch, intracellular acidification, and arachidonic acid could activate a TREK-1-like current in cardiomyocytes. The slope conductances of cardiac TREK-1 and CHO/TREK-1 channels were 123 ± 7 and 113 ± 17 pS, respectively. The TREK-1 inhibitor L-3-n-butylphthalide (10 μM) reduced the currents in CHO/TREK-1 cells, normal cardiomyocytes, and hypertrophic cardiomyocytes by 48.5%, 54.3%, and 55.5%, respectively. The percentage of L-3-n-butylphthalide-inhibited outward whole-cell current in hypertrophic cardiomyocytes (23.7%) was larger than that in normal cardiomyocytes (14.2%). The percentage of chloroform-activated outward whole-cell current in hypertrophic cardiomyocytes (58.3%) was also larger than normal control (40.2%). Our results demonstrated that in hypertrophic rats, TREK-1 protein expression in endocardium was specifically increased and the ratio of TREK-1 channel current in cardiac outward currents was also enhanced. TREK-1 might balance potassium ion flow during hypertrophy and might be a potential drug target for heart protection.

  7. 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.

  8. Increased reactive oxygen species, metabolic maladaptation, and autophagy contribute to pulmonary arterial hypertension-induced ventricular hypertrophy and diastolic heart failure.

    Science.gov (United States)

    Rawat, Dhawjbahadur K; Alzoubi, Abdallah; Gupte, Rakhee; Chettimada, Sukrutha; Watanabe, Makino; Kahn, Andrea G; Okada, Takao; McMurtry, Ivan F; Gupte, Sachin A

    2014-12-01

    Pulmonary arterial hypertension (PAH) is a debilitating and deadly disease with no known cure. Heart failure is a major comorbidity and a common cause of the premature death of patients with PAH. Increased asymmetrical right ventricular hypertrophy and septal wall thickening compress the left ventricular cavity and elicit diastolic heart failure. In this study, we used the Sugen5416/hypoxia/normoxia-induced PAH rat to determine whether altered pyridine nucleotide signaling in the failing heart contributes to 1) increased oxidative stress, 2) changes in metabolic phenotype, 3) autophagy, and 4) the PAH-induced failure. We found that increased reactive oxygen species, metabolic maladaptation, and autophagy contributed to the pathogenesis of right ventricular remodeling and hypertrophy that lead to left ventricular diastolic dysfunction. In addition, arterial elastance increased in PAH rats. Glucose-6-phosphate dehydrogenase is a major source of pyridine molecule (nicotinamide adenine dinucleotide phosphate), which is a substrate for nicotinamide adenine dinucleotide phosphate oxidases in the heart. Dehydroepiandrosterone, a 17-ketosteroid that reduces pulmonary hypertension and right ventricular hypertrophy, inhibited glucose-6-phosphate dehydrogenase, decreased oxidative stress, increased glucose oxidation and acetyl-coA, and reduced autophagy in the hearts of PAH rats. It also decreased arterial stiffness and improved left ventricular diastolic function. These findings demonstrate that pyridine nucleotide signaling, at least partly, mediates PAH-induced diastolic heart failure, and that reduction of glucose-6-phosphate dehydrogenase-derived nicotinamide adenine dinucleotide phosphate is beneficial to improve left ventricle diastolic function. © 2014 American Heart Association, Inc.

  9. 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.

  10. Loss of MicroRNA-155 protects the heart from pathological cardiac hypertrophy.

    Science.gov (United States)

    Seok, Hee Young; Chen, Jinghai; Kataoka, Masaharu; Huang, Zhan-Peng; Ding, Jian; Yan, Jinglu; Hu, Xiaoyun; Wang, Da-Zhi

    2014-05-09

    In response to mechanical and pathological stress, adult mammalian hearts often undergo mal-remodeling, a process commonly characterized as pathological hypertrophy, which is associated with upregulation of fetal genes, increased fibrosis, and reduction of cardiac dysfunction. The molecular pathways that regulate this process are not fully understood. To explore the function of microRNA-155 (miR-155) in cardiac hypertrophy and remodeling. Our previous work identified miR-155 as a critical microRNA that repressed the expression and function of the myocyte enhancer factor 2A. In this study, we found that miR-155 is expressed in cardiomyocytes and that its expression is reduced in pressure overload-induced hypertrophic hearts. In mouse models of cardiac hypertrophy, miR-155 null hearts suppressed cardiac hypertrophy and cardiac remodeling in response to 2 independent pathological stressors, transverse aortic restriction and an activated calcineurin transgene. Most importantly, loss of miR-155 prevents the progress of heart failure and substantially extends the survival of calcineurin transgenic mice. The function of miR-155 in hypertrophy is confirmed in isolated cardiomyocytes. We identified jumonji, AT rich interactive domain 2 (Jarid2) as an miR-155 target in the heart. miR-155 directly represses Jarid2, whose expression is increased in miR-155 null hearts. Inhibition of endogenous Jarid2 partially rescues the effect of miR-155 loss in isolated cardiomyocytes. Our studies uncover miR-155 as an inducer of pathological cardiomyocyte hypertrophy and suggest that inhibition of endogenous miR-155 might have clinical potential to suppress cardiac hypertrophy and heart failure.

  11. Compromised Myocardial Energetics in Hypertrophied Mouse Hearts Diminish the Beneficial Effect of Overexpressing SERCA2a

    OpenAIRE

    Pinz, Ilka; Tian, Rong; Belke, Darrell; Swanson, Eric; Dillmann, Wolfgang; Ingwall, Joanne S.

    2011-01-01

    The sarcoplasmic reticulum calcium ATPase (SERCA) plays a central role in regulating intracellular Ca2+ homeostasis and myocardial contractility. Several studies show that improving Ca2+ handling in hypertrophied rodent hearts by increasing SERCA activity results in enhanced contractile function. This suggests that SERCA is a potential target for gene therapy in cardiac hypertrophy and failure. However, it raises the issue of increased energy cost resulting from a higher ATPase activity. In t...

  12. Valsartan attenuates cardiac and renal hypertrophy in rats with experimental cardiorenal syndrome possibly through down-regulating galectin-3 signaling.

    Science.gov (United States)

    Zhang, M-J; Gu, Y; Wang, H; Zhu, P-F; Liu, X-Y; Wu, J

    2016-01-01

    Aortocaval fistula (AV) induced chronic volume overload in rats with preexisting mild renal dysfunction (right kidney remove: UNX) could mimic the type 4 cardiorenal syndrome (CRS): chronic renocardiac syndrome. Galectin-3, a β-galactoside binding lectin, is an emerging biomarker in cardiovascular as well as renal diseases. We observed the impact of valsartan on cardiac and renal hypertrophy and galectin-3 changes in this model. Adult male Sprague-Dawley (SD) rats (200-250 g) were divided into S (Sham, n = 7), M (UNX+AV, n = 7) and M+V (UNX+AV+valsartan, n = 7) groups. Eight weeks later, cardiac function was measured by echocardiography. Renal outcome was measured by glomerular filtration rate, effective renal plasma flow, renal blood flow and 24 hours albuminuria. Immunohistochemistry and real-time PCR were used to evaluate the expressions of galectin-3 in heart and renal. Cardiac hypertrophy and renal hypertrophy as well as cardiac enlargement were evidenced in this AV shunt induced chronic volume overload rat model with preexisting mild renal dysfunction. Cardiac and renal hypertrophy were significantly attenuated but cardiac enlargement was unaffected by valsartan independent of its blood pressure lowering effect. 24 hours urine albumin was significantly increased, which was significantly reduced by valsartan in this model. Immunohistochemistry and real-time PCR evidenced significantly up-regulated galectin-3 expression in heart and kidney and borderline increased myocardial collagen I expression, which tended to be lower post valsartan treatment. Up-regulated galectin-3 signaling might also be involved in the pathogenesis in this CRS model. The beneficial effects of valsartan in terms of attenuating cardiac and renal hypertrophy and reducing 24 hours albumin in this model might partly be mediated through down-regulating galectin-3 signal pathway.

  13. Molecular switches under TGFβ signalling during progression from cardiac hypertrophy to heart failure.

    Science.gov (United States)

    Heger, J; Schulz, R; Euler, G

    2016-01-01

    Cardiac hypertrophy is a mechanism to compensate for increased cardiac work load, that is, after myocardial infarction or upon pressure overload. However, in the long run cardiac hypertrophy is a prevailing risk factor for the development of heart failure. During pathological remodelling processes leading to heart failure, decompensated hypertrophy, death of cardiomyocytes by apoptosis or necroptosis and fibrosis as well as a progressive dysfunction of cardiomyocytes are apparent. Interestingly, the induction of hypertrophy, cell death or fibrosis is mediated by similar signalling pathways. Therefore, tiny changes in the signalling cascade are able to switch physiological cardiac remodelling to the development of heart failure. In the present review, we will describe examples of these molecular switches that change compensated hypertrophy to the development of heart failure and will focus on the importance of the signalling cascades of the TGFβ superfamily in this process. In this context, potential therapeutic targets for pharmacological interventions that could attenuate the progression of heart failure will be discussed. © 2015 The British Pharmacological Society.

  14. 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.

  15. 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.

  16. The adult heart responds to increased workload with physiologic hypertrophy, cardiac stem cell activation, and new myocyte formation.

    Science.gov (United States)

    Waring, Cheryl D; Vicinanza, Carla; Papalamprou, Angela; Smith, Andrew J; Purushothaman, Saranya; Goldspink, David F; Nadal-Ginard, Bernardo; Torella, Daniele; Ellison, Georgina M

    2014-10-14

    It is a dogma of cardiovascular pathophysiology that the increased cardiac mass in response to increased workload is produced by the hypertrophy of the pre-existing myocytes. The role, if any, of adult-resident endogenous cardiac stem/progenitor cells (eCSCs) and new cardiomyocyte formation in physiological cardiac remodelling remains unexplored. In response to regular, intensity-controlled exercise training, adult rats respond with hypertrophy of the pre-existing myocytes. In addition, a significant number (∼7%) of smaller newly formed BrdU-positive cardiomyocytes are produced by the exercised animals. Capillary density significantly increased in exercised animals, balancing cardiomyogenesis with neo-angiogenesis. c-kit(pos) eCSCs increased their number and activated state in exercising vs. sedentary animals. c-kit(pos) eCSCs in exercised hearts showed an increased expression of transcription factors, indicative of their commitment to either the cardiomyocyte (Nkx2.5(pos)) or capillary (Ets-1(pos)) lineages. These adaptations were dependent on exercise duration and intensity. Insulin-like growth factor-1, transforming growth factor-β1, neuregulin-1, bone morphogenetic protein-10, and periostin were significantly up-regulated in cardiomyocytes of exercised vs. sedentary animals. These factors differentially stimulated c-kit(pos) eCSC proliferation and commitment in vitro, pointing to a similar role in vivo. Intensity-controlled exercise training initiates myocardial remodelling through increased cardiomyocyte growth factor expression leading to cardiomyocyte hypertrophy and to activation and ensuing differentiation of c-kit(pos) eCSCs. This leads to the generation of new myocardial cells. These findings highlight the endogenous regenerative capacity of the adult heart, represented by the eCSCs, and the fact that the physiological cardiac adaptation to exercise stress is a combination of cardiomyocyte hypertrophy and hyperplasia (cardiomyocytes and capillaries

  17. The complex regulation of tanshinone IIA in rats with hypertension-induced left ventricular hypertrophy.

    Directory of Open Access Journals (Sweden)

    Hui Pang

    Full Text Available Tanshinone IIA has definite protective effects on various cardiovascular diseases. However, in hypertension-induced left ventricular hypertrophy (H-LVH, the signaling pathways of tanshinone IIA in inhibition of remodeling and cardiac dysfunction remain unclear. Two-kidney, one-clip induced hypertensive rats (n = 32 were randomized to receive tanshinone IIA (5, 10, 15 mg/kg per day or 5% glucose injection (GS. Sham-operated rats (n = 8 received 5%GS as control. Cardiac function and dimensions were assessed by using an echocardiography system. Histological determination of the fibrosis and apoptosis was performed using hematoxylin eosin, Masson's trichrome and TUNEL staining. Matrix metalloproteinase 2 (MMP2 and tissue inhibitor of matrix metalloproteinases type 2 (TIMP2 protein expressions in rat myocardial tissues were detected by immunohistochemistry. Rat cardiomyocytes were isolated by a Langendorff perfusion method. After 48 h culture, the supernatant and cardiomyocytes were collected to determine the potential related proteins impact on cardiac fibrosis and apoptosis. Compared with the sham rats, the heart tissues of H-LVH (5%GS group suffered severely from the oxidative damage, apoptosis of cardiomyocytes and extracellular matrix (ECM deposition. In the H-LVH group, tanshinone IIA treated decreased malondialdehyde (MDA content and increased superoxide dismutase (SOD activity. Tanshinone IIA inhibited cardiomyocytes apoptosis as confirmed by the reduction of TUNEL positive cardiomyocytes and the down-regulation of Caspase-3 activity and Bax/Bcl-2 ratio. Meanwhile, plasma apelin level increased with down-regulation of APJ receptor. Tanshinone IIA suppressed cardiac fibrosis through regulating the paracrine factors released by cardiomyocytes and the TGF-β/Smads signaling pathway activity. In conclusion, our in vivo study showed that tanshinone IIA could improve heart function by enhancing myocardial contractility, inhibiting ECM

  18. Preservation of diastolic function in monocrotaline-induced right ventricular hypertrophy in rats.

    Science.gov (United States)

    Lamberts, Regis R; Caldenhoven, Eric; Lansink, Mirian; Witte, Gerrit; Vaessen, Rob J; St Cyr, John A; Stienen, Ger J M

    2007-09-01

    During ischemic heart diseases and when heart failure progresses depletion of myocardial energy stores occurs. D-Ribose (R) has been shown to improve cardiac function and energy status after ischemia. Folic acid (FA) is an essential cofactor in the formation of adenine nucleotides. Therefore, we assessed whether chronic R-FA administration during the development of hypertrophy resulted in an improved cardiac function and energy status. In Wistar rats (n = 40) compensatory right ventricular (RV) hypertrophy was induced by monocrotaline (30 mg/kg; MCT), whereas saline served as control. Both groups received a daily oral dose of either 150 mg.kg(-1).day(-1) dextrose (placebo) or R-FA (150 and 40 mg.kg(-1).day(-1), respectively). In Langendorff-perfused hearts, RV and left ventricular (LV) pressure development and collagen content as well as total RV adenine nucleotides (TAN), creatine content, and RV and LV collagen content were determined. In the control group R-FA had no effect. In the MCT-placebo group, TAN and creatine content were reduced, RV and LV diastolic pressure-volume relations were steeper, RV systolic pressures were elevated, RV and LV collagen content was increased, and RV-LV diastolic interaction was altered compared with controls. In the MCT-R-FA group, TAN, RV and LV diastolic stiffness, RV and LV collagen content, and RV-LV diastolic interaction were normalized to the values in the control group while creatine content remained depressed and RV systolic function remained elevated. In conclusion, the depression of energy status in compensated hypertrophic myocardium observed was partly prevented by chronic R-FA administration and accompanied by a preservation of diastolic function and collagen deposition.

  19. Early and transient sodium-hydrogen exchanger isoform 1 inhibition attenuates subsequent cardiac hypertrophy and heart failure following coronary artery ligation.

    Science.gov (United States)

    Kilić, Ana; Huang, Cathy X; Rajapurohitam, Venkatesh; Madwed, Jeffrey B; Karmazyn, Morris

    2014-12-01

    Na(+)/H(+) exchanger 1 (NHE-1) inhibition attenuates the hypertrophic response and heart failure in various experimental models. As the hypertrophic program is rapidly initiated following insult, we investigated whether early and transient administration of a NHE-1 inhibitor will exert salutary effects on cardiomyocyte hypertrophy or heart failure using both in vitro and in vivo approaches. Neonatal cardiomyocytes were treated with the novel, potent, and highly specific NHE-1 inhibitor BIX (N-[4-(1-acetyl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine; 100 nM) for 1 hour in the presence of 10 µM phenylephrine, after which the cells were maintained for a further 23 hours in the absence of NHE-1 inhibition. One-hour treatment with the NHE-1 inhibitor prevented phenylephrine-induced hypertrophy, which was associated with prevention of activation of calcineurin, a key component of the hypertrophic process. Experiments were then performed in rats subjected to coronary artery ligation, in which the NHE-1 inhibitor was administered immediately after infarction for a 1-week period followed by a further 5 weeks of sustained coronary artery occlusion in the absence of drug treatment. This approach significantly attenuated left ventricular hypertrophy and improved both left ventricular systolic and diastolic dysfunction, which was also associated with inhibition of calcineurin activation. Our findings indicate that early and transient administration of an NHE-1 inhibitor bestows subsequent inhibition of cardiomyocyte hypertrophy in culture as well as cardiac hypertrophy and heart failure in vivo, suggesting a critical early NHE-1-dependent initiation of the hypertrophic program. The study also suggests a preconditioning-like phenomenon in preventing hypertrophy and heart failure by early and transient NHE-1 inhibition. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

  20. 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

  1. Chronic inhibition of the Na+/H+ - exchanger causes regression of hypertrophy, heart failure, and ionic and electrophysiological remodelling.

    Science.gov (United States)

    Baartscheer, A; Hardziyenka, M; Schumacher, C A; Belterman, C N W; van Borren, M M G J; Verkerk, A O; Coronel, R; Fiolet, J W T

    2008-07-01

    Increased activity of the Na+/H+ -exchanger (NHE-1) in heart failure underlies raised [Na+]i causing disturbances of calcium handling. Inhibition of NHE-1, initiated at the onset of pressure/volume overload, prevents development of hypertrophy, heart failure and remodelling. We hypothesized that chronic inhibition of NHE-1, initiated at a later stage, would induce regression of hypertrophy, heart failure, and ionic and electrophysiological remodelling. Development of heart failure in rabbits was monitored electrocardiographically and echocardiographically, after one or three months. Cardiac myocytes were also isolated. One group of animals were treated with cariporide (inhibitor of NHE-1) in the diet after one month. Cytoplasmic calcium, sodium and action potentials were measured with fluorescent markers and sarcoplasmic reticulum calcium content by rapid cooling. Calcium after-transients were elicited after rapid pacing. Sodium channel current (INa) was measured using patch-clamp techniques. Hypertrophy and heart failure developed after one month and progressed during the next two months. After one month, dietary treatment with cariporide was initiated. Two months of treatment reduced hypertrophy and heart failure, duration of action potential QT-interval and QRS, and restored sodium and calcium handling and the incidence of calcium after-transients. In cardiac myocytes, parameters of INa were not changed by cariporide. In rabbit hearts with hypertrophy and signs of heart failure one month after induction of pressure/volume overload, two months of dietary treatment with the NHE-1 inhibitor cariporide caused regression of hypertrophy, heart failure and ionic and electrophysiological remodelling.

  2. Etanercept protects rat cardiomyocytes against hypertrophy by regulating inflammatory cytokines secretion and cell apoptosis.

    Science.gov (United States)

    Li, Q; Yu, Q; Na, R; Liu, B

    2017-05-15

    We aimed to investigate the effect of etanercept, a tumor necrosis factor-α (TNF-α) inhibitor, on rat cardiomyocyte hypertrophy and its underlying mechanism. Primary neonatal rat cardiomyocytes were isolated from Sprague-Dawley rats. The model of rat cardiomyocyte hypertrophy was induced by endothelin, and then treated with different concentrations of etanercept (1, 10, and 50 μM). After treatment, cell counts, viability and cell apoptosis were evaluated. The mRNA levels of myocardial hypertrophy marker genes, including atrial natriuretic factor (ANF), matrix metalloproteinase (MMP)-9 and MMP-13, were detected by qRT-PCR, and the expressions of apoptosis-related proteins (Bcl-2 and Bax) were measured by western blotting. The protein levels of transforming growth factor-β1 (TGF-β1), interleukin (IL)-1β, IL-6, leukemia inhibitory factor (LIF) and cardiotrophin-1 (CT-1) were determined using enzyme linked immunosorbent assay (ELISA) kits. In the present study, TNF-α level in cardiomyocytes with hypertrophy was significantly enhanced (Petanercept (Petanercept remarkably reduced the mRNA levels of ANF, MMP-9 and MMP-13, inhibited the expression of Bax, and increased the expression of Bcl-2 compared to the model group (Petanercept lowered the levels of IL-1β, IL-6, LIF and CT-1 but not TGF-β1 compared to the model group (PEtanercept may protect rat cardiomyocytes from hypertrophy by inhibiting inflammatory cytokines secretion and cell apoptosis.

  3. Atrial natriuretic factor gene expression in ventricles of rats with spontaneous biventricular hypertrophy.

    Science.gov (United States)

    Lee, R T; Bloch, K D; Pfeffer, J M; Pfeffer, M A; Neer, E J; Seidman, C E

    1988-02-01

    A subset of Wistar-Kyoto (WKY) rats that spontaneously develops biventricular hypertrophy (BVH) in response to increased cardiac output was evaluated for ventricular expression of the atrial natriuretic factor (ANF) gene. Normal WKY rats had low levels of left ventricular ANF mRNA and minimally detectable ANF transcripts in the right ventricle. In contrast, BVH rats showed a sixfold greater ANF mRNA concentration in the left ventricle than age-matched WKY controls. BVH right ventricular ANF mRNA levels equaled those found in BVH left ventricles and were dramatically greater than WKY right ventricular controls. Unlike experimental models of hypertrophy, both left and right ventricles significantly increase ANF gene transcripts in the natural development of BVH. The left and right ventricles can concordantly respond to hypertrophy and increase ANF gene transcription.

  4. Angiogenesis and cardiac hypertrophy: maintenance of cardiac function and causative roles in heart failure.

    Science.gov (United States)

    Oka, Toru; Akazawa, Hiroshi; Naito, Atsuhiko T; Komuro, Issei

    2014-01-31

    Cardiac hypertrophy is an adaptive response to physiological and pathological overload. In response to the overload, individual cardiac myocytes become mechanically stretched and activate intracellular hypertrophic signaling pathways to re-use embryonic transcription factors and to increase the synthesis of various proteins, such as structural and contractile proteins. These hypertrophic responses increase oxygen demand and promote myocardial angiogenesis to dissolve the hypoxic situation and to maintain cardiac contractile function; thus, these responses suggest crosstalk between cardiac myocytes and microvasculature. However, sustained pathological overload induces maladaptation and cardiac remodeling, resulting in heart failure. In recent years, specific understanding has increased with regard to the molecular processes and cell-cell interactions that coordinate myocardial growth and angiogenesis. In this review, we summarize recent advances in understanding the regulatory mechanisms of coordinated myocardial growth and angiogenesis in the pathophysiology of cardiac hypertrophy and heart failure.

  5. Transcriptional profiling of rat skeletal muscle hypertrophy under restriction of blood flow.

    Science.gov (United States)

    Xu, Shouyu; Liu, Xueyun; Chen, Zhenhuang; Li, Gaoquan; Chen, Qin; Zhou, Guoqing; Ma, Ruijie; Yao, Xinmiao; Huang, Xiao

    2016-12-15

    Blood flow restriction (BFR) under low-intensity resistance training (LIRT) can produce similar effects upon muscles to that of high-intensity resistance training (HIRT) while overcoming many of the restrictions to HIRT that occurs in a clinical setting. However, the potential molecular mechanisms of BFR induced muscle hypertrophy remain largely unknown. Here, using a BFR rat model, we aim to better elucidate the mechanisms regulating muscle hypertrophy as induced by BFR and reveal possible clinical therapeutic targets for atrophy cases. We performed genome wide screening with microarray analysis to identify unique differentially expressed genes during rat muscle hypertrophy. We then successfully separated the differentially expressed genes from BRF treated soleus samples by comparing the Affymetrix rat Genome U34 2.0 array with the control. Using qRT-PCR and immunohistochemistry (IHC) we also analyzed other related differentially expressed genes. Results suggested that muscle hypertrophy induced by BFR is essentially regulated by the rate of protein turnover. Specifically, PI3K/AKT and MAPK pathways act as positive regulators in controlling protein synthesis where ubiquitin-proteasome acts as a negative regulator. This represents the first general genome wide level investigation of the gene expression profile in the rat soleus after BFR treatment. This may aid our understanding of the molecular mechanisms regulating and controlling muscle hypertrophy and provide support to the BFR strategies aiming to prevent muscle atrophy in a clinical setting. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Atrial natriuretic factor gene expression in ventricles of rats with spontaneous biventricular hypertrophy.

    OpenAIRE

    Lee, R.T.; Bloch, K.D.; Pfeffer, J.M.; Pfeffer, M.A.; Neer, E J; Seidman, C E

    1988-01-01

    A subset of Wistar-Kyoto (WKY) rats that spontaneously develops biventricular hypertrophy (BVH) in response to increased cardiac output was evaluated for ventricular expression of the atrial natriuretic factor (ANF) gene. Normal WKY rats had low levels of left ventricular ANF mRNA and minimally detectable ANF transcripts in the right ventricle. In contrast, BVH rats showed a sixfold greater ANF mRNA concentration in the left ventricle than age-matched WKY controls. BVH right ventricular ANF m...

  7. Long-Term Administration of Neuropeptide Y in the Subcutaneous Infusion Results in Cardiac Dysfunction and Hypertrophy in Rats.

    Science.gov (United States)

    Zhang, Rong; Niu, Huifang; Kang, Xiaohui; Ban, Tao; Hong, Hong; Ai, Jing

    2015-01-01

    The purpose of the present study was to clarify whether chronically elevated plasma neuropeptide Y (NPY) might affect heart function and cardiac remodeling in rats. Male Wistar rats were administered NPY (85 μg for 30 days) by mini-osmotic pump subcutaneously implanted between the scapulae. Associated indices for heart function, cardiac remodeling and hypertrophy were evaluated. Compared to the sham group, the baseline systolic blood pressure (SBP) in rats administered NPY was significantly increased; cardiac function was significantly decreased, as indicated by reduced ejection fraction (EF), left ventricular end-systolic pressure (LVESP), maximum change velocity of left ventricular pressure in the isovolumic contraction or relaxation period (± dp/dtmax) and increased left ventricular end-diastolic pressure (LVEDP); hematoxylin-eosin (H&E) staining detection displayed enlarged cell areas and a consistent increase in heart-to-body weight ratios (HW/BW) was observed; quantitative real time PCR (qRT-PCR) and Western blot analysis showed markedly increased expressions of β-myosin heavy chain (β-MHC), calcineurin (CaN) and phosphorylated p38 proteins, while no changes were found in the expressions of p38 total protein and the phosphorylations of JNK and ERK. This study reported for the first time that long-term elevated plasma concentration of NPY could induce cardiac dysfunction and cardiac hypertrophy and this phenomenon could, in part, be mediated by the Ca2+/CaM-dependent CaN pathway and p38 mitogen-activated protein kinase (MAPK) signal pathway in rats. © 2015 S. Karger AG, Basel.

  8. microRNA-340-5p Functions Downstream of Cardiotrophin-1 to Regulate Cardiac Eccentric Hypertrophy and Heart Failure via Target Gene Dystrophin.

    Science.gov (United States)

    Zhou, Jian; Gao, Jie; Zhang, Xiaoya; Liu, Yan; Gu, Song; Zhang, Xitao; An, Xiangguang; Yan, Jun; Xin, Yue; Su, Pixiong

    2015-01-01

    Pathological cardiac hypertrophy inevitably leads to the unfavorable outcomes of heart failure (HF) or even sudden death. microRNAs are key regulation factors participating in many pathophysiological processes. Recently, we observed upregulation of microRNA-340-5p (miR-340) in failing human hearts because of dilated cardiomyopathy, but the functional consequence of miR-340 remains to be clarified.We transfected neonatal cardiomyocytes with miR-340 and found fetal gene expression including Nppa, Nppb and Myh7. We also observed eccentric hypertrophy development upon treatment which was analogous to the phenotype after cardiotrophin-1 (CT-1) stimulation. As a potent inducer of cardiac eccentric hypertrophy, treatment by IL-6 family members CT-1 and leukemia inhibitory factor (LIF) led to the elevation of miR-340. Knockdown of miR-340 using antagomir attenuated fetal gene expression and hypertrophy formation, which means miR-340 could convey the hypertrophic signal of CT-1. To demonstrate the initial factor of miR-340 activation, we constructed a volume overloaded abdominal aorta-inferior vena cava fistula rat HF model. miR-340 and CT-1 were found to be up-regulated in the left ventricle. Dystrophin (DMD), a putative target gene of miR-340 which is eccentric hypertrophy-susceptible, was decreased in this HF model upon Western blotting and immunohistochemistry tests. Luciferase assay constructed in two seed sequence of DMD gene 3'UTR showed decreased luciferase activities, and miR-340 transfected cells resulted in the degradation of DMD.miR-340 is a pro-eccentric hypertrophy miRNA, and its expression is dependent on volume overload and cytokine CT-1 activation. Cardiomyocyte structure protein DMD is a target of miR-340.

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

    Directory of Open Access Journals (Sweden)

    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.

  10. Neonatal Diesel Exhaust Particulate Exposure Does Not Predispose Mice to Adult Cardiac Hypertrophy or Heart Failure.

    Science.gov (United States)

    Liu, Yonggang; Weldy, Chad S; Chin, Michael T

    2016-11-24

    Background: We have previously reported that in utero and early life exposure to diesel exhaust particulates predisposes mice to adult heart failure, and that in utero exposure alone is sufficient to confer this predisposition. This follow up study addresses whether neonatal exposure alone can also confer this predisposition. Methods: Newborn male C57BL/6 mice were exposed to diesel exhaust (DE) particulates immediately after birth until weaning at 21 days of age, whereupon they were transferred to filtered air (FA) conditions. At the age of 12 weeks, transverse aortic constriction (TAC) was performed followed by weekly echocardiography for three weeks. After the last echocardiogram, mice were euthanized for organ harvest, gravimetry and histology. Results: Neonatal exposure to DE particulates did not increase susceptibility to cardiac hypertrophy or heart failure after TAC when compared to FA exposed controls (ventricular weight/body weight ratio 7.505 vs. 7.517 mg/g, p = Not Significant (NS)). The left ventricular ejection fraction after TAC was similar between groups at one week, two weeks, and three weeks after procedure. Histological analysis showed no difference in the degree of cardiac hypertrophy or fibrosis. Conclusions: Neonatal exposure to DE particulates does not predispose mice to TAC-induced cardiac hypertrophy and heart failure in adulthood, in contrast to previously published results showing susceptibility due to in utero exposure.

  11. Myocardial energetics is not compromised during compensated hypertrophy in the Dahl salt-sensitive rat model of hypertension.

    Science.gov (United States)

    Tran, Kenneth; Han, June-Chiew; Taberner, Andrew J; Barrett, Carolyn J; Crampin, Edmund J; Loiselle, Denis S

    2016-09-01

    Salt-induced hypertension leads to development of left ventricular hypertrophy in the Dahl salt-sensitive (Dahl/SS) rat. Before progression to left ventricular failure, the heart initially undergoes a compensated hypertrophic response. We hypothesized that changes in myocardial energetics may be an early indicator of transition to failure. Dahl/SS rats and their salt-resistant consomic controls (SS-13(BN)) were placed on either a low- or high-salt diet to generate four cohorts: Dahl-SS rats on a low- (Dahl-LS) or high-salt diet (Dahl-HS), and SS-13(BN) rats on a low- (SSBN-LS) or high-salt diet (SSBN-HS). We isolated left ventricular trabeculae and characterized their mechanoenergetic performance. Our results show, at most, modest effects of salt-induced compensated hypertrophy on myocardial energetics. We found that the Dahl-HS cohort had a higher work-loop heat of activation (estimated from the intercept of the heat vs. relative afterload relationship generated from work-loop contractions) relative to the SSBN-HS cohort and a higher economy of contraction (inverse of the slope of the heat vs. active stress relation) relative to the Dahl-LS cohort. The maximum extent of shortening and maximum shortening velocity of the Dahl/SS groups were higher than those of the SS-13(BN) groups. Despite these differences, no significant effect of salt-induced hypertension was observed for either peak work output or peak mechanical efficiency during compensated hypertrophy. Copyright © 2016 the American Physiological Society.

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

    OpenAIRE

    Marques FZ; Prestes PR; Byars SG; Ritchie SC; Würtz P; Patel SK; Booth SA; Rana I; Minoda Y; Berzins SP; Curl CL; Bell JR; Wai B; Srivastava PM; Kangas AJ

    2017-01-01

    Background 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 ne...

  13. Amalaki rasayana, a traditional Indian drug enhances cardiac mitochondrial and contractile functions and improves cardiac function in rats with hypertrophy.

    Science.gov (United States)

    Kumar, Vikas; Aneesh, Kumar A; Kshemada, K; Ajith, Kumar G S; Binil, Raj S S; Deora, Neha; Sanjay, G; Jaleel, A; Muraleedharan, T S; Anandan, E M; Mony, R S; Valiathan, M S; Santhosh, Kumar T R; Kartha, C C

    2017-08-17

    We evaluated the cardioprotective effect of Amalaki Rasayana (AR), a rejuvenating Ayurvedic drug prepared from Phyllanthus emblica fruits in the reversal of remodeling changes in pressure overload left ventricular cardiac hypertrophy (LVH) and age-associated cardiac dysfunction in male Wistar rats. Six groups (aging groups) of 3 months old animals were given either AR or ghee and honey (GH) orally; seventh group was untreated. Ascending aorta was constricted using titanium clips in 3 months old rats (N = 24; AC groups) and after 6 months, AR or GH was given for further 12 months to two groups; one group was untreated. Histology, gene and protein expression analysis were done in heart tissues. Chemical composition of AR was analyzed by HPLC, HPTLC and LC-MS. AR intake improved (P < 0.05) cardiac function in aging rats and decreased LVH (P < 0.05) in AC rats as well as increased (P < 0.05) fatigue time in treadmill exercise in both groups. In heart tissues of AR administered rats of both the groups, SERCA2, CaM, Myh11, antioxidant, autophagy, oxidative phosphorylation and TCA cycle proteins were up regulated. ADRB1/2 and pCREB expression were increased; pAMPK, NF-kB were decreased. AR has thus a beneficial effect on myocardial energetics, muscle contractile function and exercise tolerance capacity.

  14. Reduction of rat cardiac hypertrophy by osthol is related to regulation of cardiac oxidative stress and lipid metabolism.

    Science.gov (United States)

    Zhou, Feng; Zhong, Wen; Xue, Jie; Gu, Zhen-lun; Xie, Mei-lin

    2012-10-01

    The objective of this study was to examine the therapeutic effect of osthol, a coumarin compound isolated from the fruit of Cnidium monnieri (L.) Cusson, on cardiac hypertrophy in rats and investigate its potential mechanisms. The rats with cardiac hypertrophy induced by renovascular hypertension were given osthol orally by gavage for 4 weeks. The results showed that in the osthol 20 mg/kg group, the blood pressure, heart weight index and myocardial malondialdehyde content were lowered (p < 0.001, p = 0.002 and p = 0.025, respectively), the myocardial superoxide dismutase and glutathione peroxidase contents were increased (p < 0.001), and the elevated unesterified fatty acids and triacylglycerols in myocardial tissues were decreased (p = 0.017 and p = 0.004, respectively). At the same time, the myocardial peroxisome proliferator-activated receptor (PPAR)-α and carnitine palmitoyltransferase (CPT)-1a mRNA expressions were increased and the myocardial diacylglycerol acyltransferase (DGAT) mRNA expression was decreased in the osthol 20 mg/kg group (p < 0.001). Osthol treatment was associated with a decreased cross-sectional area of cardiomyocytes (p < 0.001). These findings suggest that osthol may exert a therapeutic effect on cardiac hypertrophy in rats, and its mechanisms may be related to the improvement of myocardial oxidative stress and lipid metabolism via regulation of PPARα-mediated target gene expressions including an increase in CPT-1a mRNA expression and a decrease in DGAT mRNA expression.

  15. Regional differences in the dynamics of refractoriness in intact and hypertrophied in situ canine hearts.

    Science.gov (United States)

    Voss, F; Schoels, W; Lue, J; Bauer, A; Katus, H A; Becker, R

    2005-09-01

    Functional re-entry is thought to represent the predominant mechanism underlying ventricular arrhythmias. Functional conduction block may be caused by regional dispersion of refractoriness (ERP). Dispersion of ERP may not be evident at baseline, but may occur with sudden changes in heart rate, as ventricular arrhythmias are commonly induced by short-long-short cycles. We examined the dynamics of local ERPs at two left ventricular (LV) sites in dogs with either no structural heart disease or biventricular hypertrophy (BVH). ERPs were determined at each of four bipoles of two adjacent needle electrodes in the LV apex and the lateral wall. The stimulation protocol included two different basic cycle lengths, one or two longer cycles after a train of 6 or 5 shorter cycles, and one shorter cycle after a train of 6 longer cycles. In normal dogs, a significant apicolateral ERP gradient was only evident with the longer basic cycle length. One shorter cycle was sufficient to dissolve that gradient. One longer cycle was enough to create a regional ERP gradient. Dynamic regional gradients occurred because the apex responded more markedly and more readily to abrupt changes in cycle length. BVH led to an increase in ERP at both LV sites and to an aggravation of regional ERP gradients. Dynamic ERP behavior seems to depend on topography and underlying pathology. Abrupt changes in heart rate might induce dynamic refractory gradients between various regions of the normal heart, but also between adjacent regions inhomogenously affected by hypertrophy.

  16. 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.

  17. Training improves the oxidative phenotype of muscle during the transition from cardiac hypertrophy to heart failure without altering MyoD and myogenin.

    Science.gov (United States)

    Pacagnelli, Francis Lopes; Aguiar, Andreo Fernando; Campos, Dijon Henrique S; Castan, Eduardo Paulino; de Souza, Rodrigo Wagner Alves; de Almeida, Fernanda Losi Alves; Carani, Fernanda; Carvalho, Robson Francisco; Cicogna, Antonio Carlos; Silva, Maeli Dal Pai

    2016-08-01

    What is the central question of this study? We investigated the effects of physical training on phenotypic (fibre-type content) and myogenic features (MyoD and myogenin expression) in skeletal muscle during the transition from cardiac hypertrophy to heart failure. What is the main finding and its importance? We provide new insight into skeletal muscle adaptations by showing that physical training increases the type I fibre content during the transition from cardiac hypertrophy to heart failure, without altering MyoD and myogenin expression. These results have important clinical implications for patients with heart failure, because this population has reduced muscle oxidative capacity. The purpose of this study was to investigate the effects of physical training (PT) on phenotypic features (fibre-type content) and myogenic regulatory factors (MyoD and myogenin) in rat skeletal muscle during the transition from cardiac hypertrophy to heart failure. We used the model of ascending aortic stenosis (AS) to induce heart failure in male Wistar rats. Sham-operated animals were used as age-matched controls. At 18 weeks after surgery, rats with ventricular dysfunction were randomized into the following four groups: sham-operated, untrained (Sham-U; n = 8); sham-operated, trained (Sham-T; n = 6); aortic stenosis, untrained (AS-U; n = 6); and aortic stenosis, trained (AS-T; n = 8). The AS-T and Sham-T groups were submitted to a 10 week aerobic PT programme, while the AS-U and Sham-U groups remained untrained for the same period of time. After the PT programme, the animals were killed and the soleus muscles collected for phenotypic and molecular analyses. Physical training promoted type IIa-to-I fibre conversion in the trained groups (Sham-T and AS-T) compared with the untrained groups (Sham-U and AS-U). No significant (P > 0.05) differences were found in type I or IIa fibre content in the AS-U group compared with the Sham-U group. Additionally, there were no

  18. 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

  19. Chronic inhibition of the Na(+)/H(+)- exchanger causes regression of hypertrophy, heart failure, and ionic and electrophysiological remodelling

    NARCIS (Netherlands)

    Baartscheer, A.; Hardziyenka, M.; Schumacher, C. A.; Belterman, C. N. W.; van Borren, M. M. G. J.; Verkerk, A. O.; Coronel, R.; Fiolet, J. W. T.

    2008-01-01

    Background and purpose:Increased activity of the Na(+)/H(+)-exchanger (NHE-1) in heart failure underlies raised [Na(+)](i) causing disturbances of calcium handling. Inhibition of NHE-1, initiated at the onset of pressure/volume overload, prevents development of hypertrophy, heart failure and

  20. Long noncoding RNAs (LncRNAs) - The dawning of a new treatment for cardiac hypertrophy and heart failure.

    Science.gov (United States)

    Han, Dong; Gao, Quansheng; Cao, Feng

    2017-08-01

    Long noncoding RNAs (lncRNAs) represent a category of noncoding RNAs with the potential for genetic and epigenetic regulations. As important regulators of gene expression, increasing evidence has proven that lncRNAs play a significant regulatory role in various cardiovascular pathologies. In particular, lncRNAs have been proved to be participating in gene regulatory mechanisms involved in heart growth and development that can be exploited to repair the injured adult heart. Furthermore, lncRNAs have been revealed as possible therapeutic targets for heart failure with different causes and in different stages. In the journey from a healthy heart to heart failure, lncRNAs have been shown to participate in almost every landmark of heart failure pathogenesis including ischemic injury, cardiac hypertrophy, and cardiac fibrosis. Furthermore, the manipulation of lncRNAs palliates the progression of heart failure by attenuating ischemic heart injury, cardiac hypertrophy and cardiac fibrosis, as well as facilitating heart regeneration and therapeutic angiogenesis. This review will highlight recent updates regarding the involvement of lncRNAs in cardiac hypertrophy and heart failure and their potential as novel therapeutic targets. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren & Megan Yingmei Zhang. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. MicroRNAs Association in the Cardiac Hypertrophy Secondary to Complex Congenital Heart Disease in Children.

    Science.gov (United States)

    Sánchez-Gómez, Ma C; García-Mejía, K A; Pérez-Díaz Conti, M; Díaz-Rosas, G; Palma-Lara, I; Sánchez-Urbina, R; Klünder-Klünder, M; Botello-Flores, J A; Balderrábano-Saucedo, N A; Contreras-Ramos, A

    2017-06-01

    Complex congenital heart disease (CHD) affects cardiac blood flow, generating a pressure overload in the compromised ventricles and provoking hypertrophy that over time will induce myocardial dysfunction and cause a potential risk of imminent death. Therefore, the early diagnosis of complex CHD is paramount during the first year of life, with surgical treatment of patients favoring survival. In the present study, we analyzed cardiac tissue and plasma of children with cardiac hypertrophy (CH) secondary to CHD for the expression of 11 miRNAs specific to CH in adults. The results were compared with the miRNA expression patterns in tissue and blood of healthy children. In this way, we determined that miRNAs 1, 18b, 21, 23b, 133a, 195, and 208b constitute the expression profile of the cardiac tissue of children with CHD. Meanwhile, miRNAs 21, 23a, 23b, and 24 can be considered specific biomarkers for the diagnosis of CH in infants with CHD. These results suggest that CH secondary to CHD in children differs in its mechanism from that described for adult hypertrophy, offering a new perspective to study the development of this pathology and to determine the potential of hypertrophic miRNAs to be biomarkers for early CH.

  2. Prevention of angiotensin II-induced hypertension, cardiovascular hypertrophy and oxidative stress by acetylsalicylic acid in rats.

    Science.gov (United States)

    Wu, Rong; Laplante, Marc-André; De Champlain, Jacques

    2004-04-01

    Angiotensin II (Ang II)-induced oxidative stress has been suspected to play an important part in the pathogenesis of many cardiovascular diseases. Our previous study demonstrated that acetylsalicylic acid (ASA) possesses potent antioxidative properties. To evaluate the pathogenetic role of oxidative stress in Ang II-induced hypertension and cardiovascular hypertrophy. Chronic infusion of Ang II (200 ng/kg per min for 12 days) increased the aortic and cardiac tissue production of superoxide anion (O2) (lucigenin-enhanced chemiluminescence method) by 77 and 35%, respectively. These effects were associated with progressive increases in systolic blood pressure (from 135 to 194 mmHg) and heart/body weight ratio (from 2.25 to 2.69). Chronic treatment with oral ASA alone (100 mg/kg per day for 12 days) significantly reduced aortic and cardiac production of O2 (by 31 and 33%, respectively), without alteration in blood pressure and heart/body weight ratio in control normotensive animals. However, concurrent treatment with ASA in Ang II-infused rats completely prevented the Ang II-induced production of O2, in addition to hypertension and cardiac hypertrophy. Similar protective effects were observed in cultured aortic smooth muscle cells, in which increases in O2 production and [H]leucine incorporation (221 and 38%, respectively) induced by Ang II (10 mol/l) were totally prevented by concurrent incubation with ASA (10 mol/l). Losartan, but not PD 123319, also blocked the Ang II-induced oxidative and hypertrophic effects in those cells. Other anti-inflammatory drugs, such as salicylic acid, indomethacin and ibuprofen, did not show similar anti-Ang II and antioxidative effects in vivo. Oxidative stress plays a major part in chronic Ang II-induced hypertension and cardiovascular hypertrophy. Chronic concurrent treatment with ASA was found to prevent those Ang II-induced effects on the cardiovascular system, presumably through its antioxidative properties.

  3. p38 MAPK Inhibition Improves Heart Function in Pressure-Loaded Right Ventricular Hypertrophy.

    Science.gov (United States)

    Kojonazarov, Baktybek; Novoyatleva, Tatyana; Boehm, Mario; Happe, Chris; Sibinska, Zaneta; Tian, Xia; Sajjad, Amna; Luitel, Himal; Kriechling, Philipp; Posern, Guido; Evans, Steven M; Grimminger, Friedrich; Ghofrani, Hossein A; Weissmann, Norbert; Bogaard, Harm J; Seeger, Werner; Schermuly, Ralph T

    2017-11-01

    Although p38 mitogen-activated protein kinase (MAPK) is known to have a role in ischemic heart disease and many other diseases, its contribution to the pathobiology of right ventricular (RV) hypertrophy and failure is unclear. Therefore, we sought to investigate the role of p38 MAPK in the pathophysiology of pressure overload-induced RV hypertrophy and failure. The effects of the p38 MAPK inhibitor PH797804 were investigated in mice with RV hypertrophy/failure caused by exposure to hypoxia or pulmonary artery banding. In addition, the effects of p38 MAPK inhibition or depletion (by small interfering RNA) were studied in isolated mouse RV fibroblasts. Echocardiography, invasive hemodynamic measurements, immunohistochemistry, collagen assays, immunofluorescence staining, and Western blotting were performed. Expression of phosphorylated p38 MAPK was markedly increased in mouse and human hypertrophied/failed RVs. In mice, PH797804 improved RV function and inhibited cardiac fibrosis compared with placebo. In isolated RV fibroblasts, p38 MAPK inhibition reduced transforming growth factor (TGF)-β-induced collagen production as well as stress fiber formation. Moreover, p38 MAPK inhibition/depletion suppressed TGF-β-induced SMAD2/3 phosphorylation and myocardin-related transcription factor A (MRTF-A) nuclear translocation, and prevented TGF-β-induced cardiac fibroblast transdifferentiation. Moreover, p38 MAPK inhibition in mice exposed to pulmonary artery banding led to diminished nuclear levels of MRTF-A and phosphorylated SMAD3 in RV fibroblasts. Together, our data indicate that p38 MAPK inhibition significantly improves RV function and inhibits RV fibrosis. Inhibition of p38 MAPK in RV cardiac fibroblasts, resulting in coordinated attenuation of MRTF-A cytoplasmic-nuclear translocation and SMAD3 deactivation, indicates that p38 MAPK signaling contributes to distinct disease-causing mechanisms.

  4. The effect of resveratrol on angiotensin II levels and the rate of transcription of its receptors in the rat cardiac hypertrophy model.

    Science.gov (United States)

    Dorri Mashhadi, Fahimeh; Zavvar Reza, Javad; Jamhiri, Mohabbat; Hafizi, Zeinab; Zare Mehrjardi, Fatemeh; Safari, Fatemeh

    2017-03-01

    This study investigated the effect of resveratrol on serum and cardiac levels of angiotensin II and transcription of its main receptors following pressure overload induced-hypertrophy. Rats were divided into untreated (Hyp) and resveratrol treated hypertrophied groups (H + R). Intact animals served as the control (Ctl). Cardiac hypertrophy was induced by abdominal aortic banding. Blood pressure (BP) was recorded via left carotid artery cannula. Fibrosis was confirmed by Masson trichrome staining. Angiotensin II level was measured using an ELIZA test. Gene expression was assessed by a real time PCR (RT-PCR) technique. We observed that in the H + R group BP and heart weight/body weight were decreased significantly (p < 0.001, p < 0.05, respectively vs Hyp). The cardiac levels of angiotensin II and AT1a mRNA were increased in the Hyp group (p < 0.01 vs Ctl). In the H + R group the AT1a mRNA level was decreased significantly (p < 0.05 vs Hyp). It could be concluded that resveratrol protects the heart against hypertrophy progression in part by affecting cardiac AT1a transcription.

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

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    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.

  6. Electrocardiographic left ventricular hypertrophy Cornell product is a feasible predictor of cardiac prognosis in patients with chronic heart failure.

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    Otaki, Yoichiro; Takahashi, Hiroki; Watanabe, Tetsu; Kadowaki, Shinpei; Narumi, Taro; Honda, Yuki; Hasegawa, Hiromasa; Honda, Shintaro; Funayama, Akira; Nishiyama, Satoshi; Arimoto, Takanori; Shishido, Tetsuro; Miyashita, Takehiko; Miyamoto, Takuya; Kubota, Isao

    2014-04-01

    Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular disease and is associated with heart failure development. The Cornell product is an easily measured electrocardiographic parameter for assessing LVH. However, it is undetermined whether the Cornell product can predict the cardiac prognosis of chronic heart failure (CHF) patients. We performed standard 12-lead electrocardiography and calculated the Cornell product in 432 consecutive CHF patients. LV geometry was assessed as normal, concentric remodeling, concentric or eccentric hypertrophy. The Cornell product was significantly higher in patients with eccentric hypertrophy, and increased with advancing New York Heart Association functional class. During a median follow-up of 660 days, there were 121 cardiac events including 36 cardiac deaths and 85 re-hospitalizations for worsening heart failure. Multivariate Cox proportional hazard analysis showed that the Cornell product was an independent predictor of cardiac events in CHF patients. Patients in the highest quartile of Cornell product had a higher prevalence of LV eccentric hypertrophy (22, 29, 33 and 67 % for quartiles one through four). Kaplan-Meier analysis demonstrated that the highest quartile of Cornell product was associated with the greatest risk among CHF patients. The Cornell product is associated with LV eccentric hypertrophy and can be used to predict future cardiac events in CHF patients.

  7. Diosmin prevents left ventricular hypertrophy, adenosine triphosphatases dysfunction and electrolyte imbalance in experimentally induced myocardial infarcted rats.

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    Sabarimuthu, Sharmila Queenthy; Ponnian, Stanely Mainzen Prince; John, Babu

    2017-11-05

    Currently, there has been an increased interest globally to identify natural compounds that are pharmacologically potent and have low or no adverse effects for use in preventive medicine. Myocardial infarction is a vital pathological feature resulting in high levels of mortality and morbidity. Left ventricular hypertrophy (LVH), adenosine triphosphatases (ATPases) dysfunction and electrolyte imbalance play a vital role in the pathogenesis of myocardial infarction. This study aims to evaluate the preventive effects of diosmin on LVH, ATPases dysfunction and electrolyte imbalance in isoproterenol induced myocardial infarcted rats. Male albino Wistar rats were pretreated orally with diosmin (10mg/kg body weight) daily for a period of 10 days. After pretreatment, isoproterenol (100mg/kg body weight) was injected subcutaneously into the rats twice at an interval of 24h to induce myocardial infarction. Isoproterenol induced myocardial infarcted rats showed increased LVH, altered levels/ concentrations of serum cardiac troponin-T, heart ATPases, heart sodium ion, calcium ion and potassium ion, and increased myocardial infarct size. Pretreatment with diosmin revealed preventive effects on LVH, and all the above mentioned biochemical parameters evaluated in isoproterenol induced myocardial infarcted rats. The 2, 3, 5-triphenyl tetrazolium chloride staining on myocardial infarct size confirmed the prevention of myocardial infarction. Further, the 1, 1 diphenyl-2- picryl-hydrazyl (DPPH) radical in vitro study revealed a potent DPPH free radical scavenging action of diosmin. Thus, the observed effects of diosmin are due to its antihypertrophic and free radical scavenging activities in isoproterenol induced myocardial infarcted rats. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. 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

  9. Effect of Thymol on Serum Antioxidant Capacity of Rats Following Myocardial Hypertrophy

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    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.

  10. Cardiomyocyte Overexpression of FABP4 Aggravates Pressure Overload-Induced Heart Hypertrophy.

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    Ji Zhang

    Full Text Available Fatty acid binding protein 4 (FABP4 is a member of the intracellular lipid-binding protein family, responsible for the transportation of fatty acids. It is considered to express mainly in adipose tissues, and be strongly associated with inflammation, obesity, diabetes and cardiovasculardiseases. Here we report that FABP4 is also expressed in cardiomyocytes and plays an important role in regulating heart function under pressure overload. We generated heart-specific transgenic FABP4 (FABP4-TG mice using α myosin-heavy chain (α-MHC promoter and human FABP4 sequence, resulting in over-expression of FABP4 in cardiomyocytes. The FABP4-TG mice displayed normal cardiac morphology and contractile function. When they were subjected to the transverse aorta constriction (TAC procedure, the FABP4-TG mice developed more cardiac hypertrophy correlated with significantly increased ERK phosphorylation, compared with wild type controls. FABP4 over-expression in cardiomyocytes activated phosphor-ERK signal and up-regulate the expression of cardiac hypertrophic marker genes. Conversely, FABP4 induced phosphor-ERK signal and hypertrophic gene expressions can be markedly inhibited by an ERK inhibitor PD098059 as well as the FABP4 inhibitor BMS309403. These results suggest that FABP4 over-expression in cardiomyocytes can aggravate the development of cardiac hypertrophy through the activation of ERK signal pathway.

  11. Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure.

    Science.gov (United States)

    Hall, Duane D; Ponce, Jessica M; Chen, Biyi; Spitler, Kathryn M; Alexia, Adrianne; Oudit, Gavin Y; Song, Long-Sheng; Grueter, Chad E

    2017-08-03

    Widespread changes in cardiac gene expression occur during heart failure, yet the mechanisms responsible for coordinating these changes remain poorly understood. The Mediator complex represents a nodal point for modulating transcription by bridging chromatin-bound transcription factors with RNA polymerase II activity; it is reversibly regulated by its cyclin-dependent kinase 8 (Cdk8) kinase submodule. Here, we identified increased Cdk8 protein expression in human failing heart explants and determined the consequence of this increase in cardiac-specific Cdk8-expressing mice. Transgenic Cdk8 overexpression resulted in progressive dilated cardiomyopathy, heart failure, and premature lethality. Prior to functional decline, left ventricular cardiomyocytes were dramatically elongated, with disorganized transverse tubules and dysfunctional calcium handling. RNA sequencing results showed that myofilament gene isoforms not typically expressed in adult cardiomyocytes were enriched, while oxidative phosphorylation and fatty acid biosynthesis genes were downregulated. Interestingly, candidate upstream transcription factor expression levels and MAPK signaling pathways thought to determine cardiomyocyte size remained relatively unaffected, suggesting that Cdk8 functions within a novel growth regulatory pathway. Our findings show that manipulating cardiac gene expression through increased Cdk8 levels is detrimental to the heart by establishing a transcriptional program that induces pathological remodeling and eccentric hypertrophy culminating in heart failure.

  12. [Evaluation of pulmonary venous flow pattern in hypertrophied and dilated hearts: a study with transesophageal pulsed Doppler echocardiography].

    Science.gov (United States)

    Iuchi, A; Oki, T; Ogawa, S; Kawano, T; Hayashi, M; Aoyama, Y; Emi, S; Hosoi, K; Fukuda, N; Mori, H

    1991-01-01

    In order to evaluate the clinical significance of pulmonary venous flow (PVF) pattern, transesophageal pulsed Doppler echocardiography (TEE) was performed in 25 patients with hypertrophied heart (all with hypertrophic cardiomyopathy), 15 patients with dilated heart (10 with old myocardial infarction and 5 with dilated cardiomyopathy) and 10 normal controls. Parameters obtained from the PVF pattern were compared with those of transmitral flow (MVF) pattern, % fractional shortening (%FS) of left ventricle (LV) and amplitude of mitral anular motion (MAM) during a cardiac cycle. Results were as follows: 1. PVF pattern in cases of sinus rhythm was divided into four components, atrial systolic backward flow (PVA), ventricular systolic (PVS1, PVS2) and diastolic (PVD) forward flows. 2. In patients with dilated heart, peak velocities of PVS1 and PVS2 were markedly decreased compared with those of hypertrophied and normal hearts. 3. Peak velocity of PVD in hypertrophied and dilated hearts was significantly decreased compared with that of normal controls, and PV-D/S (ratio of peak velocity of PVD to PVS2) was significantly lower in hypertrophied heart than in normal controls. 4. Time interval from the first heart sound to the peak of PVS2 (TS) was significantly longer in dilated heart, and time interval from the second heart sound to the peak of PVD (TD) was longer in hypertrophied heart than in the other two groups. 5. MAM and %FS of dilated heart were significantly lower than those in normal and hypertrophied hearts, and peak velocity of PVS2 in dilated heart group correlated well with MAM or %FS. 6. There were significant correlations among the diastolic parameters from PVD of PVF (peak velocity of PVD, PV-D/S) and early diastolic wave (D) of MVF (peak velocity, deceleration time and deceleration of rapid filling). 7. In a case of hypertrophic cardiomyopathy with mid-diastolic wave of MVF, distinct forward wave was observed after PVD of PVF, and this wave coincided in

  13. Natural biventricular hypertrophy in normotensive rats. I. Physical and hemodynamic characteristics.

    Science.gov (United States)

    Pfeffer, M A; Pfeffer, J M; Dunn, F G; Nishiyama, K; Tsuchiya, M; Frohlich, E D

    1979-04-01

    The Wistar-Kyoto strain of normotensive rats (WKY) is being used as a control animal for studies involving the spontaneously hypertensive rats (SHR). A subset of the WKY demonstrating an inheritable transmission of biventricular cardiac hypertrophy (BVH) has been identified. The cardiac enlargement is pronounced, with right and left ventricular weights greater than twice normal in some animals. This natural development of BVH appears to be in response to an increased cardiac output. Blood pressure is normal and, therefore, peripheral resistance is reduced. Left ventricular injection of 15-micrometer radioactively labeled microspheres demonstrated that WKY with BVH had a substantial shunt fraction of their cardiac output (45 +/- 7% radioactivity recovered in the lungs vs. 3 +/- 2% in normal WKY). This subset of WKY with BVH provides a natural model of volume-load hypertrophy. In addition, investigators using the WKY for comparison with SHR should exclude animals with BVH.

  14. Changes in T-Tubules and Sarcoplasmic Reticulum in Ventricular Myocytes in Early Cardiac Hypertrophy in a Pressure Overload Rat Model

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    Perla Pérez-Treviño

    2015-10-01

    Full Text Available Background/Aims: Pressure-overload (PO causes cardiac hypertrophy (CH, and eventually leads to heart failure (HF. HF ventricular myocytes present transverse-tubules (TT loss or disarrangement and decreased sarcoplasmic reticulum (SR density, and both contribute to altered Ca2+ signaling and heart dysfunction. It has been shown that TT remodeling precedes HF, however, it is unknown whether SR structural and functional remodeling also starts early in CH. Methods: Using confocal microscopy, we assessed TT (with Di-8-ANNEPS and SR (with SR-trapped Mag-Fluo-4 densities, as well as SR fluorophore diffusion (fluorescence recovery after photobleach; FRAP, cytosolic Ca2+ signaling and ex vivo cardiac performance in a PO rat hypertrophy model induced by abdominal aortic constriction (at 6 weeks. Results: Rats developed CH, while cardiac performance, basal and upon β-adrenergic stimulation, remained unaltered. TT density decreased by ∼14%, without spatial disarrangement, while SR density decreased by ∼7%. More important, FRAP was ∼30% slower, but with similar maximum recovery, suggesting decreased SR interconnectivity. Systolic and diastolic Ca2+ signaling and SR Ca2+ content were unaltered. Conclusion: SR remodeling is an early CH event, similar to TT remodeling, appearing during compensated hypertrophy. Nevertheless, myocytes can withstand those moderate structural changes in SR and TT, preserving normal Ca2+ signaling and contractility.

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

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    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

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

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    Xia, Jihan; Zhang, Yuanyuan; Xin, Leilei; Kong, Siyuan; Chen, Yaoxing; Yang, Shulin; Li, Kui

    2015-01-01

    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, Pcardiac steatosis and hypertrophy, nine pig heart cRNA samples were hybridized to porcine GeneChips. Microarray analyses revealed that 1,022 genes were significantly differentially expressed (Pcardiac steatosis, and hypertrophy and provides insights into the molecular mechanisms of hypertrophy and fatty heart to facilitate further research.

  17. Major salivary gland hypertrophy model in immature rats: morphometric and histochemical epithelial cell characteristics

    Directory of Open Access Journals (Sweden)

    Vera V. Ivanova

    2017-01-01

    Full Text Available The purpose of the study is to estimate the functional state of epithelial cells of acini and ducts of major salivary glands with hypertrophy caused by repeated incisor amputations in immature rats.Materials and methods. The experiment was carried out on immature (20 days, white male rats, divided into 3 groups: intact, control and group of rats with repeated incisor amputations. Animals were taken out in 2d, 3d, 4th, 6th, 8th, 10th and 12th weeks after the first incisor amputation. Morphofunctional state of rat major salivary glands was assessed by histological (hematoxylin and eosin, histochemistrical (Alcian blue, PAS-reaction, Brachet method and morphometrical (acini area, intralobular ducts volume methods.Results. Repeated incisor amputations led to the increase of acini area and the decrease of intralobular duct volume in submandibular glands in 2nd–4th weeks of the experiment. Cytoplasm pyroninophilia of submandibular gland acinar cells was less pronounced and intensity of PAS-reaction was more pronounced than in intact animals in 3rd week of the experiment. Morphological and functional changes of parotid and sublingual gland epithelial cells were not observed after repeated amputations of incisors in immature rats.Conclusion. Repeated incisor amputations in immature male rats lead to submandibular gland acinar cell hypertrophy in the early stages of the experiment (2d–4th weeks with accumulation of glycoproteins and protein synthesis weakening in these cells. Hypertrophy of acinar cells are accompanied by retardation in the development of granular convoluted tubule cells which are the source of synthesis and secretion of the endocrine biologically active factors of submandibular glands.

  18. Hypertension in African Americans with heart failure: progression from hypertrophy to dilatation; perhaps not.

    Science.gov (United States)

    Solanki, Pallavi; Zakir, Ramzan M; Patel, Rajiv J; Pentakota, Sri-Ram; Maher, James; Gerula, Christine; Saric, Muhamed; Kaluski, Edo; Klapholz, Marc

    2015-03-01

    Concentric hypertrophy is thought to transition to left ventricular (LV) dilatation and systolic failure in the presence of long standing hypertension (HTN). Whether or not this transition routinely occurs in humans is unknown. We consecutively enrolled African American patients hospitalized for acute decompensated volume overload heart failure (HF) in this retrospective study. All patients had a history of HTN and absence of obstructive coronary disease. Patients were divided into those with normal left ventricular ejection fraction (LVEF) and reduced LVEF. LV dimensions were measured according to standard ASE recommendations. LV mass was calculated using the ASE formula with Devereux correction. Patients with normal LVEF HF were significantly older, female and had a longer duration of HTN with higher systolic blood pressure on admission. LV wall thickness was similarly elevated in both groups. LV mass was elevated in both groups however was significantly greater in the reduced LVEF HF group compared to the normal LVEF HF group. Furthermore, gender was an independent predictor for LV wall thickness in normal LVEF HF group. In African American patients with HF our study questions the paradigm that concentric hypertrophy transitions to LV dilatation and systolic failure in the presence of HTN. Genetics and gender likely play a role in an individual's response to long standing hypertension.

  19. Normalization of cardiac substrate utilization and left ventricular hypertrophy precede functional recovery in heart failure regression.

    Science.gov (United States)

    Byrne, Nikole J; Levasseur, Jody; Sung, Miranda M; Masson, Grant; Boisvenue, Jamie; Young, Martin E; Dyck, Jason R B

    2016-05-15

    Impaired cardiac substrate metabolism plays an important role in heart failure (HF) pathogenesis. Since many of these metabolic changes occur at the transcriptional level of metabolic enzymes, it is possible that this loss of metabolic flexibility is permanent and thus contributes to worsening cardiac function and/or prevents the full regression of HF upon treatment. However, despite the importance of cardiac energetics in HF, it remains unclear whether these metabolic changes can be normalized. In the current study, we investigated whether a reversal of an elevated aortic afterload in mice with severe HF would result in the recovery of cardiac function, substrate metabolism, and transcriptional reprogramming as well as determined the temporal relationship of these changes. Male C57Bl/6 mice were subjected to either Sham or transverse aortic constriction (TAC) surgery to induce HF. After HF development, mice with severe HF (% ejection fraction hypertrophy/HF were returned to values observed in healthy controls. Interestingly, pressure-overload-induced left ventricular hypertrophy (LVH) and cardiac substrate metabolism were restored at 1-week post-DB, which preceded functional recovery. The regression of severe HF is associated with early and dramatic improvements in cardiac energy metabolism and LVH normalization that precede restored cardiac function, suggesting that metabolic and structural improvements may be critical determinants for functional recovery. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

  20. 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

  1. Sphaeranthus indicus attenuates testosterone induced prostatic hypertrophy in albino rats.

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    Nahata, Alok; Dixit, Vinod Kumar

    2011-12-01

    The present study reports the attenuating effect of Sphaeranthus indicus extracts (SI) on prostatic hyperplasia induced by testosterone in albino rats. In vitro studies were conducted to assess the 5α-reductase inhibitory potential of the petroleum ether, ethanolic and aqueous extracts of SI. A biochemical marker, β-sitosterol, was isolated and extracts were characterized utilizing HPTLC. Testosterone (3 mg/kg s.c.) was administered to the rats along with the test extracts and isolated β-sitosterol for a period of 28 days. The weight of the rats, the urine output, serum testosterone concentrations and prostate-specific antigen (PSA) levels were recorded. The prostate/body weight ratio (P/BW) was calculated and histological studies were performed to observe the changes in the histoarchitecture of the prostate. Finasteride was used as a positive control (1 mg/kg p.o.). Sphaeranthus indicus extracts attenuated the increase in the P/BW ratio induced by testosterone in the treated groups. The petroleum ether extract exhibited the best activity, although the ethanol and aqueous extracts also exhibited significant activity. Urine output was also improved significantly, demonstrating the clinical implications of the study. Histological studies, testosterone levels which were measured weekly and PSA levels measured at the end of the study also support claims for the potential use of Sphaeranthus indicus in the treatment of prostatic hyperplasia. Copyright © 2011 John Wiley & Sons, Ltd.

  2. Cellular and molecular basis of RV hypertrophy in congenital heart disease

    Science.gov (United States)

    Iacobazzi, D; Suleiman, M-S; Ghorbel, M; George, SJ; Caputo, M; Tulloh, RM

    2016-01-01

    RV hypertrophy (RVH) is one of the triggers of RV failure in congenital heart disease (CHD). Therefore, improving our understanding of the cellular and molecular basis of this pathology will help in developing strategic therapeutic interventions to enhance patient benefit in the future. This review describes the potential mechanisms that underlie the transition from RVH to RV failure. In particular, it addresses structural and functional remodelling that encompass contractile dysfunction, metabolic changes, shifts in gene expression and extracellular matrix remodelling. Both ischaemic stress and reactive oxygen species production are implicated in triggering these changes and will be discussed. Finally, RV remodelling in response to various CHDs as well as the potential role of biomarkers will be addressed. PMID:26516182

  3. Cellular and molecular basis of RV hypertrophy in congenital heart disease.

    Science.gov (United States)

    Iacobazzi, D; Suleiman, M-S; Ghorbel, M; George, S J; Caputo, M; Tulloh, R M

    2016-01-01

    RV hypertrophy (RVH) is one of the triggers of RV failure in congenital heart disease (CHD). Therefore, improving our understanding of the cellular and molecular basis of this pathology will help in developing strategic therapeutic interventions to enhance patient benefit in the future. This review describes the potential mechanisms that underlie the transition from RVH to RV failure. In particular, it addresses structural and functional remodelling that encompass contractile dysfunction, metabolic changes, shifts in gene expression and extracellular matrix remodelling. Both ischaemic stress and reactive oxygen species production are implicated in triggering these changes and will be discussed. Finally, RV remodelling in response to various CHDs as well as the potential role of biomarkers will be addressed. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

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

    Directory of Open Access Journals (Sweden)

    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

  5. Insight into hypertrophied hearts: a cardiovascular magnetic resonance study of papillary muscle mass and T1 mapping.

    Science.gov (United States)

    Kozor, Rebecca; Nordin, Sabrina; Treibel, Thomas A; Rosmini, Stefania; Castelletti, Silvia; Fontana, Marianna; Captur, Gabriella; Baig, Shanat; Steeds, Richard P; Hughes, Derralynn; Manisty, Charlotte; Grieve, Stuart M; Figtree, Gemma A; Moon, James C

    2017-09-01

    Left ventricular papillary muscles (LVPM) can appear disproportionately hypertrophied, particularly in Fabry disease (FD) where storage appears detectable by cardiovascular magnetic resonance (CMR) T1 mapping. The aim of the study was to measure LVPM mass in heart diseases with left ventricular hypertrophy (LVH) and to gain insight into the mechanisms of LVPM hypertrophy in FD. Four hundred and seventy-eight cases were retrospectively recruited: 125 FD, 85 hypertrophic cardiomyopathy (HCM), 67 amyloid, 82 aortic stenosis (AS), 40 hypertension, 79 controls. LVPM contribution to LVM was manually contoured on CMR short axis cines. T1 values (septal, LVPM) were measured using ShMOLLI sequences in FD and controls. LVPM contribution to LVM was highest in LVH+ve FD and significantly increased compared to all other LVH+ve groups (FD 13 ± 3%, HCM 10 ± 3%, amyloid 8 ± 2%, AS 7 ± 3%, hypertension 7 ± 2%, controls 7 ± 1%; P < 0.001). LVH+ve HCM also had significantly increased LVPM. In LVH-ve cohorts, only FD had significantly increased LVPM (11 ± 3%; P < 0.001). In FD there was concordant septal and LVPM T1. LVH+ve FD: when septal T1 was low, LVPM T1 was low in 90%. LVH-ve FD: when septal T1 was normal, LVPM T1 was normal in 70% (indicating no detectable storage); when septal T1 was low, 75% had low LVPM T1 (indicating storage). LVPM hypertrophy was similar between the low and normal septal T1 groups (11 ± 3% vs. 10 ± 3%, P = 0.08). Disproportionate hypertrophy of LVPMs in LVH+ve hearts occurred in FD and HCM. This phenomenon also occurred in LVH-ve FD. Low T1 was not always present in FD LVPM hypertrophy, implying additional mechanisms activating hypertrophy signalling pathways.

  6. A long non-coding RNA protects the heart from pathological hypertrophy

    Science.gov (United States)

    Han, Pei; Yang, Jin; Shang, Ching; Nuernberg, Sylvia T.; Jin, Kevin Kai; Xu, Weihong; Lin, Chieh-Yu; Lin, Chien-Jung; Xiong, Yiqin; Chien, Huanchieh; Zhou, Bin; Ashley, Euan; Bernstein, Daniel; Chen, Peng-Sheng; Chen, Huei-sheng Vincent; Quertermous, Thomas; Chang, Ching-Pin

    2014-01-01

    Summary The role of long noncoding RNA (lncRNA) in adult hearts is unknown; also unclear is how lncRNA modulates nucleosome remodeling. An estimated 70% of mouse genes undergo antisense transcription1, including myosin heavy chain 7 (Myh7) that encodes molecular motor proteins for heart contraction2. Here, we identify a cluster of lncRNA transcripts from Myh7 loci and show a new lncRNA–chromatin mechanism for heart failure. In mice, these transcripts, which we named Myosin Heavy Chain Associated RNA Transcripts (MyHEART or Mhrt), are cardiac-specific and abundant in adult hearts. Pathological stress activates the Brg1-Hdac-Parp chromatin repressor complex3 to inhibit Mhrt transcription in the heart. Such stress-induced Mhrt repression is essential for cardiomyopathy to develop: restoring Mhrt to the pre-stress level protects the heart from hypertrophy and failure. Mhrt antagonizes the function of Brg1, a chromatin-remodeling factor that is activated by stress to trigger aberrant gene expression and cardiac myopathy3. Mhrt prevents Brg1 from recognizing its genomic DNA targets, thus inhibiting chromatin targeting and gene regulation by Brg1. Mhrt binds to the helicase domain of Brg1, and this domain is crucial for tethering Brg1 to chromatinized DNA targets. Brg1 helicase has dual nucleic acid-binding specificities: it is capable of binding lncRNA (Mhrt) and chromatinized—but not naked—DNA. This dual-binding feature of helicase enables a competitive inhibition mechanism by which Mhrt sequesters Brg1 from its genomic DNA targets to prevent chromatin remodeling. A Mhrt-Brg1 feedback circuit is thus crucial for heart function. Human MHRT also originates from MYH7 loci and is repressed in various types of myopathic hearts, suggesting a conserved lncRNA mechanism in human cardiomyopathy. Our studies identify the first cardioprotective lncRNA, define a new targeting mechanism for ATP-dependent chromatin-remodeling factors, and establish a new paradigm for lnc

  7. 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.

  8. Association of heart failure hospitalizations with combined electrocardiography and echocardiography criteria for left ventricular hypertrophy

    DEFF Research Database (Denmark)

    Gerdts, Eva; Okin, Peter M; Boman, Kurt

    2012-01-01

    The value of performing echocardiography in hypertensive patients with electrocardiographic left ventricular hypertrophy (LVH) is uncertain.......The value of performing echocardiography in hypertensive patients with electrocardiographic left ventricular hypertrophy (LVH) is uncertain....

  9. Salubrinal attenuates right ventricular hypertrophy and dysfunction in hypoxic pulmonary hypertension of rats.

    Science.gov (United States)

    He, Yun-Yun; Liu, Chun-Lei; Li, Xin; Li, Rui-Jun; Wang, Li-Li; He, Kun-Lun

    2016-12-01

    The phosphorylation of eukaryotic translation initiation factor 2 alpha (p-eIF2α) is essential for cell survival during hypoxia. The aim of this study was to investigate whether salubrinal, an inhibitor of p-eIF2α dephosphorylation could attenuate pulmonary arterial hypertension (PAH) and right ventricular (RV) hypertrophy in rats exposed to hypobaric hypoxia. PAH of rats was induced by hypobaric hypoxia. Salubrinal supplemented was randomized in either a prevention or a reversal protocol. At the end of the follow-up point, we measured echocardiography, hemodynamics, hematoxylin-eosin and Masson's trichrome stainings. RNA-seq analysis is explored to identify changes in gene expression associated with hypobaric hypoxia with or without salubrinal. Compared with vehicle-treatment rats exposed to hypobaric hypoxia, salubrinal prevented and partly reversed the increase of the mean pulmonary artery pressure and RV hypertrophy. What's more, salubrinal reduced the percentage wall thickness (WT%) of pulmonary artery and RV collagen volume fraction (CVF) in both prevention and reversal protocols. We also found that salubrinal was capable of reducing endoplasmic reticulum stress and oxidative stress. The result of RNA-seq analysis revealed that chronic hypoxia stimulated the differential expression of a series of genes involved in cell cycle regulation and ventricular hypertrophy and so on. Some of these genes could be ameliorated by salubrinal. These results indicate that salubrinal could prevent and reverse well-established RV remodeling, and restore the genes and pathways altered in the right ventricles of rats exposed to hypobaric hypoxia. Copyright © 2016. Published by Elsevier Inc.

  10. Dual effects of amiodarone on pacemaker currents in hypertrophied ventricular myocytes isolated from spontaneously hypertensive rats.

    Science.gov (United States)

    Li, Hongxia; Zhou, Yafeng; Jiang, Bin; Zhao, Xin; Li, Xun; Yang, Xiangjun; Jiang, Wenping

    2014-09-01

    The pacemaker current If conducted by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels plays a critical role in the regulation of cardiac automaticity, with If density increased in hypertrophied ventricular myocytes. Amiodarone, a highly effective anti-arrhythmic agent, blocks human HCN currents and native If under normal conditions. To determine the effects of amiodarone under pathological conditions, we monitored If under after both acute (0.01, 0.1, 1, 10 and 100 μmol/L) and chronic (10 μmol/L) amiodarone treatment in ventricular myocytes from spontaneously hypertensive rats (SHR) with left ventricular hypertrophy using the whole-cell patch-clamp technique. The If current density was significantly greater in SHR ventricular myocytes than in cells from healthy normotensive control Wistar-Kyoto (WKY) rats. Acute application of amiodarone significantly decreased If density in myocytes from both SHR and WKY rats. The inhibition was concentration dependent with an IC50 of 4.9 ± 1.2 and 6.9 ± 1.3 μmol/L in myocytes from SHR and WKY rats, respectively. Amiodarone increased the activation and deactivation times of If in myocytes from SHR, although it did not alter the relationship of voltage-dependent activation and the reversal potential of If in myocytes from SHR. Chronic exposure of myocytes from SHR to amiodarone potently inhibited If and downregulated HCN2 and HCN4, the major channel subtypes underlying native If , at both the mRNA and protein level. These findings indicate that amiodarone inhibits If under hypertrophied conditions through dual mechanisms: (i) direct channel blockade of If currents; and (ii) indirect suppression via negative regulation of HCN channel gene expression. These unique properties of amiodarone may contribute to its anti-arrhythmic properties under pathological conditions. © 2014 Wiley Publishing Asia Pty Ltd.

  11. [Study on tissue Doppler imaging in diagnosis of right ventricular hypertrophy in patients with silicosis complicated by chronic pulmonary heart disease].

    Science.gov (United States)

    Chen, Gongquan

    2014-12-01

    To investigate the value of tissue Doppler imaging (TDI) in the diagnosis of right ventricular hypertrophy in patients with silicosis complicated by chronic pulmonary heart disease. A total of 50 cases of silicosis complicated by chronic pulmonary heart disease in our hospital underwent conventional electrocardiography (ECG) and TDI. The detection rates for right ventricular hypertrophy by two methods were compared. Of 50 cases of silicosis complicated by chronic pulmonary heart disease, 19 were diagnosed with right ventricular hypertrophy by ECG, with a detection rate of 38.0%; 29 were diagnosed with right ventricular hypertrophy by TDI, with a detection rate off 58.0%. Statistical analysis suggested that TDI leads to a significantly higher detection rate for right ventricular hypertrophy in patients with silicosis complicated by chronic pulmonary heart disease (χ² = 4.006, P = 0.036). Both TDI and ECG can be used for detecting right ventricular hypertrophy in patients with silicosis complicated by chronic pulmonary heart disease, but the detection rate is higher when TDI is employed. In addition, ECG cannot directly reflect the increase in pulmonary artery pressure. Therefore, TDI is more suitable for the diagnosis of right ventricular hypertrophy in patients with silicosis complicated by chronic pulmonary heart disease and provides a strong diagnostic basis for the clinical treatment of silicosis complicated by pulmonary heart disease.

  12. Construction of the Database of Rat Repeated-dose Toxicity Tests of Pesticides for the Toxicological Characterization of Hepatocyte Hypertrophy.

    Science.gov (United States)

    Masuda, Akane; Masuda, Miyabi; Kawano, Takuya; Kitsunai, Yoko; Nakayama, Haruka; Nakajima, Hiroyuki; Kojima, Hiroyuki; Kitamura, Shigeyuki; Uramaru, Naoto; Hosaka, Takuomi; Sasaki, Takamitsu; Yoshinari, Kouichi

    2017-01-01

    Liver and hepatocyte hypertrophy can be induced by exposure to chemical compounds, but the mechanisms and toxicological characteristics of these phenomena have not yet been investigated extensively. In particular, it remains unclear whether the hepatocyte hypertrophy induced by chemical compounds should be judged as an adaptive response or an adverse effect. Thus, understanding of the toxicological characteristics of hepatocyte hypertrophy is of great importance to the safety evaluation of pesticides and other chemical compounds. To this end, we have constructed a database of potentially toxic pesticides. Using risk assessment reports of pesticides that are publicly available from the Food Safety Commission of Japan, we extracted all observations/findings that were based on 90-day subacute toxicity tests and 2-year chronic toxicity and carcinogenicity tests in rats. Analysis of the database revealed that hepatocyte hypertrophy was observed for 37-47% of the pesticides investigated (varying depending on sex and testing period), and that centrilobular hepatocyte hypertrophy was the most frequent among the various types of hepatocyte hypertrophy in both the 90-day and 2-year studies. The database constructed in this study enables us to investigate the relationships between hepatocyte hypertrophy and other toxicological observations/findings, and thus will be useful for characterizing hepatocyte hypertrophy.

  13. MiR-139-3p is related to left ventricular hypertrophy and cardiomyocyte apoptosis in two-kidney one-clip hypertensive rats

    Directory of Open Access Journals (Sweden)

    Yang Xiaomin

    2015-01-01

    Full Text Available MicroRNAs (miRNAs are important post-transcriptional regulators of gene expression in many physiological and pathological processes. Previous studies have reported the role of miR-139-3p in cancer. However, its specific roles and functions in the heart undergoing hypertrophy have yet to be fully elucidated. In the present study, a significant upregulation of miR-139-3p expression was demonstrated in the left ventricular myocardium of two-kidney one-clip (2K1C hypertensive rats using microarray and quantitative real-time PCR (qRT-PCR. Based on computational analysis, we observed that miR-139-3p can control the expression of mitogen-activated protein kinase 1 (MAPK1 as a target gene, which is essential for the induction of cardiac hypertrophy and cardiomyocyte apoptosis. This study provides first information that the highly expressed miR-139-3p might be closely involved in MAPK1-mediated cardiac hypertrophy and cardiomyocyte apoptotic processes in 2K1C rat.

  14. Myocardial glucose metabolism is different between hypertrophic cardiomyopathy and hypertensive heart disease associated with asymmetrical septal hypertrophy

    Energy Technology Data Exchange (ETDEWEB)

    Shiba, Nobuyuki; Kagaya, Yutaka; Ishide, Nobumasa; Takeyama, Daiya; Yamane, Yuriko; Chida, Masanobu; Otani, Hiroki; Shirato, Kunio [Tohoku Univ., Sendai (Japan). School of Medicine; Ido, Tatsuo

    1997-06-01

    Myocardial glucose metabolism has been shown to be heterogeneous in patients with hypertrophic cardiomyopathy (HCM). We tested the hypothesis that myocardial glucose metabolism differs between patients with HCM and those with hypertensive heart disease (HHD) associated with asymmetrical septal hypertrophy. We studied 12 patients with HCM, 7 HHD patients associated with asymmetrical septal hypertrophy using {sup 18}F 2-deoxyglucose (FDG) and positron emission tomography. We calculated % FDG fractional uptake in the interventricular septum and posterolateral wall. Heterogeneity of FDG uptake was evaluated by % interregional coefficient of variation of FDG fractional uptake in each wall segment. In both the interventricular septum and posterolateral wall, % FDG fractional uptake was not significantly different between the two groups. The % interregional coefficient of variation for both interventricular septum (10.6{+-}1.6 vs. 4.1{+-}0.5, p<0.01) and posterolateral wall (5.9{+-}0.7 vs. 3.8{+-}0.5, p< 0.05) was significantly larger in patients with HCM than in HHD patients associated with asymmetrical septal hypertrophy. Echocardiography demonstrated that the degree of asymmetrical septal hypertrophy was similar between the two groups. These results suggest that myocardial glucose metabolism may be more heterogeneous in patients with HCM compared to HHD patients associated with asymmetrical septal hypertrophy, although the left ventricular shape is similar. The difference in the heterogeneity might have resulted from differences in the pathogeneses of the two diseases. (author)

  15. Myocardial reverse remodeling after pressure unloading is associated with maintained cardiac mechanoenergetics in a rat model of left ventricular hypertrophy.

    Science.gov (United States)

    Ruppert, Mihály; Korkmaz-Icöz, Sevil; Li, Shiliang; Németh, Balázs Tamás; Hegedűs, Péter; Brlecic, Paige; Mátyás, Csaba; Zorn, Markus; Merkely, Béla; Karck, Matthias; Radovits, Tamás; Szabó, Gábor

    2016-09-01

    Pressure unloading represents the only effective therapy in increased afterload-induced left ventricular hypertrophy (LVH) as it leads to myocardial reverse remodeling (reduction of increased left ventricular mass, attenuated myocardial fibrosis) and preserved cardiac function. However, the effect of myocardial reverse remodeling on cardiac mechanoenergetics has not been elucidated. Therefore, we aimed to provide a detailed hemodynamic characterization in a rat model of LVH undergoing pressure unloading. Pressure overload was induced in Sprague-Dawley rats by abdominal aortic banding for 6 (AB 6th wk) or 12 wk (AB 12th wk). Sham-operated animals served as controls. Aortic debanding procedure was performed after the 6th experimental week (debanded 12th wk) to investigate the regression of LVH. Pressure unloading resulted in significant reduction of LVH (heart weight-to-tibial length ratio: 0.38 ± 0.01 vs. 0.58 ± 0.02 g/mm, cardiomyocyte diameter: 18.3 ± 0.1 vs. 24.1 ± 0.8 μm debanded 12th wk vs. AB 12th wk, P cardiac mechanoenergetics. Copyright © 2016 the American Physiological Society.

  16. Association of left ventricular dilatation and hypertrophy with chronotropic incompetence in the Framingham Heart Study.

    Science.gov (United States)

    Lauer, M S; Larson, M G; Evans, J C; Levy, D

    1999-05-01

    Chronotropic incompetence and left ventricular (LV) dilatation have both been shown to be markers of an adverse cardiovascular prognosis. Chronotropic incompetence has been described in patients with symptomatic LV dilatation and dysfunction, but the effect of asymptomatic LV dilatation and hypertrophy on exercise heart rate response has not been well characterized. Members of the Framingham Offspring Study underwent M-mode echocardiography and graded exercise testing as part of a routine evaluation. Subjects receiving beta-blockers and digitalis and subjects with preexisting coronary heart disease, heart failure, and baseline ST-segment abnormalities were excluded. Chronotropic incompetence was assessed in 2 ways: (1) failure to achieve an age--predicted target heart rate and (2) a low chronotropic index, a measure of heart rate response that takes into account effects of age, resting heart rate, and physical fitness. Echocardiographic variables studied included LV diastolic and systolic dimensions, LV wall thickness, LV mass, and fractional shortening. There were 1414 men and 1601 women eligible for analyses; failure to reach target heart rate occurred in 20% of men and 23% of women; a low chronotropic index was noted in 14% of men and 12% of women. In unadjusted categorical analyses, an abnormally high LV mass, as defined by exceeding the 90th percentile predicted value of a healthy reference group, was associated with failure to achieve target heart rate in men (31% vs 18%, odds ratio [OR] 2.05, 95% confidence interval [CI] 1.49 to 2.83) and women (34% vs 20%, OR 2.09, 95% CI 1.63 to 2.69). Similarly, an abnormally high LV mass was predictive of a low chronotropic index in men (18% vs 13%, OR 1. 47, 95% CI 1.01 to 2.14) and women (17% vs 10%, OR 1.78, 95% CI 1.29 to 2.45). When considered as a continuous variable, LV diastolic dimension predicted failure to achieve target heart rate in men (ageadjusted OR for 1 SD increase 1.30, 95% CI 1.00 to 1.33) and in

  17. Respiratory Muscle Training Improves Diaphragm Citrate Synthase Activity and Hemodynamic Function in Rats with Heart Failure.

    Science.gov (United States)

    Jaenisch, Rodrigo Boemo; Bertagnolli, Mariane; Borghi-Silva, Audrey; Arena, Ross; Lago, Pedro Dal

    2017-01-01

    Enhanced respiratory muscle strength in patients with heart failure positively alters the clinical trajectory of heart failure. In an experimental model, respiratory muscle training in rats with heart failure has been shown to improve cardiopulmonary function through mechanisms yet to be entirely elucidated. The present report aimed to evaluate the respiratory muscle training effects in diaphragm citrate synthase activity and hemodynamic function in rats with heart failure. Wistar rats were divided into four experimental groups: sedentary sham (Sed-Sham, n=8), trained sham (RMT-Sham, n=8), sedentary heart failure (Sed-HF, n=7) and trained heart failure (RMT-HF, n=7). The animals were submitted to a RMT protocol performed 30 minutes a day, 5 days/week, for 6 weeks. In rats with heart failure, respiratory muscle training decreased pulmonary congestion and right ventricular hypertrophy. Deleterious alterations in left ventricular pressures, as well as left ventricular contractility and relaxation, were assuaged by respiratory muscle training in heart failure rats. Citrate synthase activity, which was significantly reduced in heart failure rats, was preserved by respiratory muscle training. Additionally, a negative correlation was found between citrate synthase and left ventricular end diastolic pressure and positive correlation was found between citrate synthase and left ventricular systolic pressure. Respiratory muscle training produces beneficial adaptations in the diaphragmatic musculature, which is linked to improvements in left ventricular hemodynamics and blood pressure in heart failure rats. The RMT-induced improvements in cardiac architecture and the oxidative capacity of the diaphragm may improve the clinical trajectory of patients with heart failure.

  18. The urinary bladder of spontaneously hypertensive rat demonstrates bladder hypertrophy, inflammation, and fibrosis but not hyperplasia.

    Science.gov (United States)

    Shen, Shanwei; Xia, Chun-Mei; Qiao, Li-Ya

    2015-01-15

    The present study aims to systemically characterize the factors that are associated with urinary bladder organ enlargement in spontaneously hypertensive rats (SHR). We compared the SHR to age-matched normotensive Wistar-Kyoto (WKY) control rats in the levels of bladder pro-inflammatory factors, collagen expression (type I), and detrusor smooth muscle growth. Our results showed that enhanced inflammatory responses and fibrosis were key factors that were closely associated with bladder wall thickening in SHR. Specifically the mRNA levels of inflammatory factors interleukin (IL)-1α, IL-6 and TNFα were significantly higher in SHR than those in WKY rats. The SHR also had a higher number of mast cells in the suburothelium space. Type I collagen production was also significantly higher in SHR when compared to that in control rats. However, the smooth muscle content stayed the same in SHR and WKY rats. This was shown by the results that the ratio of α-smooth muscle actin (SMA) to the nuclear protein histone H3 had no difference between these two rat strains. The mRNA and protein levels of proliferating cell nuclear antigen (PCNA) also showed no change in the urinary bladder of SHR and WKY rats. Further study showed that the phosphorylation level of Akt in the urinary bladder was not changed in SHR when compared to WKY rats. In contrast, the phosphorylation level of ERK1/2 was significantly higher in SHR bladder when compared to that of WKY rats. These results suggest that inflammation and fibrosis are primary factors that may lead to urinary bladder hypertrophy in SHR. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Metabolic adaptations of skeletal muscle to voluntary wheel running exercise in hypertensive heart failure rats

    DEFF Research Database (Denmark)

    Schultz, R L; Kullman, E L; Waters, Ryan

    2013-01-01

    The Spontaneously Hypertensive Heart Failure (SHHF) rat mimics the human progression of hypertension from hypertrophy to heart failure. However, it is unknown whether SHHF animals can exercise at sufficient levels to observe beneficial biochemical adaptations in skeletal muscle. Thirty-seven female...... and expression, and glycogen utilization. The SHHFex rats ran a greater distance and duration as compared to the WFex rats (PSkeletal muscle citrate synthase and beta-hydroxyacyl-CoA dehydrogenase enzyme activity was not altered in the SHHFex group...... robust amounts of aerobic activity, voluntary wheel running exercise was not sufficiently intense to improve the oxidative capacity of skeletal muscle in adult SHHF animals, indicating an inability to compensate for declining heart function by improving peripheral oxidative adaptations in the skeletal...

  20. Hydroxysafflor yellow A (HSYA) attenuates hypoxic pulmonary arterial remodelling and reverses right ventricular hypertrophy in rats.

    Science.gov (United States)

    Li, Lei; Dong, Pengda; Hou, Congjia; Cao, Fangyuan; Sun, Shouli; He, Fa; Song, Yanping; Li, Sen; Bai, Yuhua; Zhu, Daling

    2016-06-20

    Carthamus tinctorius L. is a traditional herbal medicine native to China with properties of promoting blood circulation and removing blood stasis, which is used for the treatment of cerebrovascular and cardiovascular diseases. Hydroxysafflor yellow A (HSYA) is the main constituent isolated from the flower of Carthamus tinctorius L. which is used as a marker substance in the quality control of Carthamus tinctorius L. in Chinese Pharmacopeia. This study is to investigate the hypertension attenuating effect of HSYA on hypoxia-induced pulmonary artery hypertension model rats, and the possible mechanism. The animal models were made by treating adult male Wistar rats (of the same age with the same weight of 200±25g) under hypoxia 24h per day for 9 days with or without administration of HSYA. The pulmonary arterial pressure of rats was measured after anesthetization; The right ventricular hypotrophy was evaluated by the right ventricular hypotrophy index (RVHI=[RV/(LV+S)]) as well as histomorphology assay with Hematoxylin and Eosin (HE) staining; The reducing of pulmonary artery remodelling was evaluated by histomorphology assay with HE staining; The proliferation of pulmonary artery smooth muscle cells (PASMCs) was evaluated by immunohistochemistry assays (PCNA and Ki67) and MTT assay. Cell cycle analysis and Weston-blot analysis were also performed in the study. HSYA reduced the mean right ventricular systolic pressure (RVSP) of rats with hypoxic pulmonary arterial hypertension (HPH) in a manner of concentration dependency. It significantly inhibited the PASMCs proliferation and attenuated the remodelling of the pulmonary artery and right ventricular hypertrophy. These findings suggested that HSYA protected against hypoxic induced pulmonary hypertension by reversing the remodelling of the pulmonary artery through inhibiting the proliferation and hypertrophy of PASMCs. This is in accordance with our previous finding that HSYA protects against the pulmonary artery

  1. Sex-dependent alterations of Ca2+ cycling in human cardiac hypertrophy and heart failure.

    Science.gov (United States)

    Fischer, Thomas H; Herting, Jonas; Eiringhaus, Jörg; Pabel, Steffen; Hartmann, Nico H; Ellenberger, David; Friedrich, Martin; Renner, André; Gummert, Jan; Maier, Lars S; Zabel, Markus; Hasenfuss, Gerd; Sossalla, Samuel

    2016-09-01

    Clinical studies have shown differences in the propensity for malignant ventricular arrhythmias between women and men suffering from cardiomyopathies and heart failure (HF). This is clinically relevant as it impacts therapies like prophylactic implantable cardioverter-defibrillator implantation but the pathomechanisms are unknown. As an increased sarcoplasmic reticulum (SR) Ca(2+) leak is arrhythmogenic, it could represent a cellular basis for this paradox. We evaluated the SR Ca(2+) leak with respect to sex differences in (i) afterload-induced cardiac hypertrophy (Hy) with preserved left ventricular (LV) function and (ii) end-stage HF. Cardiac function did not differ between sexes in both cardiac pathologies. Human cardiomyocytes isolated from female patients with Hy showed a significantly lower Ca(2+) spark frequency (CaSpF, confocal microscopy, Fluo3-AM) compared with men (P cardiac impairment. Since the SR Ca(2+) leak triggers delayed afterdepolarizations, our findings may explain why women are less prone to ventricular arrhythmias and confirm the rationale of therapeutic measures reducing the SR Ca(2+) leak. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

  2. [Importance of hypertensive left ventricular hypertrophy in patients with ischemic events of the heart or brain].

    Science.gov (United States)

    Castilla-Guerra, L; Fernández-Moreno, M C; Aguilera-Saborido, A; Solanella-Soler, J

    2016-01-01

    Hypertensive left ventricular hypertrophy (H-LVH) is a potentially modifiable vascular risk factor (VRF) often overlooked in clinical practice. We aimed to evaluate the frequency of H-LVH in patients with coronary heart disease (CHD) or ischemic stroke (IS). We retrospectively assessed all the echocardiography studies of patients admitted with the diagnosis CHD or IS over a 4-year period. We studied 533 patients, 330 with CHD and 203 with IS. Mean age was 69 (±11) years, 61.5% males. Hypertension was the most common RF: 362 patients (67.9%) (CHD vs. IS: 70 vs. 64.5%; P=NS). H-LVH was seen in 234 patients (43.9%) (CHD vs. IS: 44.8 vs. 42.3%; P=NS). Patients with H-LVH were older and received a greater number of antihypertensive drugs at discharge. Half of patients with hypertension presented H-LVH (184 patients; 50.8%), with similar frequency in both groups (CHD vs. IS: 50.6 vs. 51.1%; P=NS). Neither patients' characteristics nor VRF with the exception of hypertension (P=.0001) were associated with H-LVH. H-LVH is a major VRF in patients with ischemic events in the heart and brain. Nearly half the patients present H-LVH, with a similar frequency in both groups. It is important to identify H-LVH in these patients to optimize treatment and improve long-term prognosis. Copyright © 2015 SEHLELHA. Published by Elsevier España, S.L.U. All rights reserved.

  3. Effect of carvedilol on pulse pressure and left ventricular hypertrophy in spontaneously hypertensive rats with adriamycin nephropathy.

    Science.gov (United States)

    Jovanovic, Dijana; Jovovic, Djurdjica; Mihailovic-Stanojevic, Nevena; Miloradovic, Zoran; Naumovic, Radomir; Dimitrijevic, Jovan; Maksic, Nebojsa; Djukanovic, Ljubica

    2009-09-01

    Recent studies indicated pulse pressure as a risk factor for left ventricular hypertrophy, myocardial infarction, congestive heart failure and stroke as well as chronic renal failure progression. The present study examined the effects of carvedilol and its combination with captopril on blood pressure, left ventricular hypertrophy, kidney vascular changes and kidney function in spontaneously hypertensive rats with adriamycin nephropathy. Four groups of 20 SHR each were involved: (1) control group: SHR; (2) ADR group: SHR treated with ADR (2mg/kg i.v. twice in 20 days); (3) ADR-C group: SHR treated with ADR and carvedilol (30 mg/kg/day) and (4) ADR-CC group: SHR treated with ADR and carvedilol (30 mg/kg/day) and captopril (60 mg/kg/day). Systolic-, diastolic- and mean-pressures and pulse pressure were determined at weeks 6 and 12 after the second ADR injection; and body weight, creatinine clearance and proteinuria at weeks -3, 6 and 12. The rats were sacrificed at week 6 or 12, the weights of the left and right ventricles and kidneys measured and the kidney vascular index was calculated as described by Bader and Mayer. Both carvedilol alone and combined with captopril significantly reduced systemic blood pressure but the effect of the latter was more pronounced and registered from week 4 till the end of the study. Carvedilol and its combination with captopril significantly decreased SBP, DBP and MAP. They also decreased PP, prevented the development of LVH, and renal vascular changes and slowed the progression of chronic renal failure and these effects were stronger in the ADR-CC group than in the ADR-C group. The antihypertensive drugs failed to prevent proteinuria in ADR SHR. Significant positive correlations were found between PP (but not SBP, DBP and MAP) and both proteinuria and Ccr in all groups of rats. In conclusion, carvedilol alone, but more strongly in combination with captopril, significantly reduced blood pressure, PP, LVH, renal blood vessel changes and

  4. Cellular Hypertrophy and Increased Susceptibility to Spontaneous Calcium-Release of Rat Left Atrial Myocytes Due to Elevated Afterload.

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    Haifei Zhang

    Full Text Available Atrial remodeling due to elevated arterial pressure predisposes the heart to atrial fibrillation (AF. Although abnormal sarcoplasmic reticulum (SR function has been associated with AF, there is little information on the effects of elevated afterload on atrial Ca2+-handling. We investigated the effects of ascending aortic banding (AoB on Ca2+-handling in rat isolated atrial myocytes in comparison to age-matched sham-operated animals (Sham. Myocytes were either labelled for ryanodine receptor (RyR or loaded with fluo-3-AM and imaged by confocal microscopy. AoB myocytes were hypertrophied in comparison to Sham controls (P<0.0001. RyR labeling was localized to the z-lines and to the cell edge. There were no differences between AoB and Sham in the intensity or pattern of RyR-staining. In both AoB and Sham, electrical stimulation evoked robust SR Ca2+-release at the cell edge whereas Ca2+ transients at the cell center were much smaller. Western blotting showed a decreased L-type Ca channel expression but no significant changes in RyR or RyR phosphorylation or in expression of Na+/Ca2+ exchanger, SR Ca2+ ATPase or phospholamban. Mathematical modeling indicated that [Ca2+]i transients at the cell center were accounted for by simple centripetal diffusion of Ca2+ released at the cell edge. In contrast, caffeine (10 mM induced Ca2+ release was uniform across the cell. The caffeine-induced transient was smaller in AoB than in Sham, suggesting a reduced SR Ca2+-load in hypertrophied cells. There were no significant differences between AoB and Sham cells in the rate of Ca2+ extrusion during recovery of electrically-stimulated or caffeine-induced transients. The incidence and frequency of spontaneous Ca2+-transients following rapid-pacing (4 Hz was greater in AoB than in Sham myocytes. In conclusion, elevated afterload causes cellular hypertrophy and remodeling of atrial SR Ca2+-release.

  5. Cardiomyocyte-specific ablation of CD36 accelerates the progression from compensated cardiac hypertrophy to heart failure.

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    Sung, Miranda M; Byrne, Nikole J; Kim, Ty T; Levasseur, Jody; Masson, Grant; Boisvenue, Jamie J; Febbraio, Maria; Dyck, Jason R B

    2017-03-01

    Previous studies have shown that loss of CD36 protects the heart from dysfunction induced by pressure overload in the presence of diet-induced insulin resistance and/or obesity. The beneficial effects of CD36 ablation in this context are mediated by preventing excessive cardiac fatty acid (FA) entry and reducing lipotoxic injury. However, whether or not the loss of CD36 can prevent pressure overload-induced cardiac dysfunction in the absence of chronic exposure to high circulating FAs is presently unknown. To address this, we utilized a tamoxifen-inducible cardiomyocyte-specific CD36 knockout (icCD36KO) mouse and genetically deleted CD36 in adulthood. Control mice (CD36 floxed/floxed mice) and icCD36KO mice were treated with tamoxifen and subsequently subjected to transverse aortic constriction (TAC) surgery to generate pressure overload-induced cardiac hypertrophy. Consistent with CD36 mediating a significant proportion of FA entry into the cardiomyocyte and subsequent FA utilization for ATP production, hearts from icCD36KO mice were metabolically inefficient and displayed signs of energetic stress, including activation of the energetic stress kinase, AMPK. In addition, impaired energetics in icCD36KO mice contributed to a rapid progression from compensated hypertrophy to heart failure. However, icCD36KO mice fed a medium-chain FA diet, whereby medium-chain FAs can enter into the cardiomyocyte independent from CD36, were protected from TAC-induced heart failure. Together these data suggest that limiting FA uptake and partial inhibition of FA oxidation in the heart via CD36 ablation may be detrimental for the compensated hypertrophic heart in the absence of sufficiently elevated circulating FAs to provide an adequate energy source. NEW & NOTEWORTHY Limiting CD36-mediated fatty acid uptake in the setting of obesity and/or insulin resistance protects the heart from cardiac hypertrophy and dysfunction. However, cardiomyocyte-specific CD36 ablation in the absence of

  6. Preservation of Myocardial Perfusion and Function by Keeping Hypertrophied Heart Empty and Beating for Valve Surgery: An In Vivo MR Study of Pig Hearts.

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    Wang, Jian; Xiang, Bo; Deng, Jixian; Lin, Hung-Yu; Freed, Darren H; Arora, Rakesh C; Tian, Ganghong

    2017-01-01

    Objectives . Normothermic hyperkalemic cardioplegia arrest (NHCA) may not effectively preserve hypertrophied myocardium during open-heart surgery. Normothermic normokalemic beating perfusion (NNBP), keeping hearts empty-beating, was utilized as an alternative to evaluate its cardioprotective role. Materials and Methods . Twelve hypertrophied pig hearts at 58.6 ± 7.2 days after ascending aorta banding underwent NNBP and NHCA, respectively. Near infrared myocardial perfusion imaging with indocyanine green (ICG) was conducted to assess myocardial perfusion. Left ventricular (LV) contractile function was assessed by cine MRI. TUNEL staining and western blotting for caspase-3 cleavage and cardiac troponin I (cTnI) degradation were conducted in LV tissue samples. Results . Ascending aortic diameter was reduced by 52.7% ± 0.4% at approximately fifty-eight days after banding. LV wall thickness was significantly higher in aorta banding than in sham operation. Myocardial blood flow reflected by maximum ICG absorbance value was markedly higher in NNBP than in NHCA. The amount of apoptotic cardiomyocyte was significantly lower in NNBP than in NHCA. NNBP alleviated caspase-3 cleavage and cTnI degradation associated with NHCA. NNBP displayed a substantially increased postoperative ejection fraction relative to NHCA. Conclusions . NNBP was better than NHCA in enhancing myocardial perfusion, inhibiting cardiomyocyte apoptosis, and preserving LV contractile function for hypertrophied hearts.

  7. Hypertrophic response of the Association of Thyroid Hormone and Exercise in the Heart of Rats

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    Souza, Fernanda Rodrigues de, E-mail: nandaeduca@yahoo.com.br; Resende, Elmiro Santos; Lopes, Leandro; Gonçalves, Alexandre; Chagas, Rafaella; Fidale, Thiago; Rodrigues, Poliana [UFU - Universidade Federal de Uberlândia, Uberlândia, MG (Brazil)

    2014-02-15

    Cardiac hypertrophy is a component of cardiac remodeling occurring in response to an increase of the activity or functional overload of the heart. Assess hypertrophic response of the association of thyroid hormone and exercise in the rat heart. We used 37 Wistar rats, male, adults were randomly divided into four groups: control, hormone (TH), exercise (E), thyroid hormone and exercise (H + E); the group received daily hormone levothyroxine sodium by gavage at a dose of 20 μg thyroid hormone/100g body weight, the exercise group took swimming five times a week, with additional weight corresponding to 20% of body weight for six weeks; in group H + E were applied simultaneously TH treatment groups and E. The statistics used was analysis of variance, where appropriate, by Tukey test and Pearson correlation test. The T4 was greater in groups TH and H + E. The total weight of the heart was greater in patients who received thyroid hormone and left ventricular weight was greater in the TH group. The transverse diameter of cardiomyocytes increased in groups TH, E and H + E. The percentage of collagen was greater in groups E and H + E Correlation analysis between variables showed distinct responses. The association of thyroid hormone with high-intensity exercise produced cardiac hypertrophy, and generated a standard hypertrophy not directly correlated to the degree of fibrosis.

  8. Extracellular high-mobility group box 1 mediates pressure overload-induced cardiac hypertrophy and heart failure.

    Science.gov (United States)

    Zhang, Lei; Liu, Ming; Jiang, Hong; Yu, Ying; Yu, Peng; Tong, Rui; Wu, Jian; Zhang, Shuning; Yao, Kang; Zou, Yunzeng; Ge, Junbo

    2016-03-01

    Inflammation plays a key role in pressure overload-induced cardiac hypertrophy and heart failure, but the mechanisms have not been fully elucidated. High-mobility group box 1 (HMGB1), which is increased in myocardium under pressure overload, may be involved in pressure overload-induced cardiac injury. The objectives of this study are to determine the role of HMGB1 in cardiac hypertrophy and cardiac dysfunction under pressure overload. Pressure overload was imposed on the heart of male wild-type mice by transverse aortic constriction (TAC), while recombinant HMGB1, HMGB1 box A (a competitive antagonist of HMGB1) or PBS was injected into the LV wall. Moreover, cardiac myocytes were cultured and given sustained mechanical stress. Transthoracic echocardiography was performed after the operation and sections for histological analyses were generated from paraffin-embedded hearts. Relevant proteins and genes were detected. Cardiac HMGB1 expression was increased after TAC, which was accompanied by its translocation from nucleus to both cytoplasm and intercellular space. Exogenous HMGB1 aggravated TAC-induced cardiac hypertrophy and cardiac dysfunction, as demonstrated by echocardiographic analyses, histological analyses and foetal cardiac genes detection. Nevertheless, the aforementioned pathological change induced by TAC could partially be reversed by HMGB1 inhibition. Consistent with the in vivo observations, mechanical stress evoked the release and synthesis of HMGB1 in cultured cardiac myocytes. This study indicates that the activated and up-regulated HMGB1 in myocardium, which might partially be derived from cardiac myocytes under pressure overload, may be of crucial importance in pressure overload-induced cardiac hypertrophy and cardiac dysfunction. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  9. Cardiac Stim1 Silencing Impairs Adaptive Hypertrophy and Promotes Heart Failure Through Inactivation of mTORC2/Akt Signaling.

    Science.gov (United States)

    Bénard, Ludovic; Oh, Jae Gyun; Cacheux, Marine; Lee, Ahyoung; Nonnenmacher, Mathieu; Matasic, Daniel S; Kohlbrenner, Erik; Kho, Changwon; Pavoine, Catherine; Hajjar, Roger J; Hulot, Jean-Sébastien

    2016-04-12

    Stromal interaction molecule 1 (STIM1) is a dynamic calcium signal transducer implicated in hypertrophic growth of cardiomyocytes. STIM1 is thought to act as an initiator of cardiac hypertrophic response at the level of the sarcolemma, but the pathways underpinning this effect have not been examined. To determine the mechanistic role of STIM1 in cardiac hypertrophy and during the transition to heart failure, we manipulated STIM1 expression in mice cardiomyocytes by using in vivo gene delivery of specific short hairpin RNAs. In 3 different models, we found that Stim1 silencing prevents the development of pressure overload-induced hypertrophy but also reverses preestablished cardiac hypertrophy. Reduction in STIM1 expression promoted a rapid transition to heart failure. We further showed that Stim1 silencing resulted in enhanced activity of the antihypertrophic and proapoptotic GSK-3β molecule. Pharmacological inhibition of glycogen synthase kinase-3 was sufficient to reverse the cardiac phenotype observed after Stim1 silencing. At the level of ventricular myocytes, Stim1 silencing or inhibition abrogated the capacity for phosphorylation of Akt(S473), a hydrophobic motif of Akt that is directly phosphorylated by mTOR complex 2. We found that Stim1 silencing directly impaired mTOR complex 2 kinase activity, which was supported by a direct interaction between STIM1 and Rictor, a specific component of mTOR complex 2. These data support a model whereby STIM1 is critical to deactivate a key negative regulator of cardiac hypertrophy. In cardiomyocytes, STIM1 acts by tuning Akt kinase activity through activation of mTOR complex 2, which further results in repression of GSK-3β activity. © 2016 American Heart Association, Inc.

  10. Antioxidant and cardioprotective effects of Danshensu (3-(3, 4-dihydroxyphenyl)-2-hydroxy-propanoic acid from Salvia miltiorrhiza) on isoproterenol-induced myocardial hypertrophy in rats.

    Science.gov (United States)

    Tang, Yiqun; Wang, Minhui; Le, Xiaoyong; Meng, Jianing; Huang, Lu; Yu, Peng; Chen, Jia; Wu, Ping

    2011-09-15

    Myocardial hypertrophy has been linked to the development of a variety of cardiovascular diseases, and is a risk factor for myocardial ischemia, arrhythmias, and sudden cardiac death. The objective of the present study was to evaluate the cardioprotective effects of Danshensu (DSS), a water-soluble active component of Danshen, on cardiac hypertrophy in rats. We are the first to report that DSS reversed Cx43 down-regulation in ventricular tissue. Cardiomyopathy in rats was produced using isoproterenol (Iso) treatment (2.5 mg/kg/d, s.c.) for seven days. DSS (3 and 10 mg/kg/d, i.p.) and Valsartan (Val) (10 mg/kg, i.g.) were administered on days 4-7 of Iso-treatment. Heart weight index, hemodynamic parameters, and ECG II parameters were monitored and recorded; protein expression of left ventricular connexin 43 (Cx43) and the activity of the redox system were assayed, and arrhythmias were produced using a coronary ligation/reperfusion procedure. The results demonstrated that DSS treatment significantly decreased heart weight/body weight (HW/BW) and left ventricular weight/body weight (LVW/BW) ratios. The protective role of DSS against Iso-induced myocardial hypertrophy was further confirmed using ECG. The incidences of ventricular tachycardia and ventricular fibrillation (VT, VF) and arrhythmic scores were higher in the model group and were suppressed by DSS. DSS decreased the serum and myocardium levels of creatine kinase, lactate dehydrogenase, and malondialdehyde (CK, LDH, and MDA) and increased serum activity of superoxide dismutase (SOD) in a dose-dependent manner. Cx43 expression in the left ventricle was down-regulated, and there was significant oxidative stress in this model of cardiomyopathy. DSS reversed the down-regulated Cx43 protein levels and showed potent anti-oxidative activities and cellular protection. These data demonstrate that DSS can prevent cardiac I/R injury and improve cardiac function in a rat model of hypertrophy, the effects partially

  11. High fat diet aggravates atrial and ventricular remodeling of hypertensive heart disease in aging rats.

    Science.gov (United States)

    Shiou, Yi-Lin; Huang, I-Chieh; Lin, Hsin-Ting; Lee, Hsiang-Chun

    2017-09-06

    Left ventricular hypertrophy is a major cause of heart failure in aging population. This study is to determine whether an excess dietary fat is lipotoxic or lipoprotein to the hypertrophic aging heart. At 44-week-old, a normal chow (12% fat) was replaced a high-fat diet (HFD; 45% fat) for randomly selective spontaneously hypertensive rats (SHR + HFD, n = 6) and Wistar-Kyoto rats (WKY + HFD, n = 6, normotensive control). Others (SHR, n = 11; WKY, n = 10) were continuously fed with normal diets. After 27 weeks, electrocardiogram, echocardiography, and femoral arterial catheterization were performed before rats being sacrificed for molecular biology analyses. HFD aggravated cardiac atrial, ventricular dilation and hypertrophy in SHR (LV mass: SHR + HFD 2026.0 ± 424.9 vs SHR 1449 ± 461.1 mg, unpaired t test P heart disease in aging rats was aggravated by HFD with worse atrial, ventricular remodeling and associated with left ventricular systolic function impairment. Copyright © 2017. Published by Elsevier B.V.

  12. Respiratory Muscle Training Improves Chemoreflex Response, Heart Rate Variability, and Respiratory Mechanics in Rats With Heart Failure.

    Science.gov (United States)

    Jaenisch, Rodrigo B; Quagliotto, Edson; Chechi, Chalyne; Calegari, Leonardo; Dos Santos, Fernando; Borghi-Silva, Audrey; Dal Lago, Pedro

    2017-04-01

    The aim of the present report was to evaluate respiratory muscle training (RMT) effects on hemodynamic function, chemoreflex response, heart rate variability, and respiratory mechanics in rats with heart failure (HF rats). Wistar rats were divided into 4 groups: sedentary-sham (Sed-Sham, n = 8), respiratory muscle trained-sham (RMT-Sham, n = 8), sedentary-HF (Sed-HF, n = 8) and respiratory muscle trained-HF (RMT-HF, n = 8). Animals were submitted to an RMT protocol performed 30 minutes per day, 5 days per week for 6 weeks, whereas the sedentary animals did not exercise. In HF rats, RMT promoted the reduction of left ventricular end-diastolic pressure, right ventricular hypertrophy, and pulmonary edema. Moreover, RMT produced a reduction in pressure response during chemoreflex activation, sympathetic modulation, and sympathetic vagal balance in addition to an increase in parasympathetic modulation. Also after RMT, HF rats demonstrated a reduction in respiratory system resistance, tissue resistance, Newtonian resistance, respiratory system compliance, and quasistatic compliance. These findings suggested that 6 weeks of RMT in HF rats promoted beneficial adaptations in hemodynamics, autonomic function, and respiratory mechanics and attenuated pressure response evoked by chemoreflex activation in HF rats. Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  13. Increased myocardial vulnerability to ischemia-reperfusion injury in the presence of left ventricular hypertrophy

    DEFF Research Database (Denmark)

    Mølgaard, Søren; Faricelli, Barbara; Salomonsson, Max

    2016-01-01

    .  Conclusion: Hearts from hypertensive (SHR-SP) rats with left ventricle hypertrophy appeared more vulnerable to ischemia-reperfusion injury, as supported by a more profound infarct development and an earlier loss of postconditioning by Exe-4. Mitochondrial complexes III and IV were identified among possible...... loci of this increased, hypertrophy-associated vulnerability....

  14. Sex Hormones Promote Opposite Effects on ACE and ACE2 Activity, Hypertrophy and Cardiac Contractility in Spontaneously Hypertensive Rats.

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    P L M Dalpiaz

    Full Text Available There is growing interest in sex differences and RAS components. However, whether gender influences cardiac angiotensin I-converting enzyme (ACE and angiotensin-converting enzyme 2 (ACE2 activity is still unknown. In the present work, we determined the relationship between ACE and ACE2 activity, left ventricular function and gender in spontaneously hypertensive rats (SHRs.Twelve-week-old female (F and male (M SHRs were divided into 2 experimental groups (n = 7 in each group: sham (S and gonadectomized (G. Fifty days after gonadectomy, we measured positive and negative first derivatives (dP/dt maximum left ventricle (LV and dP/dt minimum LV, respectively, hypertrophy (morphometric analysis and ACE and ACE2 catalytic activity (fluorimetrically. Expression of calcium handling proteins was measured by western blot. Male rats exhibited higher cardiac ACE and ACE2 activity as well as hypertrophy compared to female rats. Orchiectomy decreased the activity of these enzymes and hypertrophy, while ovariectomy increased hypertrophy and ACE2, but did not change ACE activity. For cardiac function, the male sham group had a lower +dP/dt than the female sham group. After gonadectomy, the +dP/dt increased in males and reduced in females. The male sham group had a lower -dP/dt than the female group. After gonadectomy, the -dP/dt increased in the male and decreased in the female groups when compared to the sham group. No difference was observed among the groups in SERCA2a protein expression. Gonadectomy increased protein expression of PLB (phospholamban and the PLB to SERCA2a ratio in female rats, but did not change in male rats.Ovariectomy leads to increased cardiac hypertrophy, ACE2 activity, PLB expression and PLB to SERCA2a ratio, and worsening of hemodynamic variables, whereas in males the removal of testosterone has the opposite effects on RAS components.

  15. [Preliminary Study of Necroptosis in Cardiac Hypertrophy Induced by Pressure Overload].

    Science.gov (United States)

    Zhao, Mingyue; Qin, Yupei; Lu, Lihui; Tang, Xiaoju; Wu, Wenchao; Fu, Hua; Liu, Xiaojing

    2015-06-01

    The aim of this study was to observe whether necroptosis is involved in the process of cardiac hypertrophy induced by pressure overload. SD rats underwent transverse abdominal aortic constriction (TAC) operation for establishing cardiac hypertrophy model. The structure and function of the left ventricle of rats were evaluated via echocardiography, left ventricular mass index, the expression of markers of cardiac hypertrophy and histological detection. Real-time PCR and Western blot were used to measure the gene and protein expression of receptor interacting protein kinase 1 and 3 (RIPK1 and RIPK3, the necroptosis markers) respectively. Four weeks after TAC operation, rat model for cardiac hypertrophy was established. The experimental data showed that the gene and protein expressions of RIPK1 and RIPK3 in the rat heart hypertrophic tissues after TAC for 4 weeks were increased significantly compared with those in the sham group. HE staining showed cardiomyocytes injury and hypertrophy in the hearts of TAC rat models. By transmission electron microscope, we observed that mitochondria of cardiomyocytes were damaged seriously in the TAC models. Treatment with losartan used, the selective antagonist of angiotensin II type I receptor could improve the cardiac function of TAC rats. Moreover, losartan treatment decreased the expression of RIPK1 and RIPK3 in heart tissues of TAC rats. The results suggest that necroptosis occurrs in the process of cardiac hypertrophy with pressure overload, and losartan could alleviate the cardiac hypertrophy and inhibit necroptosis.

  16. Phenotyping of left and right ventricular function in mouse models of compensated hypertrophy and heart failure with cardiac MRI.

    Directory of Open Access Journals (Sweden)

    Bastiaan J van Nierop

    Full Text Available BACKGROUND: Left ventricular (LV and right ventricular (RV function have an important impact on symptom occurrence, disease progression and exercise tolerance in pressure overload-induced heart failure, but particularly RV functional changes are not well described in the relevant aortic banding mouse model. Therefore, we quantified time-dependent alterations in the ventricular morphology and function in two models of hypertrophy and heart failure and we studied the relationship between RV and LV function during the transition from hypertrophy to heart failure. METHODS: MRI was used to quantify RV and LV function and morphology in healthy (n = 4 and sham operated (n = 3 C57BL/6 mice, and animals with a mild (n = 5 and a severe aortic constriction (n = 10. RESULTS: Mice subjected to a mild constriction showed increased LV mass (P0.05. Animals with a severe constriction progressively developed LV hypertrophy (P<0.001, depressed LVEF (P<0.001, followed by a declining RVEF (P<0.001 and the development of pulmonary remodeling, as compared to controls during a 10-week follow-up. Myocardial strain, as a measure for local cardiac function, decreased in mice with a severe constriction compared to controls (P<0.05. CONCLUSIONS: Relevant changes in mouse RV and LV function following an aortic constriction could be quantified using MRI. The well-controlled models described here open opportunities to assess the added value of new MRI techniques for the diagnosis of heart failure and to study the impact of new therapeutic strategies on disease progression and symptom occurrence.

  17. Left ventricular hypertrophy by ECG versus cardiac MRI as a predictor for heart failure.

    Science.gov (United States)

    Oseni, Abdullahi O; Qureshi, Waqas T; Almahmoud, Mohamed F; Bertoni, Alain G; Bluemke, David A; Hundley, William G; Lima, Joao A C; Herrington, David M; Soliman, Elsayed Z

    2017-01-01

    To determine if there is a significant difference in the predictive abilities of left ventricular hypertrophy (LVH) detected by ECG-LVH versus LVH ascertained by cardiac MRI-LVH in a model similar to the Framingham Heart Failure Risk Score (FHFRS). This study included 4745 (mean age 61±10 years, 53.5% women, 61.7% non-whites) participants in the Multi-Ethnic Study of Atherosclerosis. ECG-LVH was defined using Cornell voltage product while MRI-LVH was derived from left ventricular mass. Cox proportional hazard regression was used to examine the association between ECG-LVH and MRI-LVH with incident heart failure (HF). Harrell's concordance C-index was used to estimate the predictive ability of the model when either ECG-LVH or MRI-LVH was included as one of its components. ECG-LVH was present in 291 (6.1%), while MRI-LVH was present in 499 (10.5%) of the participants. Both ECG-LVH (HR 2.25, 95% CI 1.38 to 3.69) and MRI-LVH (HR 3.80, 95% CI 1.56 to 5.63) were predictive of HF. The absolute risk of developing HF was 8.81% for MRI-LVH versus 2.26% for absence of MRI-LVH with a relative risk of 3.9. With ECG-LVH, the absolute risk of developing HF 6.87% compared with 2.69% for absence of ECG-LVH with a relative risk of 2.55. The ability of the model to predict HF was better with MRI-LVH (C-index 0.871, 95% CI 0.842 to 0.899) than with ECG-LVH (C-index 0.860, 95% CI 0.833 to 0.888) (p<0.0001). ECG-LVH and MRI-LVH are predictive of HF. Substituting MRI-LVH for ECG-LVH improves the predictive ability of a model similar to the FHFRS. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  18. Cardiac insulin-resistance and decreased mitochondrial energy production precede the development of systolic heart failure after pressure-overload hypertrophy.

    Science.gov (United States)

    Zhang, Liyan; Jaswal, Jagdip S; Ussher, John R; Sankaralingam, Sowndramalingam; Wagg, Cory; Zaugg, Michael; Lopaschuk, Gary D

    2013-09-01

    Cardiac hypertrophy is accompanied by significant alterations in energy metabolism. Whether these changes in energy metabolism precede and contribute to the development of heart failure in the hypertrophied heart is not clear. Mice were subjected to cardiac hypertrophy secondary to pressure-overload as a result of an abdominal aortic constriction (AAC). The rates of energy substrate metabolism were assessed in isolated working hearts obtained 1, 2, and 3 weeks after AAC. Mice subjected to AAC demonstrated a progressive development of cardiac hypertrophy. In vivo assessment of cardiac function (via echocardiography) demonstrated diastolic dysfunction by 2 weeks (20% increase in E/E'), and systolic dysfunction by 3 weeks (16% decrease in % ejection fraction). Marked cardiac insulin-resistance by 2 weeks post-AAC was evidenced by a significant decrease in insulin-stimulated rates of glycolysis and glucose oxidation, and plasma membrane translocation of glucose transporter 4. Overall ATP production rates were decreased at 2 and 3 weeks post-AAC (by 37% and 47%, respectively) because of a reduction in mitochondrial oxidation of glucose, lactate, and fatty acids that was not accompanied by an increase in myocardial glycolysis rates. Reduced mitochondrial complex V activity was evident at 3 weeks post-AAC, concomitant with a reduction in the ratio of phosphocreatine to ATP. The development of cardiac insulin-resistance and decreased mitochondrial oxidative metabolism are early metabolic changes in the development of cardiac hypertrophy, which create an energy deficit that may contribute to the progression from hypertrophy to heart failure.

  19. Expression of mitochondrial regulatory genes parallels respiratory capacity and contractile function in a rat model of hypoxia-induced right ventricular hypertrophy

    Science.gov (United States)

    Chronic hypobaric hypoxia (CHH) increases load on the right ventricle (RV) resulting in RV hypertrophy. We hypothesized that CHH elicits distinct responses, i.e., the hypertrophied RV, unlike the left ventricle (LV), displaying enhanced mitochondrial respiratory and contractile function. Wistar rats...

  20. Early origins of heart disease: low birth weight and the role of the insulin-like growth factor system in cardiac hypertrophy.

    Science.gov (United States)

    Wang, Kimberley C W; Botting, Kimberley J; Padhee, Monalisa; Zhang, Song; McMillen, I Caroline; Suter, Catherine M; Brooks, Doug A; Morrison, Janna L

    2012-11-01

    Epidemiological studies indicate that poor growth before birth is associated with left ventricular hypertrophy and an increased risk of death from heart disease later in life. In fetal life, the insulin-like growth factor (IGF) system has been implicated in physiological growth of the heart, whereas in postnatal life IGFs can be involved in both physiological and pathological cardiac hypertrophy. A reduction in substrate supply in fetal life, resulting in chronic hypoxaemia and intrauterine growth restriction, results in increased cardiac IGF-1R, IGF-2 and IGF-2R gene expression; and there is also evidence for a role of the IGF-2 receptor in the ensuing cardiac hypertrophy. The persistent high level of cardiac IGF-2R gene expression from fetal to postnatal life may be due to epigenetic changes in key cardiac hypertrophy regulatory pathways. © 2012 The Authors Clinical and Experimental Pharmacology and Physiology © 2012 Wiley Publishing Asia Pty Ltd.

  1. Fish protein intake induces fast-muscle hypertrophy and reduces liver lipids and serum glucose levels in rats.

    Science.gov (United States)

    Kawabata, Fuminori; Mizushige, Takafumi; Uozumi, Keisuke; Hayamizu, Kohsuke; Han, Li; Tsuji, Tomoko; Kishida, Taro

    2015-01-01

    In our previous study, fish protein was proven to reduce serum lipids and body fat accumulation by skeletal muscle hypertrophy and enhancing basal energy expenditure in rats. In the present study, we examined the precise effects of fish protein intake on different skeletal muscle fiber types and metabolic gene expression of the muscle. Fish protein increased fast-twitch muscle weight, reduced liver triglycerides and serum glucose levels, compared with the casein diet after 6 or 8 weeks of feeding. Furthermore, fish protein upregulated the gene expressions of a fast-twitch muscle-type marker and a glucose transporter in the muscle. These results suggest that fish protein induces fast-muscle hypertrophy, and the enhancement of basal energy expenditure by muscle hypertrophy and the increase in muscle glucose uptake reduced liver lipids and serum glucose levels. The present results also imply that fish protein intake causes a slow-to-fast shift in muscle fiber type.

  2. 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.

  3. Transforming growth factor betas are upregulated in the rat masseter muscle hypertrophied by clenbuterol, a beta2 adrenergic agonist.

    Science.gov (United States)

    Akutsu, Satonari; Shimada, Akemi; Yamane, Akira

    2006-02-01

    1. The regulatory mechanism for the hypertrophy of skeletal muscles induced by clenbuterol is unclear. The purpose of the present study was to determine the extent to which transforming growth factor betas (TGFbetas), fibroblast growth factors (FGFs), hepatocyte growth factor (HGF), and platelet-derived growth factors (PDGFs) are involved in the hypertrophy of rat masseter muscle induced by clenbuterol. 2. We measured the mRNA expression levels for TGFbetas, FGFs, HGF, and PDGFs in rat masseter muscle hypertrophied by oral administration of clenbuterol for 3 weeks and determined correlations between the weight of masseter muscle and mRNA expression levels by regression analysis. We determined immunolocalizations of TGFbetas and their receptors (TGFbetaRs). 3. The mRNA expression levels for TGFbeta1, 2, and 3, and for PDGF-B demonstrated clenbuterol-induced elevations and positive correlations with the weight of masseter muscle. In particular, TGFbeta1, 2, and 3 showed strong positive correlations (correlation coefficients >0.6). The mRNA expression levels for PDGF-A, FGF-1 and 2, and HGF showed no significant differences between the control and clenbuterol groups, and no significant correlations. TGFbeta1, 2, and 3 were principally localized in the connective tissues interspaced among myofibers, and TGFbetaRI and II were localized in the periphery and sarcoplasm of the myofibers. 4. These results suggest that paracrine actions of TGFbeta1, 2, and 3 via TGFbetaRI and II could be involved in the hypertrophy of rat masseter muscle induced by clenbuterol. This is the first study to document the involvement of TGFbetas in the hypertrophy of skeletal muscles induced by clenbuterol.

  4. Fat Mass Reduction With Adipocyte Hypertrophy and Insulin Resistance in Heterozygous PPARγ Mutant Rats.

    Science.gov (United States)

    Gumbilai, Valentino; Ebihara, Ken; Aizawa-Abe, Megumi; Ebihara, Chihiro; Zhao, Mingming; Yamamoto, Yuji; Mashimo, Tomoji; Hosoda, Kiminori; Serikawa, Tadao; Nakao, Kazuwa

    2016-10-01

    Agonist-induced activation of peroxisome proliferator-activated receptor-γ (PPARγ) stimulates adipocyte differentiation and insulin sensitivity. Patients with heterozygous PPARγ dominant-negative mutation develop partial lipodystrophy and insulin resistance. Inconsistent with this evidence in humans, it was reported that heterozygous PPARγ knockout mice have increased insulin sensitivity and that mice with heterozygous PPARγ dominant-negative mutation have normal insulin sensitivity and improved glucose tolerance. In the context of the interspecies intranslatability of PPARγ-related findings, we generated a PPARγ mutant rat with a loss-of-function mutation (Pparg(mkyo)) without dominant-negative activity by using the ENU (N-ethyl-N-nitrosourea) mutagenesis method. Heterozygous Pparg(mkyo/+) rats showed reduced fat mass with adipocyte hypertrophy and insulin resistance, which were highly predictable from known actions of PPARγ agonists and phenotypes of patients with the PPARγ mutation. This report is the first in our knowledge to clearly demonstrate that both alleles of PPARγ are required for normal adipocyte development and insulin sensitivity in vivo. Furthermore, the study indicates that PPARγ regulates mainly adipocyte number rather than adipocyte size in vivo. The choice of appropriate species as experimental models is critical, especially for the study of PPARγ. © 2016 by the American Diabetes Association.

  5. Responses of skeletal muscle hypertrophy in Wistar rats to different resistance exercise models.

    Science.gov (United States)

    Luciano, T F; Marques, S O; Pieri, B L; de Souza, D R; Araújo, L V; Nesi, R T; Scheffer, D L; Comin, V H; Pinho, R A; Muller, A P; de Souza, C T

    2017-05-04

    This study aimed to compare the effects of three different resistance exercise models on the quadriceps muscle cross-sectional area, as well as on mTOR phosphorylation and other pivotal molecules involved in the upstream regulation of mTOR. Twenty-four male Wistar rats were divided into untrained (control), endurance resistance training, strength resistance training, and hypertrophy resistance training (HRT) groups (n=6). After 12 weeks of training, the red portion of the quadriceps was removed for histological and Western blot analyses. The results showed that the quadriceps weight and cross-sectional areas in the exercised groups were higher than those of the untrained rats. However, the HRT group presented better results than the other two experimental groups. This same pattern was observed for mTOR phosphorylation and for the most pivotal molecules involved in the upstream control of mTOR (increase of PKB, 14-3-3, ERK, p38 MAPK, and 4E-BP1 phosphorylation, and reduction of tuberin, sestrin 2, REDD1, and phospho AMPK). In summary, our study showed that HRT leads to high levels of mTOR phosphorylation as well as of other proteins involved in the upstream regulation of mTOR.

  6. 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...... by reduced hypertrophy and biomarkers of fibrosis, remodelling, inflammation and oxidative stress. In a separate study, the αAnalogue reversed AngII-induced hypertension and associated vascular and cardiac damage. The αAnalogue was effective over 5 weeks in a murine model of cardiac hypertrophy and heart......, 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...

  7. Dyrk1A-ASF-CaMKIIδ Signaling Is Involved in Valsartan Inhibition of Cardiac Hypertrophy in Renovascular Hypertensive Rats.

    Science.gov (United States)

    Yao, Jian; Qin, Xiaotong; Zhu, Jianhua; Sheng, Hongzhuan

    2016-01-01

    It is known that the expression, activity and alternative splicing of Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) are dysregulated in the cardiac remodeling process. Recently, we found a further signaling pathway, by which dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) regulates the alternative splicing of CaMKIIδ via the alternative splicing factor (ASF), i.e., Dyrk1A-ASF-CaMKIIδ. In this study, we aimed to investigate whether Dyrk1A-ASF-CaMKIIδ signaling was involved in valsartan inhibition of cardiac hypertrophy in renovascular hypertensive rats. Rats were subjected to two kidney-one clip (2K1C) surgery and then treated with valsartan (30 mg/kg/day) for 8 weeks. Hypertrophic parameter analysis was then performed. Western blot analysis was used to determine the protein expression of Dyrk1A and ASF and RT-PCR was used to analyze the alternative splicing of CaMKIIδ in the left ventricular (LV) sample. Valsartan attenuated cardiac hypertrophy in 2K1C rats but without impairment of cardiac systolic function. Increased protein expression of Dyrk1A and decreased protein expression of ASF were observed in the LV sample of 2K1C rats. Treatment of 2K1C rats with valsartan reversed the changes in Dyrk1A and ASF expression in the LV sample. Valsartan adjusted the 2K1C-induced imbalance in alternative splicing of CaMKIIδ by upregulating the mRNA expression of CaMKIIδC and downregulating the mRNA expression of CaMKIIδA and CaMKIIδB. Valsartan inhibition of cardiac hypertrophy in renovascular hypertensive rats was mediated, at least partly, by Dyrk1A-ASF-CaMKIIδ signaling. © 2015 S. Karger AG, Basel.

  8. Beneficial effects of exercise training in heart failure are lost in male diabetic rats.

    Science.gov (United States)

    Boudia, Dalila; Domergue, Valérie; Mateo, Phlippe; Fazal, Loubina; Prud'homme, Mathilde; Prigent, Heloise; Delcayre, Claude; Cohen-Solal, Alain; Garnier, Anne; Ventura-Clapier, Renee; Samuel, Jane-Lise

    2017-09-07

    Exercise training has been demonstrated to have beneficial effects in patients with heart failure (HF) or diabetes. However, it is unknown whether diabetic patients with HF will benefit from exercise training. Male Wistar rats were fed either a standard (Sham, n= 53) or high-fat, high-sucrose (HFHS) diet (D, n=66) for 6 months. After 2 months of diet, the rats were already diabetic. Rats were then randomly subjected to either myocardial infarction by coronary artery ligation (MI) or sham operation (Sham). Two months later, heart failure was documented by echocardiography and animals were randomly subjected to exercise training with treadmill for eight additional weeks or remained sedentary. At the end, rats were euthanized and tissues were assayed by RT-PCR, immunoblotting, spectrophotometry and immunohistology. MI induced a similar decrease in ejection fraction in diabetic and lean animals but a higher premature mortality in the diabetic group. Exercise for 8 weeks resulted in a higher working power developed by MI animals with diabetes, and improved glycaemia but not ejection fraction or pathological phenotype. In contrast exercise improved the ejection fraction and increased adaptive hypertrophy after MI in the lean group. Trained diabetic rats with MI were nevertheless able to develop cardiomyocyte hypertrophy but without angiogenic responses. Exercise improved stress markers and cardiac energy metabolism in lean- but not diabetic-MI rats. Hence, following HF, the benefits of exercise training on cardiac function are blunted in diabetic animals. In conclusion, exercise training only improved the myocardial profile of infarcted lean rats fed the standard diet. Copyright © 2017, Journal of Applied Physiology.

  9. Hypercholesterolemia downregulates autophagy in the rat heart.

    Science.gov (United States)

    Giricz, Zoltán; Koncsos, Gábor; Rajtík, Tomáš; Varga, Zoltán V; Baranyai, Tamás; Csonka, Csaba; Szobi, Adrián; Adameová, Adriana; Gottlieb, Roberta A; Ferdinandy, Péter

    2017-03-23

    We have previously shown that efficiency of ischemic conditioning is diminished in hypercholesterolemia and that autophagy is necessary for cardioprotection. However, it is unknown whether isolated hypercholesterolemia disturbs autophagy or the mammalian target of rapamycin (mTOR) pathways. Therefore, we investigated whether isolated hypercholesterolemia modulates cardiac autophagy-related pathways or programmed cell death mechanisms such as apoptosis and necroptosis in rat heart. Male Wistar rats were fed either normal chow (NORM; n = 9) or with 2% cholesterol and 0.25% cholic acid-enriched diet (CHOL; n = 9) for 12 weeks. CHOL rats exhibited a 41% increase in plasma total cholesterol level over that of NORM rats (4.09 mmol/L vs. 2.89 mmol/L) at the end of diet period. Animals were sacrificed, hearts were excised and briefly washed out. Left ventricles were snap-frozen for determination of markers of autophagy, mTOR pathway, apoptosis, and necroptosis by Western blot. Isolated hypercholesterolemia was associated with a significant reduction in expression of cardiac autophagy markers such as LC3-II, Beclin-1, Rubicon and RAB7 as compared to controls. Phosphorylation of ribosomal S6, a surrogate marker for mTOR activity, was increased in CHOL samples. Cleaved caspase-3, a marker of apoptosis, increased in CHOL hearts, while no difference in the expression of necroptotic marker RIP1, RIP3 and MLKL was detected between treatments. This is the first comprehensive analysis of autophagy and programmed cell death pathways of apoptosis and necroptosis in hearts of hypercholesterolemic rats. Our data show that isolated hypercholesterolemia suppresses basal cardiac autophagy and that the decrease in autophagy may be a result of an activated mTOR pathway. Reduced autophagy was accompanied by increased apoptosis, while cardiac necroptosis was not modulated by isolated hypercholesterolemia. Decreased basal autophagy and elevated apoptosis may be responsible for the

  10. The ATP-binding cassette transporter ABCG2 protects against pressure overload-induced cardiac hypertrophy and heart failure by promoting angiogenesis and antioxidant response.

    Science.gov (United States)

    Higashikuni, Yasutomi; Sainz, Julie; Nakamura, Kazuto; Takaoka, Minoru; Enomoto, Soichiro; Iwata, Hiroshi; Tanaka, Kimie; Sahara, Makoto; Hirata, Yasunobu; Nagai, Ryozo; Sata, Masataka

    2012-03-01

    ATP-binding cassette transporter subfamily G member 2 (ABCG2), expressed in microvascular endothelial cells in the heart, has been suggested to regulate several tissue defense mechanisms. This study was performed to elucidate its role in pressure overload-induced cardiac hypertrophy. Pressure overload was induced in 8- to 12-week-old wild-type and Abcg2-/- mice by transverse aortic constriction (TAC). Abcg2-/- mice showed exaggerated cardiac hypertrophy and ventricular remodeling after TAC compared with wild-type mice. In the early phase after TAC, functional impairment in angiogenesis and antioxidant response in myocardium was found in Abcg2-/- mice. In vitro experiments demonstrated that ABCG2 regulates transport of glutathione, an important endogenous antioxidant, from microvascular endothelial cells. Besides, glutathione transported from microvascular endothelial cells in ABCG2-dependent manner ameliorated oxidative stress-induced cardiomyocyte hypertrophy. In vivo, glutathione levels in plasma and the heart were increased in wild-type mice but not in Abcg2-/- mice after TAC. Treatment with the superoxide dismutase mimetic ameliorated cardiac hypertrophy in Abcg2-/- mice after TAC to the same extent as that in wild-type mice, although cardiac dysfunction with impaired angiogenesis was observed in Abcg2-/- mice. ABCG2 protects against pressure overload-induced cardiac hypertrophy and heart failure by promoting angiogenesis and antioxidant response.

  11. [Transient compensatory hypertrophy and limited regeneration of the surgically removed rat ventral prostate].

    Science.gov (United States)

    Chakrovarty, Sumana; Wadhwa, Shashi; Diwan, Manish; Malhotra, Ritu; Wadhwa, S N; Talwar, G P

    2003-09-01

    To confirm whether regeneration of prostate lobe indeed takes place on surgical lobectomy and if so, to what extent. Other issues studied are 1. whether the lobe regenerated is similar morphologically to that developing normally from neonatal origin to adulthood, and 2. the consequences of partial lobectomy on the contralateral lobe and the influence of sex steroid hormones on the regeneration process. The effect of surgical removal of one of the ventral prostate lobes on the size of the contralateral lobe has been studied at various time intervals after lobectomy. The surgically extirpated ventral prostate lobe in rats regenerates attaining plateau size at 8-16 weeks post lobectomy. The regenerated lobe, however, remains significantly smaller than the original size. In early phase of post lobectomy (at 2 weeks) the contralateral lobe was significantly hypertrophied. It reverts to normal size on regeneration of the extirpated lobe with time. Orchiectomy carried out at the time of lobectomy caused a drastic reduction in the size of the remaining lobe, which was prevented by exogenous treatment with androgens. In animals receiving treatment with estrogens, the remaining lobe was partially but not fully atrophied. However, estrogens did not support the regeneration of the surgically removed lobe, which requires androgens. These studies demonstrate that surgical removal of one of the ventral prostate lobe leads to a process of regeneration. However, the regenerated lobe does not attain the normal size.

  12. Class III PI3K-mediated prolonged activation of autophagy plays a critical role in the transition of cardiac hypertrophy to heart failure.

    Science.gov (United States)

    Yu, Peng; Zhang, Yangyang; Li, Chuanfu; Li, Yuehua; Jiang, Surong; Zhang, Xiaojin; Ding, Zhengnian; Tu, Fei; Wu, Jun; Gao, Xiang; Li, Liu

    2015-07-01

    Pathological cardiac hypertrophy often leads to heart failure. Activation of autophagy has been shown in pathological hypertrophic hearts. Autophagy is regulated positively by Class III phosphoinositide 3-kinase (PI3K). However, it is unknown whether Class III PI3K plays a role in the transition of cardiac hypertrophy to heart failure. To address this question, we employed a previously established cardiac hypertrophy model in heat shock protein 27 transgenic mice which shares common features with several types of human cardiomyopathy. Age-matched wild-type mice served as control. Firstly, a prolonged activation of autophagy, as reflected by autophagosome accumulation, increased LC3 conversion and decreased p62 protein levels, was detected in hypertrophic hearts from adaptive stage to maladaptive stage. Moreover, morphological abnormalities in myofilaments and mitochondria were presented in the areas accumulated with autophagosomes. Secondly, activation of Class III PI3K Vacuolar protein sorting 34 (Vps34), as demonstrated by upregulation of Vps34 expression, increased interaction of Vps34 with Beclin-1, and deceased Bcl-2 expression, was demonstrated in hypertrophic hearts from adaptive stage to maladaptive stage. Finally, administration with Wortmaninn, a widely used autophagy inhibitor by suppressing Class III PI3K activity, significantly decreased autophagy activity, improved morphologies of intracellular apartments, and most importantly, prevented progressive cardiac dysfunction in hypertrophic hearts. Collectively, we demonstrated that Class III PI3K plays a central role in the transition of cardiac hypertrophy to heart failure via a prolonged activation of autophagy in current study. Class III PI3K may serve as a potential target for the treatment and management of maladaptive cardiac hypertrophy. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  13. Long-Term Excessive Body Weight and Adult Left Ventricular Hypertrophy Are Linked Through Later-Life Body Size and Blood Pressure: The Bogalusa Heart Study.

    Science.gov (United States)

    Zhang, Huijie; Zhang, Tao; Li, Shengxu; Guo, Yajun; Shen, Wei; Fernandez, Camilo; Harville, Emily; Bazzano, Lydia A; Urbina, Elaine M; He, Jiang; Chen, Wei

    2017-05-12

    Childhood adiposity is associated with cardiac structure in later life, but little is known regarding to what extent childhood body weight affects adult left ventricular geometric patterns through adult body size and blood pressure (BP). Determine quantitatively the mediation effect of adult body weight and BP on the association of childhood body mass index (BMI) with adult left ventricular (LV) hypertrophy. This longitudinal study consisted of 710 adults, aged 26 to 48 years, who had been examined for BMI and BP measured ≥4× during childhood and ≥2× during adulthood, with a mean follow-up period of 28.0 years. After adjusting for age, race, and sex, adult BMI had a significant mediation effect (76.4%; Padult LV mass index association. The mediation effects of adult systolic BP (15.2%), long-term burden (12.1%), and increasing trends of systolic BP (7.9%) were all significant (Padult LV hypertrophy, eccentric hypertrophy, and concentric hypertrophy. Importantly, the mediation effects of adult BMI were all significantly stronger than those of adult systolic BP on LV mass index, LV hypertrophy, and LV remodeling patterns (Padult cardiac structure, and early life excessive body weight and adult LV hypertrophy are linked through later life excessive body weight and elevated BP. © 2017 American Heart Association, Inc.

  14. Genistein, a soy phytoestrogen, reverses severe pulmonary hypertension and prevents right heart failure in rats.

    Science.gov (United States)

    Matori, Humann; Umar, Soban; Nadadur, Rangarajan D; Sharma, Salil; Partow-Navid, Rod; Afkhami, Michelle; Amjedi, Marjan; Eghbali, Mansoureh

    2012-08-01

    Pretreatment with a phytoestrogen genistein has been shown to attenuate the development of pulmonary hypertension (PH). Because PH is not always diagnosed early, we examined whether genistein could also reverse preexisting established PH and prevent associated right heart failure (RHF). PH was induced in male rats by 60 mg/kg of monocrotaline. After 21 days, when PH was well established, rats received daily injection of genistein (1 mg/kg per day) for 10 days or were left untreated to develop RHF by day 30. Effects of genistein on human pulmonary artery smooth muscle cell and endothelial cell proliferation and neonatal rat ventricular myocyte hypertrophy were assessed in vitro. Severe PH was evident 21 days after monocrotaline, as peak systolic right ventricular pressure increased to 66.35±1.03 mm Hg and right ventricular ejection fraction reduced to 41.99±1.27%. PH progressed to RHF by day 30 (right ventricular pressure, 72.41±1.87 mm Hg; RV ejection fraction, 29.25±0.88%), and mortality was ≈75% in RHF rats. Genistein therapy resulted in significant improvement in lung and heart function as right ventricular pressure was significantly reduced to 43.34±4.08 mm Hg and right ventricular ejection fraction was fully restored to 65.67±1.08% similar to control. Genistein reversed PH-induced pulmonary vascular remodeling in vivo and inhibited human pulmonary artery smooth muscle cell proliferation by ≈50% in vitro likely through estrogen receptor-β. Genistein also reversed right ventricular hypertrophy (right ventricular hypertrophy index, 0.35±0.029 versus 0.70±0.080 in RHF), inhibited neonatal rat ventricular myocyte hypertrophy, and restored PH-induced loss of capillaries in the right ventricle. These improvements in cardiopulmonary function and structure resulted in 100% survival by day 30. Genistein restored PH-induced downregulation of estrogen receptor-β expression in the right ventricle and lung. In conclusion, genistein therapy not only rescues

  15. Selumetinib, an Oral Anti-Neoplastic Drug, May Attenuate Cardiac Hypertrophy via Targeting the ERK Pathway.

    Science.gov (United States)

    Li, Chen; Chen, Zhongxiu; Yang, Hao; Luo, Fangbo; Chen, Lihong; Cai, Huawei; Li, Yajiao; You, Guiying; Long, Dan; Li, Shengfu; Zhang, Qiuping; Rao, Li

    2016-01-01

    Although extracellular-regulated kinases (ERK) are a well-known central mediator in cardiac hypertrophy, no clinically available ERK antagonist has been tested for preventing cardiac hypertrophy. Selumetinib is a novel oral MEK inhibitor that is currently under Phase II and Phase III clinical investigation for advanced solid tumors. In this study, we investigated whether Selumetinib could inhibit the aberrant ERK activation of the heart in response to stress as well as prevent cardiac hypertrophy. In an in vitro model of PE-induced cardiac hypertrophy, Selumetinib significantly inhibited the ERK activation and prevented enlargement of cardiomyocytes or reactivation of certain fetal genes. In the pathologic cardiac hypertrophy model of ascending aortic constriction, Selumetinib provided significant ERK inhibition in the stressed heart but not in the other organs. This selective ERK inhibition prevented left ventricular (LV) wall thickening, LV mass increase, fetal gene reactivation and cardiac fibrosis. In another distinct physiologic cardiac hypertrophy model of a swimming rat, Selumetinib provided a similar anti-hypertrophy effect, except that no significant fetal gene reactivation or cardiac fibrosis was observed. Selumetinib, a novel oral anti-cancer drug with good safety records in a number of Phase II clinical trials, can inhibit ERK activity in the heart and prevent cardiac hypertrophy. These promising results indicate that Selumetinib could potentially be used to treat cardiac hypertrophy. However, this hypothesis needs to be validated in human clinical trials.

  16. Isoproterenol effects evaluated in heart slices of human and rat in comparison to rat heart in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Herrmann, Julia E.; Heale, Jason; Bieraugel, Mike; Ramos, Meg [Drug Safety Evaluation, Allergan Inc., 2525 Dupont Dr, Irvine, CA 92612 (United States); Fisher, Robyn L. [Vitron Inc., Tucson, AZ (United States); Vickers, Alison E.M., E-mail: vickers_alison@allergan.com [Drug Safety Evaluation, Allergan Inc., 2525 Dupont Dr, Irvine, CA 92612 (United States)

    2014-01-15

    Human response to isoproterenol induced cardiac injury was evaluated by gene and protein pathway changes in human heart slices, and compared to rat heart slices and rat heart in vivo. Isoproterenol (10 and 100 μM) altered human and rat heart slice markers of oxidative stress (ATP and GSH) at 24 h. In this in vivo rat study (0.5 mg/kg), serum troponin concentrations increased with lesion severity, minimal to mild necrosis at 24 and 48 h. In the rat and the human heart, isoproterenol altered pathways for apoptosis/necrosis, stress/energy, inflammation, and remodeling/fibrosis. The rat and human heart slices were in an apoptotic phase, while the in vivo rat heart exhibited necrosis histologically and further progression of tissue remodeling. In human heart slices genes for several heat shock 70 kD members were altered, indicative of stress to mitigate apoptosis. The stress response included alterations in energy utilization, fatty acid processing, and the up-regulation of inducible nitric oxide synthase, a marker of increased oxidative stress in both species. Inflammation markers linked with remodeling included IL-1α, Il-1β, IL-6 and TNFα in both species. Tissue remodeling changes in both species included increases in the TIMP proteins, inhibitors of matrix degradation, the gene/protein of IL-4 linked with cardiac fibrosis, and the gene Ccl7 a chemokine that induces collagen synthesis, and Reg3b a growth factor for cardiac repair. This study demonstrates that the initial human heart slice response to isoproterenol cardiac injury results in apoptosis, stress/energy status, inflammation and tissue remodeling at concentrations similar to that in rat heart slices. - Highlights: • Human response to isoproterenol induced cardiac injury evaluated in heart slices. • Isoproterenol altered apoptosis, energy, inflammation and remodeling pathways. • Human model verified by comparison to rat heart slices and rat heart in vivo. • Human and rat respond to isoproterenol

  17. β-Hydroxy-β-methylbutyrate (HMβ supplementation stimulates skeletal muscle hypertrophy in rats via the mTOR pathway

    Directory of Open Access Journals (Sweden)

    Pimentel Gustavo D

    2011-02-01

    Full Text Available Abstract β-Hydroxy-β-methylbutyrate (HMβ supplementation is used to treat cancer, sepsis and exercise-induced muscle damage. However, its effects on animal and human health and the consequences of this treatment in other tissues (e.g., fat and liver have not been examined. The purpose of this study was to evaluate the effects of HMβ supplementation on skeletal muscle hypertrophy and the expression of proteins involved in insulin signalling. Rats were treated with HMβ (320 mg/kg body weight or saline for one month. The skeletal muscle hypertrophy and insulin signalling were evaluated by western blotting, and hormonal concentrations were evaluated using ELISAs. HMβ supplementation induced muscle hypertrophy in the extensor digitorum longus (EDL and soleus muscles and increased serum insulin levels, the expression of the mammalian target of rapamycin (mTOR and phosphorylation of p70S6K in the EDL muscle. Expression of the insulin receptor was increased only in liver. Thus, our results suggest that HMβ supplementation can be used to increase muscle mass without adverse health effects.

  18. Cardiosphere-Derived Cells Reverse Heart Failure With Preserved Ejection Fraction in Rats by Decreasing Fibrosis and Inflammation

    Directory of Open Access Journals (Sweden)

    Romain Gallet, MD

    2016-01-01

    Full Text Available The pathogenesis of heart failure with a preserved ejection fraction (HFpEF is unclear. Myocardial fibrosis, inflammation, and cardiac hypertrophy have been suggested to contribute to the pathogenesis of HFpEF. Cardiosphere-derived cells (CDCs are heart-derived cell products with antifibrotic and anti-inflammatory properties. This study tested whether rat CDCs were sufficient to decrease manifestations of HFpEF in hypertensive rats. Starting at 7 weeks of age, Dahl salt-sensitive rats were fed a high-salt diet for 6 to 7 weeks and randomized to receive intracoronary CDCs or placebo. Dahl rats fed normal chow served as controls. High-salt rats developed hypertension, left ventricular (LV hypertrophy, and diastolic dysfunction, without impairment of ejection fraction. Four weeks after treatment, diastolic dysfunction resolved in CDC-treated rats but not in placebo. The improved LV relaxation was associated with lower LV end-diastolic pressure, decreased lung congestion, and enhanced survival in CDC-treated rats. Histology and echocardiography revealed no decrease in cardiac hypertrophy after CDC treatment, consistent with the finding of sustained, equally-elevated blood pressure in CDC- and placebo-treated rats. Nevertheless, CDC treatment decreased LV fibrosis and inflammatory infiltrates. Serum inflammatory cytokines were likewise decreased after CDC treatment. Whole-transcriptome analysis revealed that CDCs reversed changes in numerous transcripts associated with HFpEF, including many involved in inflammation and/or fibrosis. These studies suggest that CDCs normalized LV relaxation and LV diastolic pressure while improving survival in a rat model of HFpEF. The benefits of CDCs occurred despite persistent hypertension and cardiac hypertrophy. By selectively reversing inflammation and fibrosis, CDCs may be beneficial in the treatment of HFpEF.

  19. Effects of a pure alpha/beta-adrenergic receptor blocker on monocrotaline-induced pulmonary arterial hypertension with right ventricular hypertrophy in rats.

    Science.gov (United States)

    Ishikawa, Masaya; Sato, Naoki; Asai, Kuniya; Takano, Teruo; Mizuno, Kyoichi

    2009-12-01

    It is unclear how much the sympathetic nervous system is involved in the development of pulmonary arterial hypertension (PAH). The present study examined whether or not a pure alpha/beta-adrenergic receptor blocker (arotinolol) could prevent the development of PAH and right ventricular hypertrophy (RVH) in a rat model of monocrotaline (MCT)-induced PAH. The heart rate, arterial blood pressure (BP), left ventricular pressure, pulmonary artery pressure (PAP), and right ventricular pressure (RVP) were measured after administration of arotinolol or saline for 2 weeks. Ventricular weight and myocyte size were also measured. Mean PAP was increased less in the arotinolol group (n=6), (53 +/-9 vs 21 +/-2 mmHg in the control (n=6); Parotinolol group (41 +/-3 vs 91 +/-14 mmHg in the control, Parotinolol group. The pure alpha/beta-blocker arotinolol prevented the progression of MCT-induced PAH and RVH in rats, suggesting that sympathetic nervous activation might play a role in the development of PAH.

  20. Arrhythmia susceptibility in senescent rat hearts

    Directory of Open Access Journals (Sweden)

    Stefano Rossi

    2014-01-01

    Full Text Available Cardiovascular disease increases with age as well as alterations of cardiac electrophysiological properties, but a detailed knowledge about changes in cardiac electrophysiology relevant to arrhythmogenesis in the elderly is relatively lacking. The aim of this study was to determine specific age-related changes in electrophysiological properties of the ventricles which can be related to a structural-functional arrhythmogenic substrate. Multiple epicardial electrograms were recorded on the ventricular surface of in vivo control and aged rats, while arrhythmia vulnerability was investigated by premature stimulation protocols. Single or multiple ectopic beats and sustained ventricular arrhythmias were frequently induced in aged but not in control hearts. Abnormal ventricular activation patterns during sinus rhythm and unchanged conduction velocity during point stimulation in aged hearts suggest the occurrence of impaired impulse conduction through the distal Purkinje system that might create a potential reentry substrate.

  1. Sequencing of mRNA identifies re-expression of fetal splice variants in cardiac hypertrophy.

    Science.gov (United States)

    Ames, E G; Lawson, M J; Mackey, A J; Holmes, J W

    2013-09-01

    Cardiac hypertrophy has been well-characterized at the level of transcription. During cardiac hypertrophy, genes normally expressed primarily during fetal heart development are re-expressed, and this fetal gene program is believed to be a critical component of the hypertrophic process. Recently, alternative splicing of mRNA transcripts has been shown to be temporally regulated during heart development, leading us to consider whether fetal patterns of splicing also reappear during hypertrophy. We hypothesized that patterns of alternative splicing occurring during heart development are recapitulated during cardiac hypertrophy. Here we present a study of isoform expression during pressure-overload cardiac hypertrophy induced by 10 days of transverse aortic constriction (TAC) in rats and in developing fetal rat hearts compared to sham-operated adult rat hearts, using high-throughput sequencing of poly(A) tail mRNA. We find a striking degree of overlap between the isoforms expressed differentially in fetal and pressure-overloaded hearts compared to control: forty-four percent of the isoforms with significantly altered expression in TAC hearts are also expressed at significantly different levels in fetal hearts compared to control (Phypertrophy and fetal heart development are significantly enriched for genes involved in cytoskeletal organization, RNA processing, developmental processes, and metabolic enzymes. Our data strongly support the concept that mRNA splicing patterns normally associated with heart development recur as part of the hypertrophic response to pressure overload. These findings suggest that cardiac hypertrophy shares post-transcriptional as well as transcriptional regulatory mechanisms with fetal heart development. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Klotho gene delivery ameliorates renal hypertrophy and fibrosis in streptozotocin-induced diabetic rats by suppressing the Rho-associated coiled-coil kinase signaling pathway.

    Science.gov (United States)

    Deng, Minghong; Luo, Yumei; Li, Yunkui; Yang, Qiuchen; Deng, Xiaoqin; Wu, Ping; Ma, Houxun

    2015-07-01

    The present study aimed to investigate whether klotho gene delivery attenuated renal hypertrophy and fibrosis in streptozotocin-induced diabetic rats. A recombinant adeno-associated virus (rAAV) carrying mouse klotho full-length cDNA (rAAV.mKL), was constructed for in vivo investigation of klotho expression. Diabetes was induced in rats by a single tail vein injection of 60 mg/kg streptozotocin. Subsequently, the diabetic rats received an intravenous injection of rAAV.mKL, rAAV.green fluorescent protein (GFP) or phosphate-buffered saline (PBS). The Sprague-Dawley rat group received PBS and served as the control group. After 12 weeks, all the rats were sacrificed and ELISA, immunohistochemical and histological analyses, fluorescence microscopy, semi-quantitative reverse transcription-polymerase chain reaction and western blottin were performed. A single dose of rAAV.mKL was found to prevent the progression of renal hypertrophy and fibrosis for at least 12 weeks (duration of study). Klotho expression was suppressed in the diabetic rats, but was increased by rAAV.mKL delivery. rAAV.mKL significantly suppressed diabetes-induced renal hypertrophy and histopathological changes, reduced renal collagen fiber generation and decreased kidney hypertrophy index. In addition, rAAV.mKL decreased the protein expression levels of fibronectin and vimentin, while it downregulated the mRNA expression and activity of Rho-associated coiled-coil kinase (ROCK)I in the kidneys of the diabetic rats. These results indicated that klotho gene delivery ameliorated renal hypertrophy and fibrosis in diabetic rats, possibly by suppressing the ROCK signaling pathway. This may offer a novel approach for the long-term control and renoprotection of diabetes.

  3. ST segment/heart rate hysteresis improves the diagnostic accuracy of ECG stress test for coronary artery disease in patients with left ventricular hypertrophy.

    Science.gov (United States)

    Zimarino, Marco; Montebello, Elena; Radico, Francesco; Gallina, Sabina; Perfetti, Matteo; Iachini Bellisarii, Francesco; Severi, Silva; Limbruno, Ugo; Emdin, Michele; De Caterina, Raffaele

    2016-10-01

    The exercise electrocardiographic stress test (ExET) is the most widely used non-invasive diagnostic method to detect coronary artery disease. However, the sole ST depression criteria (ST-max) have poor specificity for coronary artery disease in patients with left ventricular hypertrophy. We hypothesised that ST-segment depression/heart rate hysteresis, depicting the relative behaviour of ST segment depression during the exercise and recovery phase of the test might increase the diagnostic accuracy of ExET for coronary artery disease detection in such patients. In three cardiology centres, we studied 113 consecutive patients (mean age 66 ± 2 years; 88% men) with hypertension-related left ventricular hypertrophy at echocardiography, referred to coronary angiography after an ExET. The following ExET criteria were analysed: ST-max, chronotropic index, heart rate recovery, Duke treadmill score, ST-segment depression/heart rate hysteresis. We detected significant coronary artery disease at coronary angiography in 61 patients (53%). At receiver-operating characteristic analysis, ST-segment depression/heart rate hysteresis had the highest area under the curve value (0.75, P coronary artery disease than conventional criteria in patients with hypertension-related left ventricular hypertrophy. © The European Society of Cardiology 2016.

  4. PULMONARY ARTERIAL DISEASE ASSOCIATED WITH RIGHT-SIDED CARDIAC HYPERTROPHY AND CONGESTIVE HEART FAILURE IN ZOO MAMMALS HOUSED AT 2,100 M ABOVE SEA LEVEL.

    Science.gov (United States)

    Juan-Sallés, Carles; Martínez, Liliana Sofía; Rosas-Rosas, Arely G; Parás, Alberto; Martínez, Osvaldo; Hernández, Alejandra; Garner, Michael M

    2015-12-01

    Subacute and chronic mountain sickness of humans and the related brisket disease of cattle are characterized by right-sided congestive heart failure in individuals living at high altitudes as a result of sustained hypoxic pulmonary hypertension. Adaptations to high altitude and disease resistance vary among species, breeds, and individuals. The authors conducted a retrospective survey of right-sided cardiac hypertrophy associated with pulmonary arterial hypertrophy or arteriosclerosis in zoo mammals housed at Africam Safari (Puebla, México), which is located at 2,100 m above sea level. Seventeen animals with detailed pathology records matched the study criterion. Included were 10 maras (Dolichotis patagonum), 2 cotton-top tamarins (Saguinus oedipus oedipus), 2 capybaras (Hydrochaeris hydrochaeris), and 1 case each of Bennet's wallaby (Macropus rufogriseus), nilgai antelope (Boselaphus tragocamelus), and scimitar-horned oryx (Oryx dammah). All had right-sided cardiac hypertrophy and a variety of arterial lesions restricted to the pulmonary circulation and causing arterial thickening with narrowing of the arterial lumen. Arterial lesions most often consisted of medial hypertrophy or hyperplasia of small and medium-sized pulmonary arteries. All maras also had single or multiple elevated plaques in the pulmonary arterial trunk consisting of fibrosis, accompanied by chondroid metaplasia in some cases. Both antelopes were juvenile and died with right-sided congestive heart failure associated with severe pulmonary arterial lesions. To the authors' knowledge, this is the first description of cardiac and pulmonary arterial disease in zoo mammals housed at high altitudes.

  5. 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

  6. Resveratrol improves survival, hemodynamics and energetics in a rat model of hypertension leading to heart failure.

    Science.gov (United States)

    Rimbaud, Stéphanie; Ruiz, Matthieu; Piquereau, Jérôme; Mateo, Philippe; Fortin, Dominique; Veksler, Vladimir; Garnier, Anne; Ventura-Clapier, Renée

    2011-01-01

    Heart failure (HF) is characterized by contractile dysfunction associated with altered energy metabolism. This study was aimed at determining whether resveratrol, a polyphenol known to activate energy metabolism, could be beneficial as a metabolic therapy of HF. Survival, ventricular and vascular function as well as cardiac and skeletal muscle energy metabolism were assessed in a hypertensive model of HF, the Dahl salt-sensitive rat fed with a high-salt diet (HS-NT). Resveratrol (18 mg/kg/day; HS-RSV) was given for 8 weeks after hypertension and cardiac hypertrophy were established (which occurred 3 weeks after salt addition). Resveratrol treatment improved survival (64% in HS-RSV versus 15% in HS-NT, phypertension or hypertrophy. Moreover, aortic endothelial dysfunction present in HS-NT was prevented in resveratrol-treated rats. Resveratrol treatment tended to preserve mitochondrial mass and biogenesis and completely protected mitochondrial fatty acid oxidation and PPARα (peroxisome proliferator-activated receptor α) expression. We conclude that resveratrol treatment exerts beneficial protective effects on survival, endothelium-dependent smooth muscle relaxation and cardiac contractile and mitochondrial function, suggesting that resveratrol or metabolic activators could be a relevant therapy in hypertension-induced HF.

  7. Resveratrol improves survival, hemodynamics and energetics in a rat model of hypertension leading to heart failure.

    Directory of Open Access Journals (Sweden)

    Stéphanie Rimbaud

    Full Text Available Heart failure (HF is characterized by contractile dysfunction associated with altered energy metabolism. This study was aimed at determining whether resveratrol, a polyphenol known to activate energy metabolism, could be beneficial as a metabolic therapy of HF. Survival, ventricular and vascular function as well as cardiac and skeletal muscle energy metabolism were assessed in a hypertensive model of HF, the Dahl salt-sensitive rat fed with a high-salt diet (HS-NT. Resveratrol (18 mg/kg/day; HS-RSV was given for 8 weeks after hypertension and cardiac hypertrophy were established (which occurred 3 weeks after salt addition. Resveratrol treatment improved survival (64% in HS-RSV versus 15% in HS-NT, p<0.001, and prevented the 25% reduction in body weight in HS-NT (P<0.001. Moreover, RSV counteracted the development of cardiac dysfunction (fractional shortening -34% in HS-NT as evaluated by echocardiography, which occurred without regression of hypertension or hypertrophy. Moreover, aortic endothelial dysfunction present in HS-NT was prevented in resveratrol-treated rats. Resveratrol treatment tended to preserve mitochondrial mass and biogenesis and completely protected mitochondrial fatty acid oxidation and PPARα (peroxisome proliferator-activated receptor α expression. We conclude that resveratrol treatment exerts beneficial protective effects on survival, endothelium-dependent smooth muscle relaxation and cardiac contractile and mitochondrial function, suggesting that resveratrol or metabolic activators could be a relevant therapy in hypertension-induced HF.

  8. Resveratrol Improves Survival, Hemodynamics and Energetics in a Rat Model of Hypertension Leading to Heart Failure

    Science.gov (United States)

    Rimbaud, Stéphanie; Ruiz, Matthieu; Piquereau, Jérôme; Mateo, Philippe; Fortin, Dominique; Veksler, Vladimir; Garnier, Anne; Ventura-Clapier, Renée

    2011-01-01

    Heart failure (HF) is characterized by contractile dysfunction associated with altered energy metabolism. This study was aimed at determining whether resveratrol, a polyphenol known to activate energy metabolism, could be beneficial as a metabolic therapy of HF. Survival, ventricular and vascular function as well as cardiac and skeletal muscle energy metabolism were assessed in a hypertensive model of HF, the Dahl salt-sensitive rat fed with a high-salt diet (HS-NT). Resveratrol (18 mg/kg/day; HS-RSV) was given for 8 weeks after hypertension and cardiac hypertrophy were established (which occurred 3 weeks after salt addition). Resveratrol treatment improved survival (64% in HS-RSV versus 15% in HS-NT, p<0.001), and prevented the 25% reduction in body weight in HS-NT (P<0.001). Moreover, RSV counteracted the development of cardiac dysfunction (fractional shortening −34% in HS-NT) as evaluated by echocardiography, which occurred without regression of hypertension or hypertrophy. Moreover, aortic endothelial dysfunction present in HS-NT was prevented in resveratrol-treated rats. Resveratrol treatment tended to preserve mitochondrial mass and biogenesis and completely protected mitochondrial fatty acid oxidation and PPARα (peroxisome proliferator-activated receptor α) expression. We conclude that resveratrol treatment exerts beneficial protective effects on survival, endothelium–dependent smooth muscle relaxation and cardiac contractile and mitochondrial function, suggesting that resveratrol or metabolic activators could be a relevant therapy in hypertension-induced HF. PMID:22028869

  9. 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.)

  10. 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.

  11. Deletion of Kvβ1.1 subunit leads to electrical and haemodynamic changes causing cardiac hypertrophy in female murine hearts.

    Science.gov (United States)

    Tur, Jared; Chapalamadugu, Kalyan C; Padawer, Timothy; Badole, Sachin L; Kilfoil, Peter J; Bhatnagar, Aruni; Tipparaju, Srinivas M

    2016-04-01

    What is the central question of this study? The goal of this study was to evaluate sex differences and the role of the potassium channel β1 (Kvβ1) subunit in the heart. What is the main finding and its importance? Genetic ablation of Kvβ1.1 in females led to cardiac hypertrophy characterized by increased heart size, prolonged monophasic action potentials, elevated blood pressure and increased myosin heavy chain α (MHCα) expression. In contrast, male mice showed only electrical changes. Kvβ1.1 binds the MHCα isoform at the protein level, and small interfering RNA targeted knockdown of Kvβ1.1 upregulated MHCα. Cardiovascular disease is the leading cause of death and debility in women in the USA, and cardiac arrhythmias are a major concern. Voltage-gated potassium (Kv) channels along with the binding partners; Kvβ subunits are major regulators of the action potential (AP) shape and duration (APD). The regulation of Kv channels by the Kvβ1 subunit is unknown in female hearts. In the present study, we hypothesized that the Kvβ1 subunit is an important regulator of female cardiac physiology. To test this hypothesis, we ablated (knocked out; KO) the KCNAB1 isoform 1 (Kvβ1.1) subunit in mice and evaluated cardiac function and electrical activity by using ECG, monophasic action potential recordings and echocardiography. Our results showed that the female Kvβ1.1 KO mice developed cardiac hypertrophy, and the hearts were structurally different, with enlargement and increased area. The electrical derangements caused by Kvβ1.1 KO in female mice included long QTc and QRS intervals along with increased APD (APD20-90% repolarization). The male Kvβ1.1 KO mice did not develop cardiac hypertrophy, but they showed long QTc and prolonged APD. Molecular analysis showed that several genes that support cardiac hypertrophy were significantly altered in Kvβ1.1 KO female hearts. In particular, myosin heavy chain α expression was significantly elevated in Kvβ1.1 KO mouse

  12. Tripartite motif 32 prevents pathological cardiac hypertrophy.

    Science.gov (United States)

    Chen, Lijuan; Huang, Jia; Ji, Yanxiao; Zhang, Xiaojing; Wang, Pixiao; Deng, Keqiong; Jiang, Xi; Ma, Genshan; Li, Hongliang

    2016-05-01

    TRIM32 (tripartite motif 32) is widely accepted to be an E3 ligase that interacts with and eventually ubiquitylates multiple substrates. TRIM32 mutants have been associated with LGMD-2H (limb girdle muscular dystrophy 2H). However, whether TRIM32 is involved in cardiac hypertrophy induced by biomechanical stresses and neurohumoral mediators remains unclear. We generated mice and isolated NRCMs (neonatal rat cardiomyocytes) that overexpressed or were deficient in TRIM32 to investigate the effect of TRIM32 on AB (aortic banding) or AngII (angiotensin II)-mediated cardiac hypertrophy. Echocardiography and both pathological and molecular analyses were used to determine the extent of cardiac hypertrophy and subsequent fibrosis. Our results showed that overexpression of TRIM32 in the heart significantly alleviated the hypertrophic response induced by pressure overload, whereas TRIM32 deficiency dramatically aggravated pathological cardiac remodelling. Similar results were also found in cultured NRCMs incubated with AngII. Mechanistically, the present study suggests that TRIM32 exerts cardioprotective action by interruption of Akt- but not MAPK (mitogen-dependent protein kinase)-dependent signalling pathways. Additionally, inactivation of Akt by LY294002 offset the exacerbated hypertrophic response induced by AB in TRIM32-deficient mice. In conclusion, the present study indicates that TRIM32 plays a protective role in AB-induced pathological cardiac remodelling by blocking Akt-dependent signalling. Therefore TRIM32 could be a novel therapeutic target for the prevention of cardiac hypertrophy and heart failure. © 2016 The Author(s).

  13. 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.

  14. Differential effects of chronic overload-induced muscle hypertrophy on mTOR and MAPK signaling pathways in adult and aged rats

    Science.gov (United States)

    We examined activation of the mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) signaling pathways in adult (Y; 6 mo old; n = 16) and aged (O; 30 mo old; n = 16) male rats (Fischer 344 x Brown Norway) subjected to chronic overload-induced muscle hypertrophy of the plan...

  15. Biochemical and histopathologic analysis of the effects of periodontitis on left ventricular heart tissues of rats.

    Science.gov (United States)

    Köse, O; Arabacı, T; Gedikli, S; Eminoglu, D Ö; Kermen, E; Kızıldağ, A; Kara, A; Ozkanlar, S; Yemenoglu, H

    2017-04-01

    Current epidemiological works have suggested that chronic infections, such as periodontitis, are associated with an increased risk of cardiovascular diseases, including hypertrophy and heart failure. However, mechanisms behind the association are not known. The aim of this study was to evaluate the effects of periodontitis on the serum lipid levels, inflammatory marker levels and left ventricular heart muscle tissues of rats. Eighteen male Sprague-Dawley rats were randomly divided into two groups: control (without ligature) and experimental periodontitis (EP; ligatured). Periodontitis was induced by placing ligatures (3.0 silk) at a submarginal position of the lower first molar teeth for 5 wk. Serum samples were collected for biochemical studies (C-reactive protein, interleukin-1β, tumor necrosis factor-α and serum lipids), after which the rats were killed and heart tissue samples were obtained for histopathological and immunological studies (nuclear factor kappa B and β-myosin heavy chain). Significant increases in C-reactive protein and interleukin-1β levels and no statistically significant increase in tumor necrosis factor-α level were observed in the EP group compared to the control group. In addition, total cholesterol, low-density lipoprotein cholesterol and triglyceride levels were significantly higher in the EP group. Stereological and immunological findings showed that the number of nuclear factor kappa B-p65- and β-myosin heavy chain-positive cardiomyocytes increased significantly in the left ventricular tissue samples of the rats with periodontitis. Early chronic phase effects of periodontitis on heart tissue are in the form of degenerative and hypotrophic changes. Prolonging the exposure to systemic inflammatory stress may increase the risk of occurrence of hypertrophic changes. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. 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.

  17. Alcohol-induced histone H3K9 hyperacetylation and cardiac hypertrophy are reversed by a histone acetylases inhibitor anacardic acid in developing murine hearts.

    Science.gov (United States)

    Peng, Chang; Zhang, Weihua; Zhao, Weian; Zhu, Jing; Huang, Xupei; Tian, Jie

    2015-06-01

    The expression of cardiac genes is precisely regulated, and any perturbation may cause developmental defects. In a previous study, we demonstrated that alcohol consumption during pregnancy could lead to uncontrolled expressions of cardiac genes and eventually result in cardiac dysplasia. However, the underlying mechanisms remain unclear. In the present study, we have investigated the alcohol-induced cardiac hypertrophy and its potential mechanisms. Furthermore, the protective effect of anacardic acid against the alcohol-induced cardiac hypertrophy has been explored in experimental mice. C57BL/6 pregnant mice were gavaged with 56% ethanol or saline and the hearts of their fetus were collected for analysis. Binding of p300, CBP, PCAF, SRC1, except GCN5, were increased to the NKX2.5 promoter in fetal mouse hearts exposed to alcohol. Increased acetylation of H3K9 and increased mRNA expression of NKX2.5, β-MHC and Cx43 were observed in the same samples. Treatment with a pan-acetylase inhibitor, anacardic acid, reduced the binding affinity of p300 and PCAF to the NKX2.5, β-MHC, Cx43 promoters and attenuated H3K9 hyperacetylation. Interestingly, anacardic acid down-regulated over-expression of these cardiac genes induced by alcohol and ultimately attenuated ethanol-induced cardiac hypertrophy in fetal mice. Our results indicate that alcohol exposure during pregnancy could lead to fetal cardiac hypertrophy. The over-expression of NKX2.5, β-MHC, Cx43 mediated by p300 and PCAF may be critical mechanisms of alcohol-induced cardiac hypertrophy. Anacardic acid can down-regulate the over-expression of cardiac genes and reverse cardiac hypertrophy caused by alcohol treatment in pregnant mice, suggesting it could be a potential therapeutic agent for the treatment of cardiac hypertrophy. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  18. Cardiac sympathetic afferent denervation attenuates cardiac remodeling and improves cardiovascular dysfunction in rats with heart failure.

    Science.gov (United States)

    Wang, Han-Jun; Wang, Wei; Cornish, Kurtis G; Rozanski, George J; Zucker, Irving H

    2014-10-01

    The enhanced cardiac sympathetic afferent reflex (CSAR) contributes to the exaggerated sympathoexcitation in chronic heart failure (CHF). Increased sympathoexcitation is positively related to mortality in patients with CHF. However, the potential beneficial effects of chronic CSAR deletion on cardiac and autonomic function in CHF have not been previously explored. Here, we determined the effects of chronic CSAR deletion on cardiac remodeling and autonomic dysfunction in CHF. To delete the transient receptor potential vanilloid 1 receptor-expressing CSAR afferents selectively, epicardial application of resiniferatoxin (50 μg/mL), an ultrapotent analog of capsaicin, was performed during myocardium infarction surgery in rats. This procedure largely abolished the enhanced CSAR, prevented the exaggerated renal and cardiac sympathetic nerve activity and improved baroreflex sensitivity in CHF rats. Most importantly, we found that epicardial application of resiniferatoxin largely prevented the elevated left ventricle end-diastolic pressure, lung edema, and cardiac hypertrophy, partially reduced left ventricular dimensions in the failing heart, and increased cardiac contractile reserve in response to β-adrenergic receptor stimulation with isoproterenol in CHF rats. Molecular evidence showed that resiniferatoxin attenuated cardiac fibrosis and apoptosis and reduced expression of fibrotic markers and transforming growth factor-β receptor I in CHF rats. Pressure-volume loop analysis showed that resiniferatoxin reduced the end-diastolic pressure volume relationships in CHF rats, indicating improved cardiac compliance. In summary, cardiac sympathetic afferent deletion exhibits protective effects against deleterious cardiac remodeling and autonomic dysfunction in CHF. These data suggest a potential new paradigm and therapeutic potential in the management of CHF. © 2014 American Heart Association, Inc.

  19. Transcriptional effects of E3 ligase atrogin-1/MAFbx on apoptosis, hypertrophy and inflammation in neonatal rat cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Yong Zeng

    Full Text Available Atrogin-1/MAFbx is an ubiquitin E3 ligase that regulates myocardial structure and function through the ubiquitin-dependent protein modification. However, little is known about the effect of atrogin-1 activation on the gene expression changes in cardiomyocytes. Neonatal rat cardiomyocytes were infected with adenovirus atrogin-1 (Ad-atrogin-1 or GFP control (Ad-GFP for 24 hours. The gene expression profiles were compared with microarray analysis. 314 genes were identified as differentially expressed by overexpression of atrogin-1, of which 222 were up-regulated and 92 were down-regulated. Atrogin-1 overexpression significantly modulated the expression of genes in 30 main functional categories, most genes clustered around the regulation of cell death, proliferation, inflammation, metabolism and cardiomyoctye structure and function. Moreover, overexpression of atrogin-1 significantly inhibited cardiomyocyte survival, hypertrophy and inflammation under basal condition or in response to lipopolysaccharide (LPS. In contrast, knockdown of atrogin-1 by siRNA had opposite effects. The mechanisms underlying these effects were associated with inhibition of MAPK (ERK1/2, JNK1/2 and p38 and NF-κB signaling pathways. In conclusion, the present microarray analysis reveals previously unappreciated atrogin-1 regulation of genes that could contribute to the effects of atrogin-1 on cardiomyocyte survival, hypertrophy and inflammation in response to endotoxin, and may provide novel insight into how atrogin-1 modulates the programming of cardiac muscle gene expression.

  20. Heart disease induced by AAS abuse, using experimental mice/rats models and the role of exercise-induced cardiotoxicity.

    Science.gov (United States)

    Riezzo, I; De Carlo, D; Neri, M; Nieddu, A; Turillazzi, E; Fineschi, V

    2011-05-01

    The anabolic-androgenic steroids (AAS) are all synthetic derivates of testosterone and are commonly used as sport performance enhancers in athletes. The heart is one of the organs most frequently affected by administration of anabolic steroids. A direct myocardial injury caused by AAS is supposed to determine marked hypertrophy in myocardial cells, extensive regional fibrosis and necrosis. A number of excellent studies, using animal models, were performed to evaluate the cardiac effects of AAS. It is known that exogenous administration induced cardiac hypertrophy in vitro and in vivo, and when combined with exercise, anabolic steroid use has been shown to change exercise-induced physiological cardiac hypertrophy to pathophysiological cardiac hypertrophy. However the molecular mechanisms are still poorly understood. It's described that sudden cardiac death, myocardial infarct; ventricular remodelling and cardiomyopathy do to AAS is related to apoptosis and oxidative stress when associated with exercise. Mechanical stimuli and circulating humoral factors (TNF-α, HSP-70, IL-1β) released by the heart and peripheral organs are responsible. Testosterone and derivates can work through genomic (activation of specific androgen receptor, interaction with coactivators and co-repressors transcription factors, gene regulation) and non-genomic mechanism (membrane-receptor-second messenger cascades). Chronic AAS abuse results in different patterns of pathologic alterations, which depend on type, dose, frequency, and mode of use. The difficulty in interpreting experimental data on animals (mice and rats) lies in the diversity of experiments (the diversity of substances, which show different properties, different mice / rats by sex and age, duration of treatment with AAS, dosages used, type, scope and exercise duration).

  1. Intrinsic cardiac adrenergic (ICA) cell density and MAO-A activity in failing rat hearts.

    Science.gov (United States)

    van Eif, Vincent W W; Bogaards, Sylvia J P; van der Laarse, Willem J

    2014-02-01

    The efficiency (work/oxygen consumption) of isolated papillary muscles from failing hearts is reduced. We investigated whether this can be due to an increase of intrinsic cardiac adrenergic (ICA) cell density. The number of ICA cells in the septum and both ventricular walls was determined by tyrosine hydroxylase immunohistochemistry in rats with monocrotaline-induced pulmonary hypertension. We found that the number of ICA cells is about 200,000 per rat heart. ICA cell density was significantly lower in right ventricular myocardium of hypertrophied hearts (P ICA cell density and MAO-A activity was absent. Clorgyline (2 μM) decreased the basal rate of oxygen consumption of right ventricular papillary muscles by 65 μM O(2)/s (P = 0.027). This rate can only be maintained for several seconds judging from the catecholamine content of the preparations reported previously. High ICA cell activity rather than density and/or recycling of oxidized catecholamines are discussed as alternative explanations for the low myocardial efficiency in experimental pulmonary hypertension.

  2. Supra-physiological dose of testosterone induces pathological cardiac hypertrophy.

    Science.gov (United States)

    Pirompol, Prapawadee; Teekabut, Vassana; Weerachatyanukul, Wattana; Bupha-Intr, Tepmanas; Wattanapermpool, Jonggonnee

    2016-04-01

    Testosterone and androgenic anabolic steroids have been misused for enhancement of physical performance despite many reports on cardiac sudden death. Although physiological level of testosterone provided many regulatory benefits to human health, including the cardiovascular function, supra-physiological levels of the hormone induce hypertrophy of the heart with unclear contractile activation. In this study, dose- and time-dependent effects of high-testosterone treatment on cardiac structure and function were evaluated. Adult male rats were divided into four groups of testosterone treatment for 0, 5, 10, and 20 mg/kg BW for 4, 8, or 12 weeks. Increases in both percentage heart:body weight ratio and cardiomyocyte cross-sectional area in representing hypertrophy of the heart were significantly shown in all testosterone-treated groups to the same degree. In 4-week-treated rats, physiological cardiac hypertrophy was apparent with an upregulation of α-MHC without any change in myofilament contractile activation. In contrast, pathological cardiac hypertrophy was observed in 8- and 12-week testosterone-treated groups, as indicated by suppression of myofilament activation and myocardial collagen deposition without transition of MHC isoforms. Only in 12-week testosterone-treated group, eccentric cardiac hypertrophy was demonstrated with unaltered myocardial stiffness, but significant reductions in the phosphorylation signals of ERK1/2 and mTOR. Results of our study suggest that the outcome of testosterone-induced cardiac hypertrophy is not dose dependent but is rather relied on the factor of exposure to duration in inducing maladaptive responses of the heart. © 2016 Society for Endocrinology.

  3. Pharmacological therapy can increase capillary density in post-infarction remodeled rat hearts

    NARCIS (Netherlands)

    Van Kerckhoven, R; van Veghel, R; Saxena, PR; Schoemaker, RG

    2004-01-01

    Objective: Postinfarction hypertrophied hearts have been shown to display a lower capillary density and reduced mechanical efficiency amplified by tachycardia. We investigated whether pharmacological reduction of postinfarction tachycardia would induce capillary growth by treating myocardial

  4. Myocardial {sup 99m}Tc-sestamibi extraction and washout in hypertensive heart failure using an isolated rat heart

    Energy Technology Data Exchange (ETDEWEB)

    Fukushima, Kenji [Department of Cardiology, Tokyo Women' s Medical University, Tokyo 162-8666 (Japan); Department of Radiology, Johns Hopkins University, Baltimore, MD (United States); Momose, Mitsuru, E-mail: mmomose@rad.twmu.ac.j [Department of Diagnostic Imaging and Nuclear Medicine, Tokyo Women' s Medical University, Tokyo 162-8666 (Japan); Kondo, Chisato [Department of Diagnostic Imaging and Nuclear Medicine, Tokyo Women' s Medical University, Tokyo 162-8666 (Japan); Higuchi, Takahiro [Department of Radiology, Johns Hopkins University, Baltimore, MD (United States); Kusakabe, Kiyoko [Department of Diagnostic Imaging and Nuclear Medicine, Tokyo Women' s Medical University, Tokyo 162-8666 (Japan); Hagiwara, Nobuhisa [Department of Cardiology, Tokyo Women' s Medical University, Tokyo 162-8666 (Japan)

    2010-11-15

    Purpose: Myocardial mitochondria are the primary part of energy production for healthy cardiac contraction. And mitochondrial dysfunction would play an important role in progressive heart failure. In the recent years, myocardial washout of {sup 99m}Tc-sestamibi [({sup 99m}Tc-hexakis-2-methoxy-2-methylpropyl isonitrile (MIBI)] has been introduced to be a potential marker in patients with heart failure. The objective of this study was to clarify MIBI extraction and washout kinetics using isolated perfusion system in hypertension induced model of myocardial dysfunction. Methods: Six-week-old Dahl-salt sensitive rats, allotted to 4 groups; a 5-week high-salt group (5wk-HS), 12-week high-salt group (12wk-HS) and two age-matched, low-salt diet control groups (5wk-LS and 12wk-LS). The rats in 5wk-HS and 12wk-HS groups were fed a high-salt diet (containing 8% NaCl). Cardiac function was examined by echocardiography before removing heart. Hearts were perfused according to the Langendorff method at a constant flow rate, in which 20-min MIBI washin was conducted followed by 25-min MIBI washout. Whole heart radioactivity was collected every sec by an external gamma detector. The myocardial extraction, K{sub 1} (ml/min) and washout rate, k{sub 2} (min{sup -1}) were generated. Results: High-salt diet groups showed significant high-blood pressure. Echocardiography revealed thickened LV walls in 5wk-HS, and reduced cardiac function in 12wk-HS, compared to each age-matched control group. K{sub 1} showed no significant difference among all groups (5wk-HS: 2.36{+-}1.07, 5wk-control: 2.59{+-}0.28, 12wk-HS: 1.91{+-}0.90, and 12wk-control: 2.84{+-}0.57). k{sub 2} in 5wk-HS was comparable to that in the age matched control group (0.00030{+-}0.00039 vs -0.000010{+-}0.00044), but it was increased remarkably in 18wk-HS compared to the age matched control group (0.0025{+-}0.0011 vs 0.000025{+-}0.000041, P<.01), and 5wk-HS (P<.01). Conclusion: In the course of hypertensive heart disease, MIBI

  5. Differential effects of isoproterenol on the activity of angiotensin-converting enzyme in the rat heart and aorta

    Directory of Open Access Journals (Sweden)

    Busatto V.C.W.

    1999-01-01

    Full Text Available The excessive stimulation of beta-adrenergic receptors in the heart induces myocardial hypertrophy. There are several experimental data suggesting that this hypertrophy may also depend, at least partially, on the increase of local production of angiotensin II secondary to the activation of the cardiac renin-angiotensin system. In this study we investigated the effects of isoproterenol on the activity of angiotensin-converting enzyme (ACE in the heart and also in the aorta and plasma. Male Wistar rats weighing 250 to 305 g were treated with a dose of (±-isoproterenol (0.3 mg kg-1 day-1, N = 8 sufficient to produce cardiac hypertrophy without deleterious effects on the pumping capacity of the heart. Control rats (N = 7 were treated with vehicle (corn oil. The animals were killed one week later. ACE activity was determined in vitro in the four cardiac chambers, aorta and plasma by a fluorimetric assay. A significant hypertrophy was observed in both ventricular chambers. ACE activity in the atria remained constant after isoproterenol treatment. There was a significant increase (P<0.05 of ACE activity in the right ventricle (6.9 ± 0.9 to 8.2 ± 0.6 nmol His-Leu g-1 min-1 and in the left ventricle (6.4 ± 1.1 to 8.9 ± 0.8 nmol His-Leu g-1 min-1. In the aorta, however, ACE activity decreased (P<0.01 after isoproterenol (41 ± 3 to 27 ± 2 nmol His-Leu g-1 min-1 while it remained unchanged in the plasma. These data suggest that ACE expression in the heart can be increased by stimulation of beta-adrenoceptors. However, this effect is not observed on other local renin-angiotensin systems, such as the aorta. Our data also suggest that the increased sympathetic discharge and the elevated plasma concentration of catecholamines may contribute to the upregulation of ACE expression in the heart after myocardial infarction and heart failure.

  6. Communication: Effect of diperoxovandate on isolated rat heart ...

    African Journals Online (AJOL)

    ... also produced marked disturbances in the rhythm indicating cardiac toxicity. This was further confirmed by lactate dehydrogenase (LDH) activity determination. Keywords: diperoxovanadate, reperfusion, isolated rat heart, hydrogen peroxide, lactate dehydrogenase. Ethiopian Pharmaceutical Journal, vol. 22 (2004): 47-52 ...

  7. Slow contractions characterize failing rat hearts.

    Science.gov (United States)

    Bøkenes, Janny; Aronsen, Jan Magnus; Birkeland, Jon Arne; Henriksen, Unni Lie; Louch, William E; Sjaastad, Ivar; Sejersted, Ole M

    2008-07-01

    The reduced power of the failing heart can be ascribed to a combination of reduced force and slower contraction. We hypothesized that these two properties are due to different cellular mechanisms. We measured contraction parameters both in vivo and in isolated left ventricular (LV) cardiomyocytes from a rat model of post infarction congestive heart failure (CHF). ECG was measured simultaneously with echocardiography and LV pressure, respectively. Shortening and shortening velocity (SV) in isolated cardiomyocytes were measured during different stimulation protocols. LV end diastolic pressure (LVEDP) was 24.6 +/- 0.7 mmHg in CHF. LV systolic pressure was decreased by 20%, maximum rate of pressure development in the LV (+dP/dtmax) by 36% and time in systole increased by 20% in CHF compared to sham. Electrical remodelling occurred in CHF cells, which were depolarized and had prolonged action potentials (AP) compared to sham cells. Fractional shortening (FS) was increased in CHF compared to sham independent of stimulation protocol. Larger FS was accompanied by increased sarcoplasmic reticulum (SR) Ca2+ load and depended on the electrical remodelling. Time to peak contraction (TTP) was increased in CHF compared to sham cells, but in contrast to FS, TTP was only slightly affected when the cells were stimulated with sham APs and sham diastolic membrane potential (DMP). Contraction duration (corresponding to systolic duration) was 25% longer in CHF than in sham independent on stimulation protocol. We conclude that electrical remodelling affecting DMP and AP duration (APD) significantly affects the size of contraction, whereas the mechanism for slowing of contraction in CHF is different.

  8. Isorhamnetin protects against cardiac hypertrophy through blocking PI3K-AKT pathway.

    Science.gov (United States)

    Gao, Lu; Yao, Rui; Liu, Yuzhou; Wang, Zheng; Huang, Zhen; Du, Binbin; Zhang, Dianhong; Wu, Leiming; Xiao, Lili; Zhang, Yanzhou

    2017-05-01

    Isorhamnetin, a flavonoid compound extracted from the Chinese herb Hippophae rhamnoides L., is well known for its anti-inflammatory, anti-oxidative, anti-adipogenic, anti-proliferative, and anti-tumor activities. However, the role of isorhamnetin in cardiac hypertrophy has not been reported. The aims of the present study were to find whether isorhamnetin could alleviate cardiac hypertrophy and to define the underlying molecular mechanisms. Here, we investigated the effects of isorhamnetin (100 mg/kg/day) on cardiac hypertrophy induced by aortic banding in mice. Cardiac hypertrophy was evaluated by echocardiographic, hemodynamic, pathological, and molecular analyses. Our data demonstrated that isorhamnetin could inhibit cardiac hypertrophy and fibrosis 8 weeks after aortic banding. The results further revealed that the effect of isorhamnetin on cardiac hypertrophy was mediated by blocking the activation of phosphatidylinositol 3-kinase-AKT signaling pathway. In vitro studies performed in neonatal rat cardiomyocytes confirmed that isorhamnetin could attenuate cardiomyocyte hypertrophy induced by angiotensin II, which was associated with phosphatidylinositol 3-kinase-AKT signaling pathway. In conclusion, these data indicate for the first time that isorhamnetin has protective potential for targeting cardiac hypertrophy by blocking the phosphatidylinositol 3-kinase-AKT signaling pathway. Thus, our study suggests that isorhamnetin may represent a potential therapeutic strategy for the treatment of cardiac hypertrophy and heart failure.

  9. Smad Nuclear Interacting Protein 1 Acts as a Protective Regulator of Pressure Overload-Induced Pathological Cardiac Hypertrophy.

    Science.gov (United States)

    Lu, Yu-Yan; Xu, Da-Chun; Zhao, Yi-Fan; Zhu, Guo-Fu; Zhu, Meng-Yun; Liu, Wei-Jing; Yu, Xue-Jing; Chen, Wei; Liu, Zheng; Xu, Ya-Wei

    2016-10-26

    Smad nuclear interacting protein 1 (SNIP1) plays a critical role in cell proliferation, transformation of embryonic fibroblasts, and immune regulation. However, the role of SNIP1 in cardiac hypertrophy remains unclear. Here we examined the role of SNIP1 in pressure overload-induced cardiac hypertrophy and its mechanisms. Our results demonstrated that SNIP1 expression was downregulated in human dilated cardiomyopathic hearts, aortic banding-induced mice hearts, and angiotensin II-treated cardiomyocytes. Accordingly, SNIP1 deficiency significantly exacerbated aortic banding-induced cardiac hypertrophy, fibrosis, and contractile dysfunction, whereas cardiac-specific overexpression of SNIP1 markedly recovered pressure overload-induced cardiac hypertrophy and fibrosis. Besides that, SNIP1 protected neonatal rat cardiomyocytes against angiotensin II-induced hypertrophy in vitro. Moreover, we identified that SNIP1 suppressed nuclear factor-κB signaling during pathological cardiac hypertrophy, and inhibition of nuclear factor-κB signaling by a cardiac-specific conditional inhibitor of κB S 32A/S36A transgene blocked these adverse effects of SNIP1 deficiency on hearts. Together, our findings demonstrated that SNIP1 had protective effects in pressure overload-induced pathological cardiac hypertrophy via inhibition of nuclear factor-κB signaling. Thus, SNIP1 may be a novel approach for the treatment of heart failure. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  10. Effects of low level laser in the morphology of the skeletal muscle fiber during compensatory hypertrophy in plantar muscle of rats

    Science.gov (United States)

    Terena, Stella Maris Lins; Fernandes, Kristianne Porta Santos; Kalil, Sandra; Alves, Agnelo Neves; Mesquita Ferrari, Raquel Agnelli

    2015-06-01

    The hypertrophy is known as an increase the cross-sectional area of the muscle as a result of a muscular work against an overload, and it is compensatory because the overload is induced by functional elimination of synergistic muscles. The importance of study the compensatory hypertrophy is understand how this process can be influenced by the irradiation with regard to the weight and muscle cross-sectional area, to assist in the rehabilitation process and the effectiveness functional return. The aim was evaluate the effects of low-level laser irradiation on morphological aspects of muscle tissue, comparing the weight and cross-sectional area in rat skeletal muscle. Wistar rats were divided into three groups: control, hypertrophy group without irradiation (right plantar muscle) and hypertrophy group and irradiation (left plantar muscle), both analyzed after 7 and 14 days. The irradiation was performed daily immediately after the surgery. The parameters were: λ = 780nm, beam spot of 0.04 cm2, output power of 40mW, power density of 1W/cm2, energy density of 10J / cm2 and 10s exposure time with a total energy of 3.2 J. The results revealed that low level laser irradiation an increase the weight of the plantaris muscle after 7 and 14 days with a difference of 7.06% and 11.51% respectively. In conclusion, low level laser irradiation has an effect on compensatory hypertrophy to produce increased muscle weight and promoted an increase in cross-sectional area of muscle fibers in the compensatory hypertrophy model after 14 days with parameters cited above.

  11. Hypertrophy Stimulation at the Onset of Type I Diabetes Maintains the Soleus but Not the EDL Muscle Mass in Wistar Rats

    Directory of Open Access Journals (Sweden)

    Marco A. S. Fortes

    2017-10-01

    Full Text Available Diabetes mellitus induces a reduction in skeletal muscle mass and strength. Strength training is prescribed as part of treatment since it improves glycemic control and promotes increase of skeletal muscle mass. The mechanisms involved in overload-induced muscle hypertrophy elicited at the establishment of the type I diabetic state was investigated in Wistar rats. The purpose was to examine whether the overload-induced hypertrophy can counteract the hypotrophy associated to the diabetic state. The experiments were performed in oxidative (soleus or glycolytic (EDL muscles. PI3K/Akt/mTOR protein synthesis pathway was evaluated 7 days after overload-induced hypertrophy of soleus and of EDL muscles. The mRNA expression of genes associated with different signaling pathways that control muscle hypertrophy was also evaluated: mechanotransduction (FAK, Wnt/β-catenin, myostatin, and follistatin. The soleus and EDL muscles when submitted to overload had similar hypertrophic responses in control and diabetic animals. The increase of absolute and specific twitch and tetanic forces had the same magnitude as muscle hypertrophic response. Hypertrophy of the EDL muscle from diabetic animals mostly involved mechanical loading-stimulated PI3K/Akt/mTOR pathway besides the reduced activation of AMP-activated protein kinase (AMPK and decrease of myostatin expression. Hypertrophy was more pronounced in the soleus muscle of diabetic animals due to a more potent activation of rpS6 and increased mRNA expression of insulin-like growth factor-1 (IGF-1, mechano-growth factor (MGF and follistatin, and decrease of myostatin, MuRF-1 and atrogin-1 contents. The signaling changes enabled the soleus muscle mass and force of the diabetic rats to reach the values of the control group.

  12. Heart dysfunction and fibrosis in rat treated with myocardial ...

    African Journals Online (AJOL)

    Because cardiovascular disease remains a serious problem in modern human society, the aim of this study was to establish the rat model animal and to compare the heart dysfunction and fibrosis with SD and LE rats when treated with myocardial ischemia and reperfusion operation. A 20-minute thoracotomy was performed ...

  13. Transforming growth factor βs are upregulated in the rat masseter muscle hypertrophied by clenbuterol, a β2 adrenergic agonist

    Science.gov (United States)

    Akutsu, Satonari; Shimada, Akemi; Yamane, Akira

    2006-01-01

    The regulatory mechanism for the hypertrophy of skeletal muscles induced by clenbuterol is unclear. The purpose of the present study was to determine the extent to which transforming growth factor βs (TGFβs), fibroblast growth factors (FGFs), hepatocyte growth factor (HGF), and platelet-derived growth factors (PDGFs) are involved in the hypertrophy of rat masseter muscle induced by clenbuterol. We measured the mRNA expression levels for TGFβs, FGFs, HGF, and PDGFs in rat masseter muscle hypertrophied by oral administration of clenbuterol for 3 weeks and determined correlations between the weight of masseter muscle and mRNA expression levels by regression analysis. We determined immunolocalizations of TGFβs and their receptors (TGFβRs). The mRNA expression levels for TGFβ1, 2, and 3, and for PDGF-B demonstrated clenbuterol-induced elevations and positive correlations with the weight of masseter muscle. In particular, TGFβ1, 2, and 3 showed strong positive correlations (correlation coefficients >0.6). The mRNA expression levels for PDGF-A, FGF-1 and 2, and HGF showed no significant differences between the control and clenbuterol groups, and no significant correlations. TGFβ1, 2, and 3 were principally localized in the connective tissues interspaced among myofibers, and TGFβRI and II were localized in the periphery and sarcoplasm of the myofibers. These results suggest that paracrine actions of TGFβ1, 2, and 3 via TGFβRI and II could be involved in the hypertrophy of rat masseter muscle induced by clenbuterol. This is the first study to document the involvement of TGFβs in the hypertrophy of skeletal muscles induced by clenbuterol. PMID:16402040

  14. 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.

  15. 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

  16. Left Ventricular Hypertrophy

    Science.gov (United States)

    ... AskMayoExpert. What tests are needed to confirm the diagnosis of hypertrophic cardiomyopathy (HCM) and what is the role of genetic testing? Rochester, Minn.: Mayo Foundation for Medical Education and Research; ... diagnosis in patients with hypertrophied left ventricles. Heart. 2014; ...

  17. Oxidative profiling of the failing right heart in rats with pulmonary hypertension.

    Directory of Open Access Journals (Sweden)

    Xinhong Wang

    Full Text Available Right heart failure is the major cause of death among patients with pulmonary arterial hypertension (PAH. Understanding the biology of the right ventricle (RV should help developing new therapeutic strategies. Rats subjected to the injection of Sugen5416 (an inhibitors of vascular endothelial growth factor receptor plus the ovalbumin immunization had increased pulmonary arterial pressure and severe vascular remodeling. RVs of these rats were hypertrophied and had severe cardiac fibrosis. No apoptosis was, however, detected. Metabolomics analysis revealed that oxidized glutathione, xanthine and uric acid had increased in PAH RVs, suggesting the production of reactive oxygen species by xanthine oxidase. PAH RVs were also found to have a 30-fold lower level of α-tocopherol nicotinate, consistent with oxidative stress decreasing antioxidants and also demonstrating for the first time that the nicotinate ester of vitamin E is endogenously expressed. Oxidative/nitrosative protein modifications including S-glutathionylation, S-nitrosylation and nitrotyrosine formation, but not protein carbonylation, were found to be increased in RVs of rats with PAH. Mass spectrometry identified that S-nitrosylated proteins include heat shock protein 90 and sarcoplasmic reticulum Ca2+-ATPase. These results demonstrate that RV failure is associated with the promotion of specific oxidative and nitrosative stress.

  18. Angiotensin II induced inflammation in the kidney and in the heart of double transgenic rats

    Directory of Open Access Journals (Sweden)

    Haller Hermann

    2002-01-01

    Full Text Available Abstract Background We are investigating a double transgenic rat (dTGR model, in which rats transgenic for the human angiotensinogen and renin genes are crossed. These rats develop moderately severe hypertension but die of end-organ cardiac and renal damage by week 7. The heart shows necrosis and fibrosis, whereas the kidneys resemble the hemolytic-uremic syndrome vasculopathy. Surface adhesion molecules (ICAM-1 and VCAM-1 are expressed early on the endothelium, while the corresponding ligands are found on circulating leukocytes. Leukocyte infiltration in the vascular wall accompanies PAI-1, MCP-1, iNOS and Tissue Factor expression. Furthermore we show evidence that Ang II causes the upregulation of NF-kB in our model. Methods We started PDTC-treatment on four weeks old dTGR (200 mg/kg sc and age-matched SD rats.. Blood-pressure- and albuminuria- measurements were monitored during the treatement period (four weeks. The seven weeks old animals were killed, hearts and kidneys were isolated and used for immunohistochemical-and electromobility shift assay analsis. Results Chronic treatment with the antioxidant PDTC decreased blood pressure (162 ± 8 vs. 190 ± 7 mm Hg, p = 0.02. Cardiac hypertrophy index was significantly reduced (4.90 ± 0.1 vs. 5.77 ± 0.1 mg/g, p Conclusion Our data show that inhibition of NF-κB by PDTC markedly reduces inflammation, iNOS expression in the dTGR most likely leading to decreased cytotoxicity, and cell proliferation. Thus, NF-κB activation plays an important role in ANG II-induced end-organ damage.

  19. [Effects of sapindus saponins on inflammatory response mediated by Ang II/p38MAPK pathway and cardiac hypertrophy in spontaneously hypertensive rats].

    Science.gov (United States)

    Chen, Ming; Chen, Zhi-Wu; Long, Zi-Jiang; Liu, Jin-Lin; Gao, Hua-Wu; Wang, Ya-Juan

    2013-04-01

    To investigate the effects of sapindus saponins on myocardial inflammation mediated by Ang II/ p38MAPK signal pathway and cardiac hypertrophy in spontaneously hypertensive rats. And also to explore the correlation of cardiac hypertrophy and inflammation. Thirty-two 16-week-old spontaneously hypertensive rats (SHR) were randomly divided into four groups, one with placebo as model group, one with captopril tablets (27 mg x kg(-1)) as positive control, one with low-dose sapindus saponins (27 mg x kg(-1)), one with high-dose (108 mg x kg(-1)). And another eight healthy Wistar-Kyoto strain (WKY) rats were used as the normal group. The animals were treated for eight weeks, and the indicators detected were as follows: (1) left ventricular mass index (LVMI); (2) the content of Ang II and hs-CRP in plasma were determined by ELISA; (3) the protein expression of AT1R and VEGF were determined by immunohistochemical method; (4) the protein expression of p-p38MAPK in myocardial cells was determined by Western blot. Sapindus saponins reduced LVMI, and blocked the expression level of Ang II, AT1R, p-p38MAPK, VEGF and hs-CRP in myocardial tissue. Vs the SHR model group, there were significant differences (P sapindus saponins could inhibited cardiac hypertrophy, the possible mechanisms may be related to the inhibition on inflammatory response mediated by Ang II/p38MAPK pathway.

  20. Effects of dopamine on isolated failing rat heart.

    Science.gov (United States)

    Paterna, S; Di Pasquale, P; Antona, A; Damico, C; Listro, G; Bucca, V; Palazzoadriano, M; Arrostuto, A; Cannavo, M G; Scalzo, S

    1994-01-01

    Dopamine has been used for many years to treat patients with severe heart failure. It is not clear whether improvements of cardiac function may be due to a direct action on heart. This study was aimed to investigate the direct action of dopamine on failing heart. we chose male Wistar rats which had undergone uninephrectomy under ether anaesthesia to induce hypertension to result in heart failure. After 5 weeks the hearts were excised and perfused according to Langerdoff's technique. Heart rate, systolic and diastolic ventricular pressures, the derivative of the intraventricular pressure time ratio, and coronary flow were measured at baseline, at 2 and 5 min and then every 5 min during a 30-min period. Rat hearts were divided into 4 groups of 5 hearts: group 1, perfused without drug; group 2, perfused with dopamine at 4 micrograms/kg/min; group 3, perfused with dopamine at 8 micrograms/kg/min; group 4, perfused with dopamine at 8 micrograms/kg/min and with 100 nM I.C.I. 118.551 (beta 2-ant: beta-2 receptors antagonist) at the same time. Our results show that dopamine induced a negative inotropic effect and a reduction of coronary flow. Moreover, there was a significant chronotropic action even when dopamine was administered at high concentrations. So we found no positive dopamine effect on isolated failured hearts of rat. This might be explained by both alpha-1-induced vasoconstriction and the stimulation of alpha-1B receptors. We conclude that the favourable effects of dopamine in heart failure could be due to DA1 vasodilation rather than to a direct inotropic action on the heart.

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

    Science.gov (United States)

    Aubdool, Aisah A; Thakore, Pratish; Argunhan, Fulye; Smillie, Sarah-Jane; Schnelle, Moritz; Srivastava, Salil; Alawi, Khadija M; Wilde, Elena; Mitchell, Jennifer; Farrell-Dillon, Keith; Richards, Daniel A; Maltese, Giuseppe; Siow, Richard C; Nandi, Manasi; Clark, James E; Shah, Ajay M; Sams, Anette; Brain, Susan D

    2017-07-25

    Research into the therapeutic potential of α-calcitonin gene-related peptide (α-CGRP) has been limited because of its peptide nature and short half-life. Here, we evaluate whether a novel potent and long-lasting ( t ½ ≥7 hours) acylated α-CGRP analogue (αAnalogue) could alleviate and reverse cardiovascular disease in 2 distinct murine models of hypertension and heart failure in vivo. The ability of the αAnalogue to act selectively via the CGRP pathway was shown in skin by using a CGRP receptor antagonist. The effect of the αAnalogue on angiotensin II-induced hypertension was investigated over 14 days. Blood pressure was measured by radiotelemetry. The ability of the αAnalogue to modulate heart failure was studied in an abdominal aortic constriction model of murine cardiac hypertrophy and heart failure over 5 weeks. Extensive ex vivo analysis was performed via RNA analysis, Western blot, and histology. The angiotensin II-induced hypertension was attenuated by cotreatment with the αAnalogue (50 nmol·kg -1 ·d -1 , SC, at a dose selected for lack of long-term hypotensive effects at baseline). The αAnalogue protected against vascular, renal, and cardiac dysfunction, characterized by reduced hypertrophy and biomarkers of fibrosis, remodeling, inflammation, and oxidative stress. In a separate study, the αAnalogue reversed angiotensin II-induced hypertension and associated vascular and cardiac damage. The αAnalogue was effective over 5 weeks in a murine model of cardiac hypertrophy and heart failure. It preserved heart function, assessed by echocardiography, while protecting against adverse cardiac remodeling and apoptosis. Moreover, treatment with the αAnalogue was well tolerated with neither signs of desensitization nor behavioral changes. These findings, in 2 distinct models, provide the first evidence for the therapeutic potential of a stabilized αAnalogue, by mediating (1) antihypertensive effects, (2) attenuating cardiac remodeling, and (3

  2. Effect of Zhen-wu decoction on chronic heart failure in rats

    African Journals Online (AJOL)

    legislation_en.htm. 16. Seddon M, Looi YH, Shah AM. Oxidative stress and redox signalling in cardiac hypertrophy and heart failure. Heart 2006; 12: 131-138. 17. Azevedo PS, Minicucci MF, Santos PP. Energy metabolism in cardiac remodeling and ...

  3. Calhex₂₃₁ Ameliorates Cardiac Hypertrophy by Inhibiting Cellular Autophagy in Vivo and in Vitro.

    Science.gov (United States)

    Liu, Lei; Wang, Chao; Sun, Dianjun; Jiang, Shuangquan; Li, Hong; Zhang, Weihua; Zhao, Yajun; Xi, Yuhui; Shi, Sa; Lu, Fanghao; Tian, Ye; Xu, Changqing; Wang, Lina

    2015-01-01

    Intracellular calcium concentration ([Ca2+]i) homeostasis, an initial factor of cardiac hypertrophy, is regulated by the calcium-sensing receptor (CaSR) and is associated with the formation of autolysosomes. The aim of this study was to investigate the role of Calhex231, a CaSR inhibitor, on the hypertrophic response via autophagy modulation. Cardiac hypertrophy was induced by transverse aortic constriction (TAC) in 40 male Wistar rats, while 10 rats underwent a sham operation and served as controls. Cardiac function was monitored by transthoracic echocardiography, and the hypertrophy index was calculated. Cardiac tissue was stained with hematoxylin and eosin (H&E) or Masson’s trichrome reagent and examined by transmission electron microscopy. An angiotensin II (Ang II)-induced cardiomyocyte hypertrophy model was established and used to test the involvement of active molecules. Intracellular calcium concentration ([Ca2+]i) was determined by the introduction of Fluo-4/AM dye followed by confocal microscopy. The expression of various active proteins was analyzed by western blot. The rats with TAC-induced hypertrophy had an increased heart size, ratio of heart weight to body weight, myocardial fibrosis, and CaSR and autophagy levels, which were suppressed by Calhex231. Experimental results using Ang II-induced hypertrophic cardiomyocytes confirmed that Calhex231 suppressed CaSR expression and downregulated autophagy by inhibiting the Ca2+/calmodulin-dependent-protein kinase-kinase-β (CaMKKβ)– AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway to ameliorate cardiomyocyte hypertrophy. Calhex231 ameliorates myocardial hypertrophy induced by pressure-overload or Ang II via inhibiting CaSR expression and autophagy. Our results may support the notion that Calhex231 can become a new therapeutic agent for the treatment of cardiac hypertrophy. © 2015 S. Karger AG, Basel.

  4. Pivotal Role of Regulator of G-protein Signaling 12 in Pathological Cardiac Hypertrophy.

    Science.gov (United States)

    Huang, Jia; Chen, Lijuan; Yao, Yuyu; Tang, Chengchun; Ding, Jiandong; Fu, Cong; Li, Hongliang; Ma, Genshan

    2016-06-01

    Cardiac hypertrophy is a major predictor of heart failure and is regulated by diverse signaling pathways. As a typical multi-domain member of the regulator of G-protein signaling (RGS) family, RGS12 plays a regulatory role in various signaling pathways. However, the precise effect of RGS12 on cardiac hypertrophy remains largely unknown. In this study, we observed increased expression of RGS12 in the development of pathological cardiac hypertrophy and heart failure. We then generated genetically engineered mice and neonatal rat cardiomyocytes to investigate the effects of RGS12 during this pathological process. Four weeks after aortic banding, RGS12-deficient hearts showed decreased cardiomyocyte cross area (374.7±43.2 μm(2) versus 487.1±47.9 μm(2) in controls; Phypertrophy in isolated cardiomyocytes. Mechanistically, our data indicated that the activation of MEK1/2-ERK1/2 signaling may be responsible for the prohypertrophic action of RGS12. In addition, the requirement of the MEK1/2-ERK1/2 signaling for RGS12-mediated cardiac hypertrophy was confirmed in rescue experiments using the MEK1/2-specific inhibitor U0126. In conclusion, our findings provide a novel diagnostic and therapeutic target for pathological cardiac hypertrophy and heart failure. © 2016 American Heart Association, Inc.

  5. 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.

  6. Physiological and pathological cardiac hypertrophy.

    Science.gov (United States)

    Shimizu, Ippei; Minamino, Tohru

    2016-08-01

    The heart must continuously pump blood to supply the body with oxygen and nutrients. To maintain the high energy consumption required by this role, the heart is equipped with multiple complex biological systems that allow adaptation to changes of systemic demand. The processes of growth (hypertrophy), angiogenesis, and metabolic plasticity are critically involved in maintenance of cardiac homeostasis. Cardiac hypertrophy is classified as physiological when it is associated with normal cardiac function or as pathological when associated with cardiac dysfunction. Physiological hypertrophy of the heart occurs in response to normal growth of children or during pregnancy, as well as in athletes. In contrast, pathological hypertrophy is induced by factors such as prolonged and abnormal hemodynamic stress, due to hypertension, myocardial infarction etc. Pathological hypertrophy is associated with fibrosis, capillary rarefaction, increased production of pro-inflammatory cytokines, and cellular dysfunction (impairment of signaling, suppression of autophagy, and abnormal cardiomyocyte/non-cardiomyocyte interactions), as well as undesirable epigenetic changes, with these complex responses leading to maladaptive cardiac remodeling and heart failure. This review describes the key molecules and cellular responses involved in physiological/pathological cardiac hypertrophy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Mesenchymal Stem Cells Improve Heart Rate Variability and Baroreflex Sensitivity in Rats with Chronic Heart Failure

    Science.gov (United States)

    de Morais, Sharon Del Bem Velloso; da Silva, Luiz Eduardo Virgilio; Lataro, Renata Maria; Silva, Carlos Alberto Aguiar; de Oliveira, Luciano Fonseca Lemos; de Carvalho, Eduardo Elias Vieira; Simões, Marcus Vinicius; da Silva Meirelles, Lindolfo; Fazan, Rubens

    2015-01-01

    Heart failure induced by myocardial infarct (MI) attenuates the heart rate variability (HRV) and baroreflex sensitivity, which are important risk factors for life-threatening cardiovascular events. Therapies with mesenchymal stem cells (MSCs) have shown promising results after MI. However, the effects of MSCs on hemodynamic (heart rate and arterial pressure) variability and baroreflex sensitivity in chronic heart failure (CHF) following MI have not been evaluated thus far. Male Wistar rats received MSCs or saline solution intravenously 1 week after ligation of the left coronary artery. Control (noninfarcted) rats were also evaluated. MI size was assessed using single-photon emission computed tomography (SPECT). The left ventricular ejection fraction (LVEF) was evaluated using radionuclide ventriculography. Four weeks after MSC injection, the animals were anesthetized and instrumented for chronic ECG recording and catheters were implanted in the femoral artery to record arterial pressure. Arterial pressure and HRVs were determined in time and frequency domain (spectral analysis) while HRV was also examined using nonlinear methods: DFA (detrended fluctuation analysis) and sample entropy. The initial MI size was the same among all infarcted rats but was reduced by MSCs. CHF rats exhibited increased myocardial interstitial collagen and sample entropy combined with the attenuation of the following cardiocirculatory parameters: DFA indices, LVEF, baroreflex sensitivity, and HRV. Nevertheless, MSCs hampered all these alterations, except the LVEF reduction. Therefore, 4 weeks after MSC therapy was applied to CHF rats, MI size and myocardial interstitial fibrosis decreased, while baroreflex sensitivity and HRV improved. PMID:26059001

  8. Effect of desferrioxamine on reperfusion damage of rat heart ...

    African Journals Online (AJOL)

    1990-09-01

    Sep 1, 1990 ... of rat heart mitochondria. H. VAN JAARSVELD, J. M. KUYL, A. J. GROENEWALD, G. M. POTGIETER. Summary. Ischaemia of the myocardium leads to necrosis unless oxygen supply is restored but it has only recently been realised that reperfusion is not without danger. The greatest rate of myocardial ...

  9. Effect of desferrioxamine on reperfusion damage of rat heart ...

    African Journals Online (AJOL)

    Ischaemia of the myocardium leads to necrosis unless oxygen supply is restored but it has only recently been realised that reperfusion is not without danger. The greatest rate of myocardial damage, as measured by mitochondrial function, occurred during the first 5 minutes of reperfusion in rat hearts subjected to ...

  10. Heart dysfunction and fibrosis in rat treated with myocardial ...

    African Journals Online (AJOL)

    use

    2011-11-16

    Nov 16, 2011 ... study was to establish the rat model animal and to compare the heart dysfunction and fibrosis with SD ..... Figure 4. The myocardial fibrosis formation after myocardial ischemia and reperfusion surgery. Pictures on the left were hematoxylin and eosin (H and E) staining results, pictures on the right were ...

  11. Ventricular hypertrophy in cardiomyopathy.

    Science.gov (United States)

    Oakley, C

    1971-01-01

    Semantic difficulties arise when hypertrophic obstructive cardiomyopathy is seen without obstruction and with congestive failure, and also when congestive cardiomyopathy is seen with gross hypertrophy but without heart failure. Retention of a small left ventricular cavity and a normal ejection fraction characterizes hypertrophic cardiomyopathy at all stages of the disorder. Congestive cardiomyopathy is recognized by the presence of a dilated left ventricular cavity and reduced ejection fraction regardless of the amount of hypertrophy and the presence or not of heart failure. Longevity in congestive cardiomyopathy seems to be promoted when hypertrophy is great relative to the amount of pump failure as measured by increase in cavity size. Conversely, death in hypertrophic cardiomyopathy is most likely when hypertrophy is greatest at a time when outflow tract obstruction has been replaced by inflow restriction caused by diminishing ventricular distensibility. Hypertrophy is thus beneficial and compensatory in congestive cardiomyopathy, whereas it may be the primary disorder and eventual cause of death in hypertrophic cardiomyopathy. Reasons are given for believing that hypertension may have been the original cause of left ventricular dilatation in some case of congestive cardiomyopathy in which loss of stroke output thenceforward is followed by normotension. Development of severe hypertension in these patients after recovery from a prolonged period of left ventricular failure with normotension lends weight to this hypothesis. No fault has been found in the large or small coronary arteries in either hypertrophic cardiomyopathy or congestive cardiomyopathy when they have been examined in life by selective coronary angiography, or by histological methods in biopsy or post-mortem material. Coronary blood supply may be a limiting factor in the compensatory hypertrophy of congestive cardiomyopathy, and the ability to hypertrophy may explain the better prognosis of some

  12. Preventive effect of Eucommia leaf extract on aortic media hypertrophy in Wistar-Kyoto rats fed a high-fat diet.

    Science.gov (United States)

    Hosoo, Shingo; Koyama, Masahiro; Watanabe, Akira; Ishida, Ryuya; Hirata, Tetsuya; Yamaguchi, Yasuyo; Yamasaki, Hiroo; Wada, Keiji; Higashi, Yukihito; Nakamura, Kozo

    2017-06-01

    Eucommia ulmoides Oliver leaf extract (ELE) has been shown to have anti-hypertensive and anti-obesity effects in rats that are fed a high-fat diet (HFD). To explore the effects of chronic administration of ELE on body weight, blood pressure and aortic media thickness, 7-week-old male Wistar-Kyoto (WKY) rats were orally administered a normal diet, a 30% HFD, or a 5% ELE plus HFD ad libitum for 10 weeks. The HFD treatment caused mild obesity and hypertension in the normotensive rats, while rats receiving both ELE and the HFD had significantly lower body weights, less visceral and perirenal fat, lower blood pressure and thinner aortic media than the control rats receiving the HFD only. The plasma adiponectin/leptin ratio also improved in ELE-treated rats. Although plasma leptin levels were elevated in all HFD rats, adiponectin levels increased only in the ELE-treated rats. Anti-hypertensive and anti-obesity effects may be caused by the geniposidic acid (GEA) and/or asperuloside present in ELE. These findings suggest that chronic ELE administration prevents aortic media hypertrophy in early-stage obesity with hypertension. Long-term administration of ELE might inhibit the development of arteriosclerosis.

  13. Early Spironolactone Treatment Attenuates Heart Failure Development by Improving Myocardial Function and Reducing Fibrosis in Spontaneously Hypertensive Rats

    Directory of Open Access Journals (Sweden)

    Marcelo D.M. Cezar

    2015-07-01

    Full Text Available Background: We evaluated the role of the aldosterone blocker spironolactone in attenuating long-term pressure overload-induced cardiac remodeling and heart failure (HF in spontaneously hypertensive rats (SHR. Methods and Results: Thirteen month-old male SHR were assigned to control (SHR-C, n=20 or spironolactone (SHR-SPR, 20 mg/kg/day, n=24 groups for six months. Normotensive Wistar-Kyoto rats (WKY, n=15 were used as controls. Systolic blood pressure was higher in SHR groups and unchanged by spironolactone. Right ventricular hypertrophy, which characterizes HF in SHR, was less frequent in SHR-SPR than SHR-C. Echocardiographic parameters did not differ between SHR groups. Myocardial function was improved in SHR-SPR compared to SHR-C [developed tension: WKY 4.85±0.68; SHR-C 5.22±1.64; SHR-SPR 6.80±1.49 g/mm2; -dT/dt: WKY 18.0 (16.0-19.0; SHR-C 20.8 (18.4-25.1; SHR-SPR 28.9 (24.2-34.6 g/mm2/s]. Cardiomyocyte cross-sectional area and total collagen concentration (WKY 1.06±0.34; SHR-C 1.85±0.63; SHR-SPR 1.28±0.39 µg/mg wet tissue were greater in SHR-C than WKY and SHR-SPR. Type 3 collagen expression was lower in SHR-C than WKY and unchanged by spironolactone. Soluble collagen, type I collagen, and lysyl oxidase did not differ between groups. Conclusion: Early spironolactone treatment decreases heart failure development frequency by improving myocardial systolic and diastolic function and attenuating hypertrophy and fibrosis in spontaneously hypertensive rats.

  14. 19-Hydroxyeicosatetraenoic acid and isoniazid protect against angiotensin II-induced cardiac hypertrophy.

    Science.gov (United States)

    Elkhatali, Samya; El-Sherbeni, Ahmed A; Elshenawy, Osama H; Abdelhamid, Ghada; El-Kadi, Ayman O S

    2015-12-15

    We have recently demonstrated that 19-hydroxyeicosatetraenoic acid (19-HETE) is the major subterminal-HETE formed in the heart tissue, and its formation was decreased during cardiac hypertrophy. In the current study, we examined whether 19-HETE confers cardioprotection against angiotensin II (Ang II)-induced cardiac hypertrophy. The effect of Ang II, with and without 19-HETE (20 μM), on the development of cellular hypertrophy in cardiomyocyte RL-14 cells was assessed by real-time PCR. Also, cardiac hypertrophy was induced in Sprague-Dawley rats by Ang II, and the effect of increasing 19-HETE by isoniazid (INH; 200mg/kg/day) was assessed by heart weight and echocardiography. Also, alterations in cardiac cytochrome P450 (CYP) and their associated arachidonic acid (AA) metabolites were determined by real-time PCR, Western blotting and liquid-chromatography-mass-spectrometry. Our results demonstrated that 19-HETE conferred a cardioprotective effect against Ang II-induced cellular hypertrophy in vitro, as indicated by the significant reduction in β/α-myosin heavy chain ratio. In vivo, INH improved heart dimensions, and reversed the increase in heart weight to tibia length ratio caused by Ang II. We found a significant increase in cardiac 19-HETE, as well as a significant reduction in AA and its metabolite, 20-HETE. In conclusion, 19-HETE, incubated with cardiomyocytes in vitro or induced in the heart by INH in vivo, provides cardioprotection against Ang II-induced hypertrophy. This further confirms the role of CYP, and their associated AA metabolites in the development of cardiac hypertrophy. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Do big athletes have big hearts? Impact of extreme anthropometry upon cardiac hypertrophy in professional male athletes

    Science.gov (United States)

    Riding, Nathan R; Salah, Othman; Sharma, Sanjay; Carré, François; O'Hanlon, Rory; George, Keith P; Hamilton, Bruce; Chalabi, Hakim; Whyte, Gregory P; Wilson, Mathew G

    2012-01-01

    Aim Differentiating physiological cardiac hypertrophy from pathology is challenging when the athlete presents with extreme anthropometry. While upper normal limits exist for maximal left ventricular (LV) wall thickness (14 mm) and LV internal diameter in diastole (LVIDd, 65 mm), it is unknown if these limits are applicable to athletes with a body surface area (BSA) >2.3 m2. Purpose To investigate cardiac structure in professional male athletes with a BSA>2.3 m2, and to assess the validity of established upper normal limits for physiological cardiac hypertrophy. Methods 836 asymptomatic athletes without a family history of sudden death underwent ECG and echocardiographic screening. Athletes were grouped according to BSA (Group 1, BSA>2.3 m2, n=100; Group 2, 2–2.29 m2, n=244; Group 3, athlete with a normal ECG presented a maximal wall thickness and LVIDd greater than 13 and 65 mm, respectively. In Group 3 athletes, Black African ethnicity was associated with larger cardiac dimensions than either Caucasian or West Asian ethnicity. Three athletes were diagnosed with a cardiomyopathy (0.4% prevalence); with two athletes presenting a maximal wall thickness >13 mm, but in combination with an abnormal ECG suspicious of an inherited cardiac disease. Conclusion Regardless of extreme anthropometry, established upper limits for physiological cardiac hypertrophy of 14 mm for maximal wall thickness and 65 mm for LVIDd are clinically appropriate for all athletes. However, the abnormal ECG is key to diagnosis and guides follow-up, particularly when cardiac dimensions are within accepted limits. PMID:23097487

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

    Science.gov (United States)

    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

  17. Gαq protein carboxyl terminus imitation polypeptide GCIP-27 improves cardiac function in chronic heart failure rats.

    Directory of Open Access Journals (Sweden)

    Xiao Lan Lu

    Full Text Available Gαq protein carboxyl terminus imitation polypeptide (GCIP-27 has been shown to alleviate pathological cardiomyocyte hypertrophy induced by various factors. Pathological cardiac hypertrophy increases the morbidity and mortality of cardiovascular diseases while it compensates for poor heart function. This study was designed to investigate the effects of GCIP-27 on heart function in rats with heart failure induced by doxorubicin.Forty-eight rats were randomly divided into the following six groups receiving vehicle (control, doxorubicin (Dox, losartan (6 mg/kg, i.g. and three doses of GCIP-27 (10, 30, 90 μg/kg; i.p., bid, respectively. Heart failure was induced by Dox, which was administered at a 20 mg/kg cumulative dose. After 10 weeks of treatment, we observed that GCIP-27 (30, 90 μg/kg significantly increased ejection fraction, fraction shortening, stroke volume and sarcoplasmic reticulum Ca2+ ATPase activity of Dox-treated hearts. Additionally, GCIP-27 decreased myocardial injury, heart weight index and left ventricular weight index, fibrosis and serum cardiac troponin-I concentration in Dox-treated mice. Immunohistochemistry, western blotting and real-time PCR experiments indicated that GCIP-27 (10-90 μg/kg could markedly upregulate the protein expression of myocardial α-myosin heavy chain (MHC, Bcl-2, protein kinase C (PKC ε and phosphorylated extracellular signal-regulated kinase (p-ERK 1/2 as well as the mRNA expression of α-MHC, but downregulated the expression of β-MHC, Bax and PKC βII, and the mRNA expression levels of β-MHC in Dox-treated mice. It was also found that GCIP-27 (30, 90 μg/L decreased cell size and protein content of cardiomyocytes significantly in vitro by comparison of Dox group.GCIP-27 could effectively ameliorate heart failure development induced by Dox. PKC-ERK1/2 signaling might represent the underlying mechanism of the beneficial effects of GCIP-27.

  18. Early activation of rat skeletal muscle IL-6/STAT1/STAT3 dependent gene expression in resistance exercise linked to hypertrophy.

    Directory of Open Access Journals (Sweden)

    Gwénaëlle Begue

    Full Text Available Cytokine interleukin-6 (IL-6 is an essential regulator of satellite cell-mediated hypertrophic muscle growth through the transcription factor signal transducer and activator of transcription 3 (STAT3. The importance of this pathway linked to the modulation of myogenic regulatory factors expression in rat skeletal muscle undergoing hypertrophy following resistance exercise, has not been investigated. In this study, the phosphorylation and nuclear localization of STAT3, together with IL-6/STAT3-responsive gene expression, were measured after both a single bout of resistance exercise and 10 weeks of training. Flexor Digitorum Profundus muscle samples from Wistar rats were obtained 2 and 6 hours after a single bout of resistance exercise and 72 h after the last bout of either 2, 4, or 10 weeks of resistance training. We observed an increase in IL-6 and SOCS3 mRNAs concomitant with phosphorylation of STAT1 and STAT3 after 2 and 6 hours of a single bout of exercise (p<0.05. STAT3-dependent early responsive genes such as CyclinD1 and cMyc were also upregulated whereas MyoD and Myf5 mRNAs were downregulated (p<0.05. BrdU-positive satellite cells increased at 2 and 6 hours after exercise (p<0.05. Muscle fiber hypertrophy reached up to 100% after 10 weeks of training and the mRNA expression of Myf5, c-Myc and Cyclin-D1 decreased, whereas IL-6 mRNA remained upregulated. We conclude that the IL-6/STAT1/STAT3 signaling pathway and its responsive genes after a single bout of resistance exercise are an important event regulating the SC pool and behavior involved in muscle hypertrophy after ten weeks of training in rat skeletal muscle.

  19. Progressive resistance-loaded voluntary wheel running increases hypertrophy and differentially affects muscle protein synthesis, ribosome biogenesis, and proteolytic markers in rat muscle.

    Science.gov (United States)

    Mobley, C B; Holland, A M; Kephart, W C; Mumford, P W; Lowery, R P; Kavazis, A N; Wilson, J M; Roberts, M D

    2018-02-01

    We examined if 6 weeks of progressive resistance-loaded voluntary wheel running in rats induced plantaris, soleus, and/or gastrocnemius hypertrophy and/or affected markers of translational efficiency, ribosome biogenesis, and markers of proteolysis. For 6 weeks, 8 male Sprague-Dawley rats (~9-10 weeks of age, ~300-325 g) rats were assigned to the progressive resistance-loaded voluntary wheel running model (EX), and ten rats were not trained (SED). For EX rats, the wheel-loading paradigm was as follows - days 1-7: free-wheel resistance, days 8-15: wheel resistance set to 20%-25% body mass, days 16-24: 40% body mass, days 25-32: 60% body mass, days 33-42: 40% body mass. Following the intervention, muscles were analysed for markers of translational efficiency, ribosome biogenesis, and muscle proteolysis. Raw gastrocnemius mass (+13%, p < .01), relative (body mass-corrected) gastrocnemius mass (+16%, p < .001), raw plantaris mass (+13%, p < .05), and relative plantaris mass (+15%, p < .01) were greater in EX vs. SED rats. In spite of gastrocnemius hypertrophy, EX animals presented a 54% decrease in basal muscle protein synthesis levels (p < .01), a 125% increase in pan 4EBP1 levels (p < .001) and a 31% decrease in pan eIF4E levels (p < .05). However, in relation to SED animals, EX animals presented a 70% increase in gastrocnemius c-Myc protein levels (p < .05). Most markers of translational efficiency and ribosome biogenesis were not altered in the plantaris or soleus muscles of EX vs. SED animals. Gastrocnemius F-box protein 32 and poly-ubiquinated protein levels were approximately 150% and 200% greater in SED vs. EX rats (p < .001). These data suggest that the employed resistance training model increases hind limb muscle hypertrophy, and this may be mainly facilitated through reductions in skeletal muscle proteolysis, rather than alterations in ribosome biogenesis or translational efficiency. © 2017 Blackwell Verlag GmbH.

  20. 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

  1. Ubiquitin-specific protease 14 regulates cardiac hypertrophy progression by increasing GSK-3β phosphorylation.

    Science.gov (United States)

    Liu, Ningning; Chai, Renjie; Liu, Bin; Zhang, Zhenhui; Zhang, Shuangwei; Zhang, Jingzhi; Liao, Yuning; Cai, Jianyu; Xia, Xiaohong; Li, Aiqun; Liu, Jinbao; Huang, Hongbiao; Liu, Shiming

    2016-09-23

    Cardiac hypertrophy, a compensatory response to various stimuli in the heart, independently predicts cardiovascular ailments and related deaths. Increasing evidence indicates ubiquitin-proteasome signaling contributes to cardiac hypertrophy regulation. Here, we identified ubiquitin-specific protease 14 (USP14), a 19S proteasome associated deubiquitinase (DUB), as a novel target for cardiac hypertrophy therapy via inhibition of the GSK-3β pathway. Indeed, USP14 expression was increased in an animal model of abdominal aorta constriction. In an angiotensin II (AngII) induced primary neonatal rat cardiomyocyte hypertrophy model, USP14 expression was increased in a time-dependent manner, and reduced USP14 deubiquitinase activity or USP14 knockdown resulted in lower expression levels of the myocardial hypertrophy specific marker β-MHC, and subsequent decreased GSK-3β phosphorylation. In conclusion, USP14 mediates the development of cardiac hypertrophy by promoting GSK-3β phosphorylation, suggesting that USP14 might represent a novel therapeutic target for cardiac hypertrophy treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. miR-34a Modulates Angiotensin II-Induced Myocardial Hypertrophy by Direct Inhibition of ATG9A Expression and Autophagic Activity

    Science.gov (United States)

    Huang, He; Ye, Jing; Pan, Wei; Zhong, Yun; Cheng, Chuanfang; You, Xiangyu; Liu, Benrong; Xiong, Longgen; Liu, Shiming

    2014-01-01

    Cardiac hypertrophy is characterized by thickening myocardium and decreasing in heart chamber volume in response to mechanical or pathological stress, but the underlying molecular mechanisms remain to be defined. This study investigated altered miRNA expression and autophagic activity in pathogenesis of cardiac hypertrophy. A rat model of myocardial hypertrophy was used and confirmed by heart morphology, induction of cardiomyocyte autophagy, altered expression of autophagy-related ATG9A, LC3 II/I and p62 proteins, and decrease in miR-34a expression. The in vitro data showed that in hypertrophic cardiomyocytes induced by Ang II, miR-34a expression was downregulated, whereas ATG9A expression was up-regulated. Moreover, miR-34a was able to bind to ATG9A 3′-UTR, but not to the mutated 3′-UTR and inhibited ATG9A protein expression and autophagic activity. The latter was evaluated by autophagy-related LC3 II/I and p62 levels, TEM, and flow cytometry in rat cardiomyocytes. In addition, ATG9A expression induced either by treatment of rat cardiomyocytes with Ang II or ATG9A cDNA transfection upregulated autophagic activity and cardiomyocyte hypertrophy in both morphology and expression of hypertrophy-related genes (i.e., ANP and β-MHC), whereas knockdown of ATG9A expression downregulated autophagic activity and cardiomyocyte hypertrophy. However, miR-34a antagonized Ang II-stimulated myocardial hypertrophy, whereas inhibition of miR-34a expression aggravated Ang II-stimulated myocardial hypertrophy (such as cardiomyocyte hypertrophy-related ANP and β-MHC expression and cardiomyocyte morphology). This study indicates that miR-34a plays a role in regulation of Ang II-induced cardiomyocyte hypertrophy by inhibition of ATG9A expression and autophagic activity. PMID:24728149

  3. The Inverted Heart Model for Interstitial Transudate Collection from the Isolated Rat Heart.

    Science.gov (United States)

    Tan, Kezhe; Ding, Zhaoping; Steckel, Bodo; Hartwig, Sonja; Lehr, Stefan; Deng, Xiaoming; Schrader, Jürgen

    2017-06-20

    The present protocol describes a unique approach that enables the collection of cardiac transudate (CT) from the isolated, saline-perfused rat heart. After isolation and retrograde perfusion of the heart according to the Langendorff technique, the heart is inverted into an upside-down position and is mechanically stabilized by a balloon catheter inserted into the left ventricle. Then, a thin latex cap - previously cast to match the average size of the rat heart - is placed over the epicardial surface. The outlet of the latex cap is connected to silicon tubing, with the distal opening 10 cm below the base level of the heart, creating slight suction. CT continuously produced on the epicardial surface is collected in ice-cooled vials for further analysis. The rate of CT formation ranged from 17 to 147 µL/min (n = 14) in control and infarcted hearts, which represents 0.1-1% of the coronary venous effluent perfusate. Proteomic analysis and high performance liquid chromatography (HPLC) revealed that the collected CT contains a wide spectrum of proteins and purinergic metabolites.

  4. Pathological alterations in liver injury following congestive heart failure induced by volume overload in rats

    OpenAIRE

    Shaqura, Mohammed; Mohamed, Doaa M.; Aboryag, Noureddin B.; Bedewi, Lama; Dehe, Lukas; Treskatsch, Sascha; Shakibaei, Mehdi; Schaefer, Michael; Mousa, Shaaban A

    2017-01-01

    Heart failure has emerged as a disease with significant public health implications. Following progression of heart failure, heart and liver dysfunction are frequently combined in hospitalized patients leading to increased morbidity and mortality. Here, we investigated the underlying pathological alterations in liver injury following heart failure. Heart failure was induced using a modified infrarenal aortocaval fistula (ACF) in male Wistar rats. Sham operated and ACF rats were compared for th...

  5. Excitability of isolated hearts from rats during postnatal development.

    Science.gov (United States)

    Gomes, Paulo Alberto Paes; de Galvão, Kleber Magalhães; Mateus, Evandro Fallaci

    2002-04-01

    After birth, cardiac myocytes undergo substantial growth and differentiation that affect their stimulation threshold. Cells from younger animals have a higher stimulation threshold than cells from adults. The aim of this work was to compare the excitability of isolated hearts of rats during postnatal development by measuring the stimulation threshold at several pulse durations. Stimulation threshold of isolated hearts were measured at eight different pulse durations between 0.1 to 20 msec. For each heart, a strength-duration curve was constructed and data were fitted using both Weiss-Lapicque and Blair models. Analysis of variance showed significant age-dependent differences in both rheobase field (E(reob)) and chronaxie (c). E(reob) decreased while c increased during development (E(reob) was 0.21, 0.16, 0.13, 0.10, and 0.09 V/cm and c was 2.0, 2.2, 2.3, 2.7, and 3.2 msec for rats aged 1, 2, 4, 8, and 20 weeks, respectively). There was a decrease in the threshold field with heart weight between 0.1 and 0.7 g, whereas the threshold was almost constant in the range from 0.7 to 2.0 g. Estimation of the energy density needed to defibrillate the heart was performed and appeared to be higher for younger than for adult animals. Hearts from younger animals have higher stimulation threshold than those from adults. This probably is due to changes in the cellular threshold as a result of maturation. The smaller excitability of younger hearts can have consequences with regard to the energy levels required for younger patients.

  6. MITOCHONDRIAL AND METABOLIC GENE EXPRESSION IN THE AGED RAT HEART

    Directory of Open Access Journals (Sweden)

    Gregory P Barton

    2016-08-01

    Full Text Available Aging is associated with a decline in cardiac function. Exercise intervention has been suggested as a way to improve this decrement. Age-related decline in cardiac function is associated with decreases in fatty acid oxidation, mitochondrial function and AMP-activated protein kinase (AMPK activity. The molecular mechanisms involved with age-related changes in mitochondrial function and substrate metabolism are poorly understood. We determined gene expression differences in hearts of Young (6 mo, Old (33 mo, and old exercise trained (Old + EXE (34 mo FBN rats, using Qiagen PCR arrays for Glucose, Fatty acid, and Mitochondrial metabolism. Old rats demonstrated decreased (p < 0.05 expression for key genes in fatty acid oxidation, mitochondrial function, and AMPK signaling. There were no differences in the expression of genes involved in glucose metabolism with age. These gene expression changes occurred prior to altered protein translation as we found no differences in the protein content of peroxisome proliferator activated receptor gamma, coactivators 1 alpha (PGC-1α, peroxisome proliferator activated receptor alpha (PPARα, and AMPKα2 between young and old hearts. Four months of exercise training did not attenuate the decline in the gene expression in aged hearts. Despite this lack of change in gene expression, exercise-trained rats demonstrated increased exercise capacity compared to their sedentary counterparts. Taken together, our results show that differential expression of genes associated with fatty acid metabolism, AMPK signaling and mitochondrial function are superfluous and decrease in the aging heart which may play a role in age-related declines in fatty acid oxidation, AMPK activity and mitochondrial function in the heart.

  7. 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,

  8. Transcapillary transport of metaiodobenzylguanidine (MIBG) in isolated rat heart

    Energy Technology Data Exchange (ETDEWEB)

    DeGrado, Timothy R.; Wang Shuyan

    1998-07-01

    A better understanding of transcapillary transport for tracer metaiodobenzylguanidine (MIBG) is desirable for development of tracer kinetic models that yield meaningful estimates of neuronal uptake function from tissue radioactivity time courses. This study utilized a multiple-indicator approach in Langendorff-perfused rat hearts to define transport mechanisms and determine the capillary permeability-surface area (PSc) over a broad range of flow (F). Multiple injections within the same heart at different flows allowed characterization of the PSc/F relationship within the same heart. The coefficient of variation of E for multiple injections within the same hearts at constant flow was 6{+-}2% (3 to 6 injections in 9 hearts). In 10 hearts (4 to 6 injections per heart), flow was varied between 2.0-16.5 mL/min. PSc was found to be nearly proportional to flow in each heart (r=0.88{+-}0.14; slope = 0.23{+-}0.10; intercept = 11{+-}7 mL/min/g dry). Tissue hypoxia at low flows, as evidenced by enhanced lactate production, did not appear to influence the PSc/F relationship. Pharmacologic blockade of uptake-1 and uptake-2 had negligible affect on E or PSc as compared with flow-matched controls, although tissue retention was markedly reduced. The results show PSc of MIBG to be nearly proportional to flow but independent of specific neuronal and extraneuronal transport mechanisms and tissue hypoxia. The results are consistent with a passive diffusion process across the capillary endothelial barrier. The increase in PSc with increasing flow could reflect capillary recruitment and/or enhanced capillary permeability.

  9. Renin-Angiotensin-Aldosterone Signaling Inhibitors-Losartan, Enalapril, and Cardosten-Prevent Infarction-induced Heart Failure Development in Rats.

    Science.gov (United States)

    Kiss, Krisztina; Fekete, Veronika; Pálóczi, János; Sárközy, Márta; Murlasits, Zsolt; Pipis, Judit; Kheyfets, Irina A; Dugina, Julia L; Sergeeva, Svetlana A; Epstein, Oleg I; Csonka, Csaba; Csont, Tamás; Ferdinandy, Péter; Bencsik, Péter

    2016-01-01

    The activation of the renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathophysiology of congestive heart failure, which is the reason that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin 2 receptor blockers (ARBs) have become established therapies for heart failure. However, it is still not known whether preventive treatment with losartan or enalapril can reduce symptoms of infarction-induced heart failure. Ultra-low dose (ULD) drug therapy is thought to exert specific activity, with a lower chance of side effects. OBJECTIVES • The research team had hypothesized that preventive treatment with inhibitors of RAAS signaling-losartan, enalapril, and a preparation of a ULD antibody (ie, cardosten), which target the angiotensin type 1 (AT1) receptor-might alleviate pathological hypertrophy and/or functional decline in infarction-induced heart failure. The research team treated male Wistar rats orally for 30 d with 20 mg/kg of losartan, 10 mg/kg enalapril, 5 or 7.5 mL/kg of cardosten, or a control solution, started 1 d prior to permanent coronary occlusion. A sham-operated group functioned as a second control group. The study was conducted at the Department of Biochemistry of the Faculty of Medicine at the University of Szeged in Szeged, Hungary, in cooperation with the Pharmahungary Group, also in Szeged, Hungary, and with OOO "NPF" Materia Medica Holding Ltd in Moscow, Russia. To determine cardiac functional parameters in vivo, the research team inserted a catheter into the left ventricle of the rats and measured the parameters of ventricular pressure, and cardiac output was determined by thermodilution. Morphological parameters were measured after heart isolation in transverse sections by a digital caliper. A total of 30 d after permanent coronary ligation, both losartan and enalapril, significantly decreased mean arterial blood pressure (MABP), attenuated the development of the left-ventricular anterior-wall and septum

  10. 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.

  11. 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

  12. TRPC1 expression and distribution in rat hearts

    Directory of Open Access Journals (Sweden)

    W. Niu

    2009-12-01

    Full Text Available Transient receptor potential canonical (TRPC proteins have been identified as a family of plasma membrane calcium-permeable channels. TRPC proteins can be activated by various stimuli and act as cellular sensors in mammals. Stretch-activated ion channels (SACs have been proposed to underlie cardiac mechano-electric feedback (MEF, although the molecular entity of SAC remains unknown. There is evidence suggesting that transient receptor potential canonical 1 (TRPC1 is a stretch-activated ion channel. As a non-selective cation channel, TRPC1 may cause stretch-induced depolarization and arrhythmia and thus may contribute to the MEF of the heart. In this study, we examined the expression patterns of TRPC1 in detail at both the mRNA and protein levels in rat hearts.We isolated total RNA from the left and right atria, and the left and right ventricles, and detected TRPC1 mRNA in these tissues using reverse-transcriptase polymerase chain reaction (RT-PCR. To study the protein localization and targeting, we performed immunohistochemistry and immunofluorescence labeling with the antibody against TRPC1. TRPC1 was detected in the cardiomyocytes of the ventricle and atrium at both the mRNA and protein levels. The cell membrane and Ttubule showed strong fluorescence labeling in the ventricular myocytes. Purkinje cells, the endothelial cells and smooth muscle cells of the coronary arterioles also displayed TRPC1 labeling. No TRPC1 was detected in fibroblasts. In conclusion, TRPC1 is widely expressed in the rat heart, including in working cells, Purkinje cells and vascular cells, suggesting that it plays an important role in the heart. The specific distribution pattern offered a useful insight into its function in adult rat ventricular cells. Further investigations are needed to clarify the role of TRPC1 in regulating cardiac activity, including cardiac MEF.

  13. MicroRNA-200c modulates DUSP-1 expression in diabetes-induced cardiac hypertrophy.

    Science.gov (United States)

    Singh, Gurinder Bir; Raut, Satish K; Khanna, Sanskriti; Kumar, Akhilesh; Sharma, Saurabh; Prasad, Rishikesh; Khullar, Madhu

    2017-01-01

    Mitogen-activated protein kinases (MAPKs) (ERK1/2, JNK, and p38) are upregulated in diabetic cardiomyopathy (DCM). Dual-specific phosphatase-1 (DUSP-1) has been reported to regulate the activity of MAPKs in cardiac hypertrophy; however, the role of DUSP-1 in regulating MAPKs activity in DCM is not known. MicroRNAs have been reported to regulate the expression of several genes in hypertrophied failing hearts. However, little is known about the microRNAs regulating DUSP-1 expression in diabetes-related cardiac hypertrophy. In the present study, we investigated the role of DUSP-1 and miR-200c in diabetes-induced cardiac hypertrophy. DCM was induced in Wistar rats by low-dose Streptozotocin high-fat diet for 12 weeks. Cardiac expression of ERK, p-38, JNK, DUSP-1, miR-200c, and hypertrophy markers (ANP and β-MHC) was studied in DCM in control rats and in high-glucose (HG)-treated rat neonatal cardiomyocytes. miR-200c inhibition was performed to validate DUSP-1 as target. A significant increase in phosphorylated ERK, p38, and JNK was observed in DCM model and in HG-treated cardiomyocytes (p 1 was significantly decreased in diabetes group and in HG-treated cardiomyocytes (p 1 causing decreased expression of phosphorylated ERK, p38, and JNK and attenuated cardiomyocyte hypertrophy in HG-treated cardiomyocytes. miR-200c plays a role in diabetes-associated cardiac hypertrophy by modulating expression of DUSP-1.

  14. Protective effects of low-dose rosuvastatin on isoproterenol-induced chronic heart failure in rats by regulation of DDAH-ADMA-NO pathway.

    Science.gov (United States)

    Zhou, Ru; Ma, Ping; Xiong, Aiqin; Xu, Yehua; Wang, Yang; Xu, Qingbin

    2017-04-01

    Cardiovascular disease is the leading cause of death with high morbidity and mortality, and chronic heart failure is the terminal phase of it. This study aimed to investigate the protective effects of the low-dose rosuvastatin on isoproterenol-induced chronic heart failure and to explore the possible related mechanisms. Male Sprague Dawley rats were given isoproterenol 5 mg/kg once a day for 7 days to establish heart failure model by subcutaneous injection. Simultaneously, low-dose rosuvastatin (5 mg/kg) was orally administrated from day 1 to day 14. Protective effects were evaluated by hemodynamic parameter, histopathological variables, serum asymmetric dimethylarginine (ADMA), cardiac troponin I (cTnI), brain natriuretic peptide (BNP) and myocardial nitric oxide (NO), and the levels of dimethylarginine dimethylaminohydrolase 2 (DDAH2), arginine methyltransferases 1 (PRMT1) and endothelial nitric oxide synthase (eNOS) expression were analyzed. Therapeutic rosuvastatin (5 mg/kg) significantly attenuated isoproterenol-induced hypertrophy, remodeling and dysfunction of ventricle, reduced the increased serum content of ADMA, cTnI, and BNP, and elevated myocardial NO in rats (Pheart failure in rats by modulating DDAH-ADMA-NO pathway, and it may present the new therapeutic value in ameliorating chronic heart failure. © 2016 John Wiley & Sons Ltd.

  15. Reiki improves heart rate homeostasis in laboratory rats.

    Science.gov (United States)

    Baldwin, Ann Linda; Wagers, Christina; Schwartz, Gary E

    2008-05-01

    To determine whether application of Reiki to noise-stressed rats can reduce their heart rates (HRs) and blood pressures. In a previous study, we showed that exposure of rats to 90 dB white noise for 15 minutes caused their HRs and blood pressures to significantly increase. Reiki has been shown to significantly decrease HR and blood pressure in a small group of healthy human subjects. However, use of humans in such studies has the disadvantage that experimental interpretations are encumbered by the variable of belief or skepticism regarding Reiki. For that reason, noise-stressed rats were used as an animal model to test the efficacy of Reiki in reducing elevated HR and blood pressure. Three unrestrained, male Sprague-Dawley rats implanted with radiotelemetric transducers were exposed daily for 8 days to a 15-minute white noise regimen (90 dB). For the last 5 days, the rats received 15 minutes of Reiki immediately before the noise and during the noise period. The experiment was repeated on the same animals but using sham Reiki. The animals were housed in a quiet room in University of Arizona Animal Facility. Mean HRs and blood pressure were determined before Reiki/sham Reiki, during Reiki/sham Reiki, and during the noise in each case. Reiki, but not sham Reiki, significantly reduced HR compared to initial values. With Reiki, there was a high correlation between change in HR and initial HR, suggesting a homeostatic effect. Reiki, but not sham Reiki, significantly reduced the rise in HR produced by exposure of the rats to loud noise. Neither Reiki nor sham Reiki significantly affected blood pressure. Reiki is effective in modulating HR in stressed and unstressed rats, supporting its use as a stress-reducer in humans.

  16. 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.).

  17. High-intensity interval training, but not continuous training, reverses right ventricular hypertrophy and dysfunction in a rat model of pulmonary hypertension.

    Science.gov (United States)

    Brown, Mary Beth; Neves, Evandro; Long, Gary; Graber, Jeremy; Gladish, Brett; Wiseman, Andrew; Owens, Matthew; Fisher, Amanda J; Presson, Robert G; Petrache, Irina; Kline, Jeffrey; Lahm, Tim

    2017-02-01

    Exercise is beneficial in pulmonary arterial hypertension (PAH), although studies to date indicate little effect on the elevated pulmonary pressures or maladaptive right ventricle (RV) hypertrophy associated with the disease. For chronic left ventricle failure, high-intensity interval training (HIIT) promotes greater endothelial stimulation and superior benefit than customary continuous exercise training (CExT); however, HIIT has not been tested for PAH. Therefore, here we investigated acute and chronic responses to HIIT vs. CExT in a rat model of monocrotaline (MCT)-induced mild PAH. Six weeks of treadmill training (5 times/wk) were performed, as either 30 min HIIT or 60 min low-intensity CExT. To characterize acute hemodynamic responses to the two approaches, novel recordings of simultaneous pulmonary and systemic pressures during running were obtained at pre- and 2, 4, 6, and 8 wk post-MCT using long-term implantable telemetry. MCT-induced decrement in maximal aerobic capacity was ameliorated by both HIIT and CExT, with less pronounced pulmonary vascular remodeling and no increase in RV inflammation or apoptosis observed. Most importantly, only HIIT lowered RV systolic pressure, RV hypertrophy, and total pulmonary resistance, and prompted higher cardiac index that was complemented by a RV increase in the positive inotrope apelin and reduced fibrosis. HIIT prompted a markedly pulsatile pulmonary pressure during running and was associated with greater lung endothelial nitric oxide synthase after 6 wk. We conclude that HIIT may be superior to CExT for improving hemodynamics and maladaptive RV hypertrophy in PAH. HIIT's superior outcomes may be explained by more favorable pulmonary vascular endothelial adaptation to the pulsatile HIIT stimulus.

  18. Tumor Suppressor A20 Protects against Cardiac Hypertrophy and Fibrosis through Blocking TAK1-Dependent Signaling

    Science.gov (United States)

    Huang, He; Tang, Qi-Zhu; Wang, Ai-Bing; Chen, Manyin; Zhou, Heng; Liu, Chen; Jiang, Hong; Yang, Qinglin; Bian, Zhou-Yan; Bai, Xue; Zhu, Li-Hua; Wang, Lang; Li, Hongliang

    2010-01-01

    A20 or tumor necrosis factor–induced protein 3 is a negative regulator of nuclear factor κB signaling. A20 has been shown previously to attenuate cardiac hypertrophy in vitro and postmyocardial infarction remodeling in vivo. In the present study, we tested the hypothesis that overexpression of A20 in the murine heart would protect against cardiac hypertrophy in vivo. The effects of constitutive human A20 expression on cardiac hypertrophy were investigated using in vitro and in vivo models. Cardiac hypertrophy was produced by aortic banding in A20 transgenic mice and control animals. The extent of cardiac hypertrophy was quantitated by echocardiography, as well as by pathological and molecular analyses of heart samples. Constitutive overexpression of human A20 in the murine heart attenuated the hypertrophicresponse and markedly reduced inflammation, apoptosis, and fibrosis. Cardiac function was also preserved in hearts with increased A20 levels in response to hypertrophic stimuli. Western blot experiments further showed A20 expression markedly blocked transforming growth factor-β–activated kinase 1–dependent c-Jun N-terminal kinase/p38 signaling cascade but with no difference in either extracellular signal-regulated kinase 1/2 or AKT activation in vivo and in vitro. In cultured neonatal rat cardiac myocytes, [3H]proline incorporation and Western blot assays revealed that A20 expression suppressed transforming growth factor-β–induced collagen synthesis and transforming growth factor-β–activated kinase 1–dependent Smad 2/3/4 activation. In conclusion, A20 improves cardiac functions and inhibits cardiac hypertrophy, inflammation, apoptosis, and fibrosis by blocking transforming growth factor-β–activated kinase 1–dependent signaling. PMID:20585109

  19. Differentiation of hypertensive heart disease with hypertrophy and hepertrophic cardiomyopathy using consecutive time-course images of Gd-DTPA enhanced MRI

    Energy Technology Data Exchange (ETDEWEB)

    Ochiai, Kouichi; Isibashi, Yutaka; Shimada, Toshio; Tsukihashi, Hironori; Sato, Hidetoshi; Kitamura, Jun; Morioka, Shigefumi; Kawamitsu, Hideaki; Sugimura, Kazuro [Shimane Medical Univ., Izumo, Shimane (Japan)

    1996-03-01

    We used consecutive time-course Gd-DTPA contrast magnetic resonance images to differentiate hypertrophic cardiomyopathy (HCM) from hypertensive heart disease with hypertrophy (HHD). Seventeen patients with HCM, 6 patients with HHD and 5 normal subjects (control) were studied. ECG-gated MRI with 1.5T system was performed before and after intravenous injection of Gd-DTPA (0.1mmol/Kg) using spin echo sequence. Gd-DTPA enhanced MRI was repeated every 10 to 55 minutes. We measured signal intensity (SI) of midleft ventricular myocardium and skeletal muscle, and then calculated the ratio between myocardial SI and skeletal muscle SI. Myocardium was enhanced by Gd-DTPA in all patients. However, there was difference in the decay of enhancement effect by Gd-DTPA between HCM and HHD. The decay in HCM was more slowly than in both HHD and control. There was no difference in the decay between HHD and control. The difference in the decay between HCM and HHD became significant 25 minutes after Gd-DTPA injection and lasted until 55 minutes. We conclude that the time-course of the decay of enhancement effect by Gd-DTPA is helpful to differentiate HCM from HHD and the difference of the decay might reflect structural changes of myocardium. (author).

  20. Pretreatment with fish oil attenuates heart ischaemia consequences in rats.

    Science.gov (United States)

    Lescano de Souza Junior, Alcione; Mancini Filho, Jorge; Pavan Torres, Rosângela; Irigoyen, Maria Cláudia; Curi, Rui

    2017-11-01

    What is the central question of this study? We investigated whether pretreatment with fish oil could prevent the major consequences of ischaemic injury to the heart. What is the main finding and its importance? Fish oil pretreatment attenuated the consequences of ischaemic injury as indicated by the small infarction area and the preservation of systolic function and coronary blood flow. These findings support the use of fish oil in order to reduce the impact of heart ischaemia. ω-3 Polyunsaturated fatty acid (ω-3 PUFA)-rich fish oil supplementation has protective effects on heart ischaemic injury. Left ventricular (LV) ischaemia was induced in rats by permanent ligation of the left descending coronary artery. Saline, fish oil or soybean oil was administered daily by gavage [3 g (kg body weight)-1 ] for 20 days before inducing ischaemia. Outcomes were assessed 24 h after left descending coronary artery ligation. Pretreatment with fish oil decreased the ω-6/ω-3 fatty acid ratio in the LV. A reduction in infarct size and in the intensity of ventricular systolic dysfunction was found in the fish oil group compared with the saline or soybean oil groups through echocardiographic evaluation. Before infarction, LV glycogen concentrations were decreased in the fish oil group compared with the saline group. Soybean oil pretreatment led to a further increase in the LV levels of CINC-2/αβ, IL-1β and TNF-α induced by the heart infarction. In heart-infarcted rats, fish oil pretreatment decreased creatine kinase and caspase-3 activities; prevented the decrease in the coronary blood flow; increased LV contents of ATP and lactate; increased the mRNA levels of iNOS, eNOS, HIF1α, GLUT1, VEGF-α and p53 in the LV as measured by RT-PCR; and did not change LV pro-inflammatory cytokine concentrations compared with the control group. Fish oil protected the heart from ischaemia, as indicated by the decrease in the heart infarction area and systolic dysfunction associated with

  1. Common Deletion (CD) in mitochondrial DNA of irradiated rat heart

    Energy Technology Data Exchange (ETDEWEB)

    Siqueira, Raquel Gomes; Ferreira-Machado, Samara C.; Almeida, Carlos E.V. de, E-mail: raquelgsiqueira@gmail.com [Universidade do Estado do Rio de Janeiro (UERJ), RJ (Brazil). Instituto de Biologia Roberto Alcanatara Gomes. Lab. de Ciencias Radiologicas; Silva, Dayse A. da; Carvalho, Elizeu F. de [Universidade do Estado do Rio de Janeiro (UERJ), RJ (Brazil). Instituto de Biologia Roberto Alcanatara Gomes. Lab. de Diagnosticos por DNA; Melo, Luiz D.B. de [Universidade do Estado do Rio de Janeiro (UERJ), RJ (Brazil). Instituto de Biofisica Carlos Chagas Filho. Lab. de Parasitologia Molecular

    2014-05-15

    The purpose of this study was to map the common deletion (CD) area in mtDNA and investigate the levels of this deletion in irradiated heart. The assays were developed in male Wistar rats that were irradiated with three different single doses (5, 10 or 15 Gy) delivered directly to the heart and the analyses were performed at various times post-irradiation (3, 15 or 120 days). The CDs area were sequenced and the CD quantified by real-time PCR. Our study demonstrated that the CD levels progressively decreased from the 3rd until the 15th day after irradiation, and then increased thereafter. Additionally, it was observed that the levels of CD are modulated differently according to the different categories of doses (moderate and high). This study demonstrated an immediate response to ionizing radiation, measured by the presence of mutations in the CD area and a decrease in the CD levels. (author)

  2. Heart Alterations after Domoic Acid Administration in Rats

    Directory of Open Access Journals (Sweden)

    Andres C. Vieira

    2016-03-01

    Full Text Available Domoic acid (DA is one of the best known marine toxins, causative of important neurotoxic alterations. DA effects are documented both in wildlife and experimental assays, showing that this toxin causes severe injuries principally in the hippocampal area. In the present study we have addressed the long-term toxicological effects (30 days of DA intraperitoneal administration in rats. Different histological techniques were employed in order to study DA toxicity in heart, an organ which has not been thoroughly studied after DA intoxication to date. The presence of DA was detected by immunohistochemical assays, and cellular alterations were observed both by optical and transmission electron microscopy. Although histological staining methods did not provide any observable tissue damage, transmission electron microscopy showed several injuries: a moderate lysis of myofibrils and loss of mitochondrial conformation. This is the first time the association between heart damage and the presence of the toxin has been observed.

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

    Directory of Open Access Journals (Sweden)

    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.

  4. Nestin expression is upregulated in the fibrotic rat heart and is localized in collagen-expressing mesenchymal cells and interstitial CD31(+- cells.

    Directory of Open Access Journals (Sweden)

    Vanessa Hertig

    Full Text Available Renal and lung fibrosis was characterized by the accumulation of collagen-immunoreactive mesenchymal cells expressing the intermediate filament protein nestin. The present study tested the hypothesis that nestin expression was increased in the hypertrophied/fibrotic left ventricle of suprarenal abdominal aorta constricted adult male Sprague-Dawley rats and induced in ventricular fibroblasts by pro-fibrotic peptide growth factors. Nestin protein levels were upregulated in the pressure-overloaded left ventricle and expression positively correlated with the rise of mean arterial pressure. In sham and pressure-overloaded hearts, nestin immunoreactivity was detected in collagen type I(+-and CD31(+-cells identified in the interstitium and perivascular region whereas staining was absent in smooth muscle α-actin(+-cells. A significantly greater number of collagen type I(+-cells co-expressing nestin was identified in the left ventricle of pressure-overloaded rats. Moreover, an accumulation of nestin(+-cells lacking collagen, CD31 and smooth muscle α-actin staining was selectively observed at the adventitial region of predominantly large calibre blood vessels in the hypertrophied/fibrotic left ventricle. Angiotensin II and TGF-β1 stimulation of ventricular fibroblasts increased nestin protein levels via phosphatidylinositol 3-kinase- and protein kinase C/SMAD3-dependent pathways, respectively. CD31/eNOS(+-rat cardiac microvascular endothelial cells synthesized/secreted collagen type I, expressed prolyl 4-hydroxylase and TGF-β1 induced nestin expression. The selective accumulation of adventitial nestin(+-cells highlighted a novel feature of large vessel remodelling in the pressure-overloaded heart and increased appearance of collagen type I/nestin(+-cells may reflect an activated phenotype of ventricular fibroblasts. CD31/collagen/nestin(+-interstitial cells could represent displaced endothelial cells displaying an unmasked mesenchymal phenotype

  5. Effect of prophylactic digitalization on the development of myocardial hypertrophy.

    Science.gov (United States)

    Cutilletta, A F; Rudnik, M; Arcilla, R A; Straube, R

    1977-11-01

    The effect of prophylactic digitalization on the development of left ventricular hypertrophy was studied in adult rats. Digitoxin, 0.1 mg/100 g body wt or solvent was given daily for 1 wk prior to either aortic constriction or sham operation and was continued until the animals were killed, either 1 or 4 wk after surgery. A hemodynamic study was done in those animals killed 1 wk after surgery; hearts of all animals were examined for evidence of myocardial hypertrophy. Constriction of the ascending aorta had no significant effect on cardiac output but did reduce peak flow velocity and flow acceleration. An increase in left ventricular mass, RNA, and hydroxyproline was found in the animals with aortic constriction. Digitoxin treatment did not alter peak flow velocity or flow acceleration, but did significantly increase isovolumic (dP/dt)P-1. Digitoxin had no effect on body weight, heart weight, RNA, or hydroxyproline in either the sham-operated animals or in the animals with aortic constriction. Therefore, despite plasma digitoxin levels sufficient to affect myocardial contractility, left ventricular hypertrophy still developed after aortic constriction.

  6. The effect of ladder-climbing exercise on atrophy/hypertrophy-related myokine expression in middle-aged male Wistar rats.

    Science.gov (United States)

    Jung, Suryun; Ahn, Nayoung; Kim, Sanghyun; Byun, Jayoung; Joo, Youngsik; Kim, Sungwook; Jung, Yeunho; Park, Solee; Hwang, Ilseon; Kim, Kijin

    2015-11-01

    We investigated the change in myokine expression related to hypertrophy (IL-4, IL-6, IL-10) and atrophy (TNF-α, NFκB, IL-1β) in middle-aged rats after resistance exercise with ladder climbing. 50- and 10-week-old male Wistar rats were randomly assigned to two groups: the sedentary and exercise groups. The exercise groups underwent a ladder-climbing exercise for 8 weeks. While the tibialis anterior muscle mass in the young group significantly increased after the ladder-climbing exercise, the middle-aged group did not show any changes after undergoing the same exercise. To understand the molecular mechanism causing this difference, we analyzed the change in hypertrophy- and atrophy-related myokine levels from the tibialis anterior muscle. After 8 weeks of ladder-climbing exercise, the IL-4 and IL-10 protein levels did not change. However, the IL-6 level significantly increased after exercise training, but the amount of increase in the young training group was higher than in the middle-aged training group. IL-1β and TNF-α as well as NFκB protein levels were significantly higher in the middle-aged group than in the young group. Except for TNF-α, exercise training did not affect IL-1β and NFκB protein levels. The TNF-α level significantly decreased in the middle-aged exercise training group. AMPK and PGC-1α levels also significantly increased after exercise training, but there was no difference between age-related groups. Therefore, 8-week high-intensity exercise training using ladder climbing downregulates the skeletal muscle production of myokine involved in atrophy and upregulates hypertrophic myokine. However, the extent of these responses was lower in the middle-aged than young group.

  7. The Influence of a High Salt Diet on a Rat Model of Isoproterenol-Induced Heart Failure

    Science.gov (United States)

    Rat models of heart failure (HF) show varied pathology and time to disease outcome, dependent on induction method. We found that subchronic (4 weeks) isoproterenol (ISO) infusion exacerbated cardiomyopathy in Spontaneously Hypertensive Heart Failure (SHHF) rats. Others have shown...

  8. Blueberry-enriched diet protects rat heart from ischemic damage.

    Directory of Open Access Journals (Sweden)

    Ismayil Ahmet

    2009-06-01

    Full Text Available to assess the cardioprotective properties of a blueberry enriched diet (BD.Reactive oxygen species (ROS play a major role in ischemia-related myocardial injury. The attempts to use synthetic antioxidants to block the detrimental effects of ROS have produced mixed or negative results precipitating the interest in natural products. Blueberries are readily available product with the highest antioxidant capacity among fruits and vegetables.Following 3-mo of BD or a regular control diet (CD, the threshold for mitochondrial permeability transition (t(MPT was measured in isolated cardiomyocytes obtained from young male Fischer-344 rats. Compared to CD, BD resulted in a 24% increase (p<0.001 of ROS indexed t(MPT. The remaining animals were subjected to a permanent ligation of the left descending coronary artery. 24 hrs later resulting myocardial infarction (MI in rats on BD was 22% less than in CD rats (p<0.01. Significantly less TUNEL(+ cardiomyocytes (2% vs 9% and 40% less inflammation cells were observed in the myocardial area at risk of BD compared to CD rats (p<0.01. In the subgroup of rats, after coronary ligation the original diet was either continued or switched to the opposite one, and cardiac remodeling and MI expansion were followed by serial echocardiography for 10 weeks. Measurements suggested that continuation of BD or its withdrawal after MI attenuated or accelerated rates of post MI cardiac remodeling and MI expansion.A blueberry-enriched diet protected the myocardium from induced ischemic damage and demonstrated the potential to attenuate the development of post MI chronic heart failure.

  9. Blueberry-enriched diet protects rat heart from ischemic damage.

    Science.gov (United States)

    Ahmet, Ismayil; Spangler, Edward; Shukitt-Hale, Barbara; Juhaszova, Magdalena; Sollott, Steven J; Joseph, James A; Ingram, Donald K; Talan, Mark

    2009-06-18

    to assess the cardioprotective properties of a blueberry enriched diet (BD). Reactive oxygen species (ROS) play a major role in ischemia-related myocardial injury. The attempts to use synthetic antioxidants to block the detrimental effects of ROS have produced mixed or negative results precipitating the interest in natural products. Blueberries are readily available product with the highest antioxidant capacity among fruits and vegetables. Following 3-mo of BD or a regular control diet (CD), the threshold for mitochondrial permeability transition (t(MPT)) was measured in isolated cardiomyocytes obtained from young male Fischer-344 rats. Compared to CD, BD resulted in a 24% increase (p<0.001) of ROS indexed t(MPT). The remaining animals were subjected to a permanent ligation of the left descending coronary artery. 24 hrs later resulting myocardial infarction (MI) in rats on BD was 22% less than in CD rats (p<0.01). Significantly less TUNEL(+) cardiomyocytes (2% vs 9%) and 40% less inflammation cells were observed in the myocardial area at risk of BD compared to CD rats (p<0.01). In the subgroup of rats, after coronary ligation the original diet was either continued or switched to the opposite one, and cardiac remodeling and MI expansion were followed by serial echocardiography for 10 weeks. Measurements suggested that continuation of BD or its withdrawal after MI attenuated or accelerated rates of post MI cardiac remodeling and MI expansion. A blueberry-enriched diet protected the myocardium from induced ischemic damage and demonstrated the potential to attenuate the development of post MI chronic heart failure.

  10. MicroRNA-297 promotes cardiomyocyte hypertrophy via targeting sigma-1 receptor.

    Science.gov (United States)

    Bao, Qinxue; Zhao, Mingyue; Chen, Li; Wang, Yu; Wu, Siyuan; Wu, Wenchao; Liu, Xiaojing

    2017-04-15

    Sigma-1 receptor (Sig-1R) is a ligand-regulated endoplasmic reticulum (ER) chaperone involved in cardiac hypertrophy, but it is not known whether Sig-1R is regulated by microRNAs (miRNAs). According to bioinformatic analysis, miR-297 was suggested as a potential target miRNA for Sig-1R. Therefore, we verified whether miR-297 could target Sig-1R and investigated the possible mechanisms underlying the role of miR-297 in cardiac hypertrophy. Bioinformatic analysis combined with laboratory experiments, including quantitative RT-PCR, Western blotting, and luciferase assay, were performed to identify the target miRNA of Sig-1R. Transverse aortic constriction (TAC) model and neonatal rat cardiomyocytes (NCMs) stimulated with angiotensin II (AngII) were used to explore the relationship between miR-297 and Sig-1R. Additionally, the function of miR-297 in cardiomyocyte hypertrophy and ER stress/unfolded protein response (UPR) signaling pathway was investigated by transfecting miR-297 mimics/inhibitor. miR-297 levels were increased in both TAC-induced hypertrophic heart tissue and AngII-induced cardiomyocyte hypertrophy. Up-regulation of miR-297 by specific mimics exacerbated AngII-induced cardiomyocyte hypertrophy, whereas inhibition of miR-297 suppressed the process. During cardiomyocyte hypertrophy, Sig-1R expression, which was negatively regulated by miR-297 by directly targeting its 3'untranslated region (UTR), was decreased. Furthermore, attenuation of miR-297 inhibited the activation of X-box binding protein 1 (Xbp1) and activating transcriptional factor 4 (ATF4) signaling pathways in NCMs. Our data demonstrate that miR-297 promotes cardiomyocyte hypertrophy by inhibiting the expression of Sig-1R and activation of ER stress signaling, which provides a novel interpretation for cardiac hypertrophy. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Effect of isoproterenol on myocardial perfusion, function, energy metabolism and nitric oxide pathway in the rat heart - a longitudinal MR study.

    Science.gov (United States)

    Desrois, Martine; Kober, Frank; Lan, Carole; Dalmasso, Christiane; Cole, Mark; Clarke, Kieran; Cozzone, Patrick J; Bernard, Monique

    2014-05-01

    The chronic administration of the β-adrenoreceptor agonist isoproterenol (IsoP) is used in animals to study the mechanisms of cardiac hypertrophy and failure associated with a sustained increase in circulating catecholamines. Time-dependent changes in myocardial blood flow (MBF), morphological and functional parameters were assessed in rats in vivo using multimodal cardiac MRI. Energy metabolism, oxidative stress and the nitric oxide (NO) pathway were evaluated in isolated perfused rat hearts following 7 days of treatment. Male Wistar rats were infused for 7 days with IsoP or vehicle using osmotic pumps. Cine-MRI and arterial spin labeling were used to determine left ventricular morphology, function and MBF at days 1, 2 and 7 after pump implantation. Isolated hearts were then perfused, and high-energy phosphate compounds and intracellular pH were followed using ³¹P MRS with simultaneous measurement of contractile function. Total creatine and malondialdehyde (MDA) contents were measured by high-performance liquid chromatography. The NO pathway was evaluated by NO synthase isoform expression and total nitrate concentration (NO(x)). In IsoP-treated rats, left ventricular mass was increased at day 1 and maintained. Wall thickness was increased with a peak at day 2 and a tendency to return to baseline values at day 7. MBF was markedly increased at day 1 and returned to normal values between days 1 and 2. The rate-pressure product and phosphocreatine/adenosine triphosphate ratio in perfused hearts were reduced. MDA, endothelial NO synthase expression and NO(x) were increased. Sustained high cardiac function and normal MBF after 24 h of IsoP infusion indicate imbalance between functional demand and blood flow, leading to morphological changes. After 1 week, cardiac hypertrophy and decreased function were associated with impaired phosphocreatine, increased oxidative stress and up-regulation of the NO pathway. These results provide supplemental information on the

  12. 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.

  13. Apoptosis and Histopathology of the Heart after Renal Ischemia-Reperfusion in Male Rat Running title: Ischemia-Reperfusion Injury

    Directory of Open Access Journals (Sweden)

    Alireza Alihemmati

    2018-01-01

    Full Text Available ABSTRACT Ischemia-reperfusion injury was seen in strokes, myocardial infarctions, acute kidney injury, mesenteric ischemia, liver and systemic shock. Renal ischemia-reperfusion is more importance in the setting of kidney transplantation that affects distant organs. In this study forty Male Albino Wistar rats (200-250g were randomly divided in four group (n=10 including control, sham operation group, nephrectomy and IRI group. All rats anesthetized with intraperitoneal injection of ketamine (50 mg/kg and xylazine (10 mg/kg and maintained the core body temperature at approximately 37°C. For inducing IRI group, it was performed right nephrectomy, and in continuing, the left kidney pedicle occluded to 45 min via nontraumatic microvascular clamp for making ischemia that followed 24 hours reperfusion. TUNEL assay was used to detect the cardiac apoptotic cells. Hematoxylin-Eosin staining and periodic acid-Schiff (PAS procedure was used to histopathological assessment and glycogen accumulation respectively. There was more heart damage at 24 h reperfusion in IRI group. Renal IRI group showed myocardial degeneration, necrosis and increasing connective tissue in myofibril. There were apparent hypertrophy and swelling of myofibril, fragmentation and vacuolization of sarcoplasm. In addition, it was shown elevated apoptotic cell at 24 hours reperfusion in renal IRI group than sham group. There were increases of glycogen accumulation in cardimyocyte of renal IRI group. Our findings suggest that renal IRI-induced cardiac damage, accompanied by an accumulation of glycogen granules, induced apoptosis and histological changes in cardiomyocytes.

  14. Distinct Endothelial Cell Responses in the Heart and Kidney Microvasculature Characterize the Progression of Heart Failure With Preserved Ejection Fraction in the Obese ZSF1 Rat With Cardiorenal Metabolic Syndrome.

    Science.gov (United States)

    van Dijk, Christian G M; Oosterhuis, Nynke R; Xu, Yan Juan; Brandt, Maarten; Paulus, Walter J; van Heerebeek, Loek; Duncker, Dirk J; Verhaar, Marianne C; Fontoura, Dulce; Lourenço, André P; Leite-Moreira, Adelino F; Falcão-Pires, Inês; Joles, Jaap A; Cheng, Caroline

    2016-04-01

    The combination of cardiac and renal disease driven by metabolic risk factors, referred to as cardiorenal metabolic syndrome (CRMS), is increasingly recognized as a critical pathological entity. The contribution of (micro)vascular injury to CRMS is considered to be substantial. However, mechanistic studies are hampered by lack of in vivo models that mimic the natural onset of the disease. Here, we evaluated the coronary and renal microvasculature during CRMS development in obese diabetic Zucker fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1) rats. Echocardiographic, urine, and blood evaluations were conducted in 3 groups (Wistar-Kyoto, lean ZSF1, and obese ZSF1) at 20 and 25 weeks of age. Immunohistological evaluation of renal and cardiac tissues was conducted at both time points. At 20 and 25 weeks, obese ZSF1 rats showed higher body weight, significant left ventricular hypertrophy, and impaired diastolic function compared with all other groups. Indices of systolic function did not differ between groups. Obese ZSF1 rats developed hyperproliferative vascular foci in the subendocardium, which lacked microvascular organization and were predilection sites of inflammation and fibrosis. In the kidney, obese ZSF1 animals showed regression of the peritubular and glomerular microvasculature, accompanied by tubulointerstitial damage, glomerulosclerosis, and proteinuria. The obese ZSF1 rat strain is a suitable in vivo model for CRMS, sharing characteristics with the human syndrome during the earliest onset of disease. In these rats, CRMS induces microvascular fibrotic responses in heart and kidneys, associated with functional impairment of both organs. © 2016 American Heart Association, Inc.

  15. A STUDY OF CHANGES IN DEFORMATION AND METABOLISM IN LEFT VENTRICLE AS A FUNCTION OF HYPERTROPHY IN SPONTANEOUS HYPERTENSIVE RATS USING MICROPET TECHNOLOGY

    Energy Technology Data Exchange (ETDEWEB)

    Gullberg, Grant, T; Huesman, Ronald, H; Reutter, Bryan, W; Sitek, Arkadiusz; Veress, Alexander, I; Weiss, Jeffrey, A; Yang, Yongfeng

    2017-06-13

    Problem: In the case of hypertrophy caused by pressure overload (hypertension) there is an increase in cardiac mass and modification cardiac metabolism. Aim: This study was designed to study the changes in glucose metabolism, ejection fraction, and deformation in the left ventricle with the progression of hypertrophy in spontaneous hypertensive rats (SHR). Methods: Dynamic PET data were acquired using the microPET II at UC Davis. Two rats were imaged at 10-week intervals for 18 months. Each time a dose of approximately 1- 1.5 mCi of F-18-FDG was injected into a normotensive Wistar Kyoto (WKY) rat and the same dose was injected into a SHR rat. Each rat was imaged using a gated dynamic acquisition for 80 minutes acquiring list mode data with cardiac gating of approximately 600-900 million total counts. For the analysis of glucose of metabolism, the list mode data were histogrammed into a dynamic sequence (42 frames over 80 mins). For each time frame, projection data of 1203 140x210 sinograms of 0.582 mm bins were formed by summing the last three gates before and one after the R-wave trigger to correspond to the diastolic phase of the cardiac cycle. Dynamic sequences of 128x128x83 matrices of 0.4x0.4x0.582 mm3 voxels in x, y, and z were reconstructed using an iterative MAP reconstruction which used a prior that penalized the high frequency components of the reconstruction using appropriate weighting between 26 nearest neighboring voxels. Time activity curves were generated from the dynamic reconstructed sequence for the blood and left ventricular tissue regions of interest which were fit to a 2-compartment model to obtain a least squares fit for the kinetic parameters. For the analysis of deformation, the list mode data were histogrammed into 8 gates of the cardiac cycle, each gate was the total sum of the later 60 mins of the 80 min acquisition. Images of 128x128x83 matrices for each gate were reconstructed using the same iterative MAP reconstruction used to

  16. Histological analysis of heart after domoic acid administration in rats

    Directory of Open Access Journals (Sweden)

    Andrés Crespo Vieira

    2014-06-01

    All data were analysed with GraphPad Prism 5.0 by a one-way analysis of variance (ANOVA. Dunnett’s Multiple Comparison test was used for post hoc comparisons between control and treatment groups. Results were expressed as means ± SEM, with a P value of Zalophus californianus (Gulland et al. 2002; Zabka et al. 2009, although these effects were no studied under experimental conditions due to that they were natural intoxications. In vitro studies showed that DOM produced alterations in the metabolism of rat cardiac myoblasts (Nijjar et al. 1999; Vranyac-Tramoundanas et al. 2008, but few in vivo observations are reduced to a previous report by Vranyac-Tramoundanas (Vranyac-Tramoundanas et al. 2011, where heart lesions were seen 3 days i.p. administration. The early onset of the heart lesions, characteristic of acute damage, led us to realize the present assay, where we expected to observe some kind of heart damage or collagen alterations. The possible observed damage would be correlated with the presence of DOM by IHQ assays. The experimental dose (2.5 mg/kg and the antibody concentration (1:5000 were determined by previous experiments (Vieira et al., in press. Our previous observations showed an important presence of DOM only in hippocampus 6h and 10h after toxin i.p. administration (Vieira et al., in press. Neuropathological studies in rodents concluded that hippocampus constitutes the principal target of DOM, due to the high concentration of KA receptors in this area (Wisden 1993. In spite of the presence of GluRs in rat heart (Gill et al. 1998, the DOM affinity for these GluRs or the concentration of GluRs might not be high enough to detect DOM presence 6h, 10h or 24h after i.p. administration. The mild collagen alterations and the lack of observable damage in the first 24 h after toxin administration concluded that DOM seems to need several days in order to produce observable damage. Further experiments with long-time expositions to DOM will be done.

  17. Discriminating between adaptive and carcinogenic liver hypertrophy in rat studies using logistic ridge regression analysis of toxicogenomic data: The mode of action and predictive models.

    Science.gov (United States)

    Liu, Shujie; Kawamoto, Taisuke; Morita, Osamu; Yoshinari, Kouichi; Honda, Hiroshi

    2017-03-01

    Chemical exposure often results in liver hypertrophy in animal tests, characterized by increased liver weight, hepatocellular hypertrophy, and/or cell proliferation. While most of these changes are considered adaptive responses, there is concern that they may be associated with carcinogenesis. In this study, we have employed a toxicogenomic approach using a logistic ridge regression model to identify genes responsible for liver hypertrophy and hypertrophic hepatocarcinogenesis and to develop a predictive model for assessing hypertrophy-inducing compounds. Logistic regression models have previously been used in the quantification of epidemiological risk factors. DNA microarray data from the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System were used to identify hypertrophy-related genes that are expressed differently in hypertrophy induced by carcinogens and non-carcinogens. Data were collected for 134 chemicals (72 non-hypertrophy-inducing chemicals, 27 hypertrophy-inducing non-carcinogenic chemicals, and 15 hypertrophy-inducing carcinogenic compounds). After applying logistic ridge regression analysis, 35 genes for liver hypertrophy (e.g., Acot1 and Abcc3) and 13 genes for hypertrophic hepatocarcinogenesis (e.g., Asns and Gpx2) were selected. The predictive models built using these genes were 94.8% and 82.7% accurate, respectively. Pathway analysis of the genes indicates that, aside from a xenobiotic metabolism-related pathway as an adaptive response for liver hypertrophy, amino acid biosynthesis and oxidative responses appear to be involved in hypertrophic hepatocarcinogenesis. Early detection and toxicogenomic characterization of liver hypertrophy using our models may be useful for predicting carcinogenesis. In addition, the identified genes provide novel insight into discrimination between adverse hypertrophy associated with carcinogenesis and adaptive hypertrophy in risk assessment. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Merit of Ginseng in the Treatment of Heart Failure in Type 1-Like Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Cheng-Chia Tsai

    2014-01-01

    Full Text Available The present study investigated the merit of ginseng in the improvement of heart failure in diabetic rats and the role of peroxisome proliferator-activated receptors δ (PPARδ. We used streptozotocin-induced diabetic rat (STZ-rat to screen the effects of ginseng on cardiac performance and PPARδ expression. Changes of body weight, water intake, and food intake were compared in three groups of age-matched rats; the normal control (Wistar rats received vehicle, STZ-rats received vehicle and ginseng-treated STZ-rats. We also determined cardiac performances in addition to blood glucose level in these animals. The protein levels of PPARδ in hearts were identified using Western blotting analysis. In STZ-rats, cardiac performances were decreased but the food intake, water intake, and blood glucose were higher than the vehicle-treated control. After a 7-day treatment of ginseng in STZ-rats, cardiac output was markedly enhanced without changes in diabetic parameters. This treatment with ginseng also increased the PPARδ expression in hearts of STZ-rats. The related signal of cardiac contractility, troponin I phosphorylation, was also raised. Ginseng-induced increasing of cardiac output was reversed by the cotreatment with PPARδ antagonist GSK0660. Thus, we suggest that ginseng could improve heart failure through the increased PPARδ expression in STZ-rats.

  19. Atorvastatin induced increase in homologous angiotensin I converting enzyme (ACE2) mRNA is associated to decreased fibrosis and decreased left ventricular hypertrophy in a rat model of diabetic cardiomyopathy

    OpenAIRE

    Aguilar, Cristian; Departamento de Anatomía Patológica, Hospital Nacional Edgardo Rebagliati Martins. Lima, Perú. Médico, Residente de Anatomía Patológica, HNERM.; Ventura, Freddy; Departamento de Ciencias Básicas, facultad de Medicina, Universidad Nacional de Trujillo. Trujillo, Perú. Químico farmacéutico, Magíster en fisiología y Biofísica.; Rodríguez-Delfín, Luis; Departamento de Anatomía Patológica, Hospital Nacional Edgardo Rebagliati Martins. Lima, Perú. Laboratorio de Biología Molecular, Facultad de Biología, Universidad Nacional Pedro Ruiz Gallo. Chiclayo, Perú. Investigación y Diagnóstico en Genética y Biología Molecular “GEN MOL”. Trujillo, Perú. Biólogo, Doctor en Ciencias, área de Genética.

    2011-01-01

    Objectives. This study has investigated the effect of atorvastatin on the progression of cardiac remodelling and ACE- 2 expression in diabetic myocardium in rats. Materials and Methods. Diabetes was induced in Holtzman rats with an intraperitoneal injection of streptozotocin. The animals were divided into 3 groups: (1) normal control rats, (2) diabetic rats and (3) diabetic rats treated orally with atorvastatin (50 mg/kg/day). After eight weeks of treatment, the hearts were removed for morpho...

  20. Isoflurane depresses baroreflex control of heart rate in decerebrate rats.

    Science.gov (United States)

    Lee, Jong S; Morrow, Don; Andresen, Michael C; Chang, Kyoung S K

    2002-05-01

    Isoflurane inhibits baroreflex control of heart rate (HR) by poorly understood mechanisms. The authors examined whether suprapontine central nervous system cardiovascular regulatory sites are required for anesthetic depression. The effects of isoflurane (1 and 2 rat minimum alveolar concentration [MAC]) on the baroreflex control of HR were determined in sham intact and midcollicular-transected decerebrate rats. Intravenous phenylephrine (0.2-12 microg/kg) and nitroprusside (1-60 microg/kg) were used to measure HR responses to peak changes in mean arterial pressure (MAP). Sigmoidal logistic curve fits to HR-MAP data assessed baroreflex sensitivity (HR/MAP), HR range, lower and upper HR plateau, and MAP at half the HR range (BP50). Four groups (two brain intact and two decerebrate) were studied before, during, and after isoflurane. To assess sympathetic and vagal contributions to HR baroreflex, beta-adrenoceptor (1 mg/kg atenolol) or muscarinic (0.5 mg/kg methyl atropine) antagonists were administered systemically. Decerebration did not alter resting MAP and HR or baroreflex parameters. Isoflurane depressed baroreflex slope and HR range in brain-intact and decerebrate rats. In both groups, 1 MAC reduced HR range by depressing peak reflex tachycardia. Maximal reflex bradycardia during increases in blood pressure was relatively preserved. Atenolol during 1 MAC did not alter maximum reflex tachycardia. In contrast, atropine during 1 MAC fully blocked reflex bradycardia. Therefore, 1 MAC predominantly depresses sympathetic components of HR baroreflex. Isoflurane at 2 MAC depressed both HR plateaus and decreased BP50 in both groups. Isoflurane depresses HR baroreflex control by actions that do not require suprapontine central nervous system sites. Isoflurane actions seem to inhibit HR baroreflex primarily by the sympathetic nervous system.

  1. Simvastatin prevents isoproterenol-induced cardiac hypertrophy through modulation of the JAK/STAT pathway

    Directory of Open Access Journals (Sweden)

    Al-Rasheed NM

    2015-06-01

    Full Text Available Nouf M Al-Rasheed,1 Maha M Al-Oteibi,1 Reem Z Al-Manee,1 Sarah A Al-Shareef,1 Nawal M Al-Rasheed,1 Iman H Hasan,1 Raeesa A Mohamad,2 Ayman M Mahmoud3 1Department of Pharmacology, Faculty of Pharmacy, 2Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia; 3Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Egypt Abstract: Simvastatin (SIM is a lipid-soluble inhibitor of hydroxy-3-methylglutaryl coenzyme A reductase with multiple reported therapeutic benefits. The present study was designed to investigate the effect of pretreatment with SIM on isoproterenol (ISO-induced cardiac hypertrophy in rats. Twenty-four male albino Wistar rats weighing 180–200 g were divided into four groups. Groups I and III received normal saline while groups II and IV received SIM (10 mg/kg body weight for 30 days per gavage. In the last 7 days, rats of groups III and IV were administered ISO (5 mg/kg intraperitoneally to induce cardiac hypertrophy. Administration of ISO induced an increase in heart-to-body weight (HW/BW ratio, an increase in serum interleukin-6, and elevated systolic and diastolic blood pressure. Serum levels of lipids, cardiovascular risk indices, and cardiac troponin I and creatine phosphokinase-MB showed significant increase in ISO-induced hypertrophic rats. Histopathological examination of heart tissue revealed focal areas of subendocardium degeneration, mononuclear cellular infiltrations, fibrous tissue deposition, and increased thickness of the myocardium of left ventricle. In addition, ISO-administered rats exhibited significant upregulation of cardiac Janus kinase, phosphorylated signal transducer and activator of transcription, and nuclear factor-kappa B. Pretreatment with SIM significantly prevented ISO-induced cardiac hypertrophy, alleviated the altered biochemical parameters, and improved the heart architecture. In conclusion, our study provides evidence that SIM

  2. Regression of altitude-produced cardiac hypertrophy.

    Science.gov (United States)

    Sizemore, D. A.; Mcintyre, T. W.; Van Liere, E. J.; Wilson , M. F.

    1973-01-01

    The rate of regression of cardiac hypertrophy with time has been determined in adult male albino rats. The hypertrophy was induced by intermittent exposure to simulated high altitude. The percentage hypertrophy was much greater (46%) in the right ventricle than in the left (16%). The regression could be adequately fitted to a single exponential function with a half-time of 6.73 plus or minus 0.71 days (90% CI). There was no significant difference in the rates of regression for the two ventricles.

  3. Development of an Assay Based on the Effects of PGBx on the Isolated Perfused Rat Heart and Rat Skeletal Muscle.

    Science.gov (United States)

    1980-09-01

    phosphorylation and enhance ATP synthesis in aged and/or damaqed mitochondria is unique (Polis et al, 1973; Devlin, �), and its lack of effect on the...rat heart, (’An. Pha’mac. 9,101-112. Aronson, C. E. and Serlick, E. R., (1977a) Effects of chlorpromazine on the isola- ted perfused rat heart, ’ Apl...euthyroid and hyperthyroid rats. Eur. J. Pharmac. 19, 12-17. Aronson, C. E. and Serlick, E. R. (1977a) Effects of chlorpromazine on the isolated

  4. Fenofibrate attenuates impaired ischemic preconditioning-mediated cardioprotection in the fructose-fed hypertriglyceridemic rat heart.

    Science.gov (United States)

    Babbar, Lalita; Mahadevan, Nanjaian; Balakumar, Pitchai

    2013-04-01

    We investigated in this study whether or not the ischemic preconditioning (IPC)-mediated cardioprotective effect against ischemia-reperfusion (I/R) injury exists in the fructose-fed hypertriglyceridemic (HTG) rat heart. Langendorff-perfused normal and fructose-fed (10 % w/v in drinking water, 8 weeks) HTG rat hearts were subjected to 30-min global ischemia and 120-min reperfusion. IPC protocol included four brief episodes (5 min each) of ischemia and reperfusion. Myocardial infarct size using triphenyltetrazolium chloride staining, markers of cardiac injury such as lactate dehydrogenase (LDH) and creatine kinase (CK-MB) release, coronary flow rate (CFR), and myocardial oxidative stress were assessed. High degree of myocardial I/R injury, by means of significant myocardial infarct size, elevated coronary LDH and CK-MB release, reduced CFR, and high oxidative stress, was noted in the HTG rat heart as compared to the normal rat heart. The IPC-mediated cardioprotection against I/R injury was markedly impaired in the HTG rat heart as compared to the normal rat heart. Interestingly, pharmacological reduction of triglycerides using 8-week treatment protocol with fenofibrate (80 mg/kg/day, p.o.) restored the IPC effect in the HTG rat heart that was blunted by coinfusion, during the IPC reperfusion protocol, of a specific inhibitor of phosphoinositide-3-kinase (PI3-K), wortmannin (100 nM). The IPC failed to protect the HTG rat heart against I/R injury. Fenofibrate treatment reduced high triglycerides in the fructose-fed HTG rat and subsequently restored the cardioprotective effect of IPC.

  5. DJ-1 activates autophagy in the repression of cardiac hypertrophy.

    Science.gov (United States)

    Xue, Ruicong; Jiang, Jingzhou; Dong, Bin; Tan, Weiping; Sun, Yu; Zhao, Jingjing; Chen, Yili; Dong, Yugang; Liu, Chen

    2017-11-01

    Cardiac hypertrophy is the risk factor of heart failure when the heart is confronted with pressure overload or neurohumoral stimuli. Autophagy, a conserved degradative pathway, is one of the important mechanisms involved in the regulation of cardiac hypertrophy. DJ-1 is a traditional anti-oxidative protein and emerging evidence suggested that DJ-1 might modulate autophagy. However, the regulation of autophagy by DJ-1 in the process of cardiac hypertrophy remains unknown. In our study, we firstly discovered that the expression of DJ-1declined in the process of pressure overload cardiac hypertrophy, and its alteration was parallel with the impairment of autophagy. Furthermore, we proved that DJ-1 knockout mice exhibited a more hypertrophied phenotype than wildtype mice in cardiac hypertrophy which indicated that DJ-1 is responsible for the repression of cardiac hypertrophy. Furthermore, DJ-1 knockout significantly exacerbated pulmonary edema due to cardiac hypertrophy. In the process of cardiac hypertrophy, DJ-1 knockout significantly impaired autophagy activation and enhanced mTORC1 and mTORC2 phosphorylation were found. Similarly, our in vitro study proved that DJ-1 overexpression ameliorated phenylephrine (PE)-induced cardiac hypertrophy and promoted autophagy activation. Taken together, DJ-1 might repress both pressure overload and PE-induced cardiac hypertrophy via the activation of autophagy. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Restoration of Circulating MFGE8 (Milk Fat Globule-EGF Factor 8) Attenuates Cardiac Hypertrophy Through Inhibition of Akt Pathway.

    Science.gov (United States)

    Deng, Ke-Qiong; Li, Jing; She, Zhi-Gang; Gong, Jun; Cheng, Wen-Lin; Gong, Fu-Han; Zhu, Xue-Yong; Zhang, Yan; Wang, Zhihua; Li, Hongliang

    2017-10-01

    Cardiac hypertrophy occurs in response to numerous stimuli like neurohumoral stress, pressure overload, infection, and injury, and leads to heart failure. Mfge8 (milk fat globule-EGF factor 8) is a secreted protein involved in various human diseases, but its regulation and function during cardiac hypertrophy remain unexplored. Here, we found that circulating MFGE8 levels declined significantly in failing hearts from patients with dilated cardiomyopathy. Correlation analyses revealed that circulating MFGE8 levels were negatively correlated with the severity of cardiac dysfunction and remodeling in affected patients. Deleting Mfge8 in mice maintained normal heart function at basal level but substantially exacerbated the hypertrophic enlargement of cardiomyocytes, reprogramming of pathological genes, contractile dysfunction, and myocardial fibrosis after aortic banding surgery. In contrast, cardiac-specific Mfge8 overexpression in transgenic mice significantly blunted aortic banding-induced cardiac hypertrophy. Whereas MAPK (mitogen-activated protein kinase) pathways were unaffected in either Mfge8 -knockout or Mfge8 -overexpressing mice, the activated Akt/PKB (protein kinase B)-Gsk-3β (glycogen synthase kinase-3β)/mTOR (mammalian target of rapamycin) pathway after aortic banding was significantly potentiated by Mfge8 deficiency but suppressed by Mfge8 overexpression. Inhibition of Akt with MK-2206 blocked the prohypertrophic effects of Mfge8 deficiency in angiotensin II-treated neonatal rat cardiomyocytes. Finally, administering a recombinant human MFGE8 in mice in vivo alleviated cardiac hypertrophy induced by aortic banding. Our findings indicate that Mfge8 is an endogenous negative regulator of pathological cardiac hypertrophy and may, thus, have potential both as a novel biomarker and as a therapeutic target for treatment of cardiac hypertrophy. © 2017 American Heart Association, Inc.

  7. Omega-3-fatty acid adds to the protective effect of flax lignan concentrate in pressure overload-induced myocardial hypertrophy in rats via modulation of oxidative stress and apoptosis.

    Science.gov (United States)

    Ghule, Arvindkumar E; Kandhare, Amit D; Jadhav, Suresh S; Zanwar, Anand A; Bodhankar, Subhash L

    2015-09-01

    Objective of the present investigation was to study the effect of the flax lignan concentrate (FLC) and Omega-3-fatty acid (O-3-FA) on myocardial apoptosis, left ventricular (LV) contractile dysfunction and electrocardiographic abnormalities in pressure overload-induced cardiac hypertrophy. The rats were divided into five groups such as sham, aortic stenosis (AS), AS+FLC, AS+O-3-FA and AS+FLC+O-3-FA. Cardiac hypertrophy was produced in rats by abdominal aortic constriction. The rats were treated with FLC (400mg/kg, p.o.), O-3-FA (400mg/kg, p.o.) and FLC+O-3-FA orally per day for four weeks. The LV function, myocardial apoptosis, and oxidative stress were quantified. FLC+O-3-FA treatment significantly reduced hemodynamic changes, improved LV contractile dysfunction, reduced cardiomyocyte apoptosis and cellular oxidative stress. Moreover, it significantly up-regulated the VEGF expression and decreased TNF-alpha level in serum. The histological analysis also revealed that FLC+O-3-FA treatment markedly preserved the cardiac structure and inhibited interstitial fibrosis. In conclusion, FLC+O-3-FA treatment improved LV dysfunction, inhibited cardiomyocyte apoptosis, improved myocardial angiogenesis, conserved activities of membrane-bound phosphatase enzymes and suppressed inflammation through reduced oxidative stress in an additive manner than FLC alone and O-3-FA alone treatment in pressure overload-induced cardiac hypertrophy. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Intermolecular failure of L-type Ca2+ channel and ryanodine receptor signaling in hypertrophy.

    Directory of Open Access Journals (Sweden)

    Ming Xu

    2007-02-01

    Full Text Available Pressure overload-induced hypertrophy is a key step leading to heart failure. The Ca(2+-induced Ca(2+ release (CICR process that governs cardiac contractility is defective in hypertrophy/heart failure, but the molecular mechanisms remain elusive. To examine the intermolecular aspects of CICR during hypertrophy, we utilized loose-patch confocal imaging to visualize the signaling between a single L-type Ca(2+ channel (LCC and ryanodine receptors (RyRs in aortic stenosis rat models of compensated (CHT and decompensated (DHT hypertrophy. We found that the LCC-RyR intermolecular coupling showed a 49% prolongation in coupling latency, a 47% decrease in chance of hit, and a 72% increase in chance of miss in DHT, demonstrating a state of "intermolecular failure." Unexpectedly, these modifications also occurred robustly in CHT due at least partially to decreased expression of junctophilin, indicating that intermolecular failure occurs prior to cellular manifestations. As a result, cell-wide Ca(2+ release, visualized as "Ca(2+ spikes," became desynchronized, which contrasted sharply with unaltered spike integrals and whole-cell Ca(2+ transients in CHT. These data suggested that, within a certain limit, termed the "stability margin," mild intermolecular failure does not damage the cellular integrity of excitation-contraction coupling. Only when the modification steps beyond the stability margin does global failure occur. The discovery of "hidden" intermolecular failure in CHT has important clinical implications.

  9. Suppressor of IKKɛ is an essential negative regulator of pathological cardiac hypertrophy

    Science.gov (United States)

    Deng, Ke-Qiong; Wang, Aibing; Ji, Yan-Xiao; Zhang, Xiao-Jing; Fang, Jing; Zhang, Yan; Zhang, Peng; Jiang, Xi; Gao, Lu; Zhu, Xue-Yong; Zhao, Yichao; Gao, Lingchen; Yang, Qinglin; Zhu, Xue-Hai; Wei, Xiang; Pu, Jun; Li, Hongliang

    2016-01-01

    Although pathological cardiac hypertrophy represents a leading cause of morbidity and mortality worldwide, our understanding of the molecular mechanisms underlying this disease is still poor. Here, we demonstrate that suppressor of IKKɛ (SIKE), a negative regulator of the interferon pathway, attenuates pathological cardiac hypertrophy in rodents and non-human primates in a TANK-binding kinase 1 (TBK1)/AKT-dependent manner. Sike-deficient mice develop cardiac hypertrophy and heart failure, whereas Sike-overexpressing transgenic (Sike-TG) mice are protected from hypertrophic stimuli. Mechanistically, SIKE directly interacts with TBK1 to inhibit the TBK1-AKT signalling pathway, thereby achieving its anti-hypertrophic action. The suppression of cardiac remodelling by SIKE is further validated in rats and monkeys. Collectively, these findings identify SIKE as a negative regulator of cardiac remodelling in multiple animal species due to its inhibitory regulation of the TBK1/AKT axis, suggesting that SIKE may represent a therapeutic target for the treatment of cardiac hypertrophy and heart failure. PMID:27249321

  10. Effects of thyroid state on respiration of perfused rat and guinea pig hearts

    Energy Technology Data Exchange (ETDEWEB)

    Read, L.C.; Wallace, P.G.; Berry, M.N. (Flinders Univ. School of Medicine, Bedford Park (Australia))

    1987-09-01

    The effects of thyroid state on the respiration of the isolated heart were investigated using retrograde perfused rat and guinea pig hearts. In both species, hypothyroidism caused a marked depression in circulating thyroid hormone concentrations and in the respiration of the isolated, retrograde perfused heart. Hypothyroidism was caused by injecting animals with Na{sup 131}I. The effects on myocardial respiration could be attributed to changes in the contraction frequency and in the oxygen consumption per beat, with little contribution from basal respiration. Treatment of animals with thyroxine elevated plasma thyroid hormones to a similar extent in rats and guinea pigs. In the latter, thyroxine treatment was associated with substantial increases in the contraction frequency and the oxygen consumption per beat of the isolated heart. In contrast, only small changes were apparent in the retrograde perfused rat heart, observations that were confirmed in rat hearts perfused at near physiological work loads. It was concluded that rat hearts isolated from normal animals function at near maximal thyroid state, in contrast to the guinea pig heart, which requires higher circulating concentrations of thyroid hormones to attain maximal responses.

  11. Dual-specificity phosphatase 14 protects the heart from aortic banding-induced cardiac hypertrophy and dysfunction through inactivation of TAK1-P38MAPK/-JNK1/2 signaling pathway.

    Science.gov (United States)

    Li, Chang-Yi; Zhou, Qing; Yang, Ling-Chao; Chen, Yi-He; Hou, Jian-Wen; Guo, Kai; Wang, Yue-Peng; Li, Yi-Gang

    2016-03-01

    Dual-specificity phosphatase 14 (Dusp14), an important negative modulator of mitogen-activated protein kinase (MAPK) signaling pathways, has been implicated in inflammatory immune response, cancers, cell differentiation and proliferation. The role of Dusp14 in chronic pressure overload-induced cardiac hypertrophy has not been explored. Here we have shown that Dusp14-/- knockout mice and cardiac-specific Dusp14 transgenic mice were generated and subjected to aortic banding (AB) for 4 weeks. Our results demonstrated that genetic loss of Dusp14 significantly aggravated cardiac hypertrophy, fibrosis, ventricular dilation and dysfunction, whereas transgenic cardiac-specific Dusp14 overexpression significantly attenuated AB-induced cardiac dysfunction and remodeling. In vitro, adenoviral overexpression of constitutive Dusp14 blocked angiotensin II-induced hypertrophic growth of cardiomyocytes, while Dusp14 knockdown led to opposite effects. Mechanistically, excessive phosphorylation of TAK1, P38MAPK and JNK1/2 was evidenced in Dusp14-/- knockout mice post-AB and inactivation of TAK1-P38MAPK and -JNK1/2 signaling using TAK1 inhibitor 5Z-7-ox shares similar antihypertrophic effect as Dusp14 overexpression. Moreover, we show that Dusp14 directly interacted with TAK1. Results from present experiments indicate that Dusp14 protects the heart from AB-induced cardiac hypertrophy and dysfunction possibly through inactivation of TAK1-P38MAPK/-JNK1/2 signaling pathway. Future studies are warranted to test the feasibility of overexpressing Dusp14 as a therapeutic strategy to attenuate cardiac hypertrophy and failure.

  12. Electrolyte content of serum, erythrocyte, kidney and heart tissue in salt induced hypertensive rats.

    Science.gov (United States)

    Mahboob, T; Mumtaz, M; Haleem, M A

    1996-01-01

    The effect of salt load on the systolic blood pressure (SBP) and electrolyte levels of serum, erythrocyte, kidney and heart tissue was studied in rats. NaCl treatment increased sodium (5.69 +/- 0.4 mmol/L p electrolyte levels of erythrocytes, serum, heart and kidney tissues in NaCl loaded rats may play a definite role in the development of salt induced hypertension.

  13. Effects of chronic overload on muscle hypertrophy and mTOR signaling in adult and aged rats

    Science.gov (United States)

    We examined the effect of 28 days of overload on mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK) signaling in young adult (Y; 6 mo old) and aged (O; 30 mo old) Fischer 344 x Brown Norway rats subjected to bilateral synergist ablation (SA) of two-thirds of the gas...

  14. Anabolic-androgenic steroid does not enhance compensatory muscle hypertrophy but significantly diminish muscle damages in the rat surgical ablation model.

    Science.gov (United States)

    Tamaki, Tetsuro; Uchiyama, Yoshiyasu; Okada, Yoshinori; Tono, Kayoko; Nitta, Masahiro; Hoshi, Akio; Akatsuka, Akira

    2009-07-01

    Cellular responses in the compensatory hypertrophied (plantaris) muscle induced by surgical ablation of synergistic muscles (soleus and gastrocnemius) were determined during 10-week anabolic androgenic steroid (AAS) treatment. Adult Wistar male rats were divided randomly into the Control and Steroid groups, and contralateral surgery was performed. Nandrolone decanoate was administered to the Steroid group. [3H]thymidine and [14C]leucine labeling were used to determine the serial changes in cellular mitotic activity and amino acid uptake. Myogenic cells and cellular responses in blood vessels and nerve fibers were analyzed by immunohistochemistry. Significantly lower cellular mitotic activity associated with lower volume of muscle fiber necrosis was observed in the Steroid group during the first week. However, amino acid uptake and final muscle wet weight gain did not differ between the groups. Marked activation/proliferation of muscular, vascular, and peripheral nerve-related cells was seen with the inflammatory responses in both groups. However, this activation was dependent on the volume of muscle fiber damage and was not preferentially accelerated by AAS loading. These results indicated that AAS loading significantly diminished muscle fiber damages, but they did not accelerate final muscle wet weight gain and activation of myogenic, vascular, and peripheral nerve related cells in the compensatory enlarged muscles.

  15. Inhibition of cyclooxygenase-2 reduces hypothalamic excitation in rats with adriamycin-induced heart failure.

    Directory of Open Access Journals (Sweden)

    Min Zheng

    Full Text Available BACKGROUND: The paraventricular nucleus (PVN of the hypothalamus plays an important role in the progression of heart failure (HF. We investigated whether cyclooxygenase-2 (COX-2 inhibition in the PVN attenuates the activities of sympathetic nervous system (SNS and renin-angiotensin system (RAS in rats with adriamycin-induced heart failure. METHODOLOGY/PRINCIPAL FINDING: Heart failure was induced by intraperitoneal injection of adriamycin over a period of 2 weeks (cumulative dose of 15 mg/kg. On day 19, rats received intragastric administration daily with either COX-2 inhibitor celecoxib (CLB or normal saline. Treatment with CLB reduced mortality and attenuated both myocardial atrophy and pulmonary congestion in HF rats. Compared with the HF rats, ventricle to body weight (VW/BW and lung to body weight (LW/BW ratios, heart rate (HR, left ventricular end-diastolic pressure (LVEDP, left ventricular peak systolic pressure (LVPSP and maximum rate of change in left ventricular pressure (LV±dp/dtmax were improved in HF+CLB rats. Angiotensin II (ANG II, norepinephrine (NE, COX-2 and glutamate (Glu in the PVN were increased in HF rats. HF rats had higher levels of ANG II and NE in plasma, higher level of ANG II in myocardium, and lower levels of ANP in plasma and myocardium. Treatment with CLB attenuated these HF-induced changes. HF rats had more COX-2-positive neurons and more corticotropin releasing hormone (CRH positive neurons in the PVN than did control rats. Treatment with CLB decreased COX-2-positive neurons and CRH positive neurons in the PVN of HF rats. CONCLUSIONS: These results suggest that PVN COX-2 may be an intermediary step for PVN neuronal activation and excitatory neurotransmitter release, which further contributes to sympathoexcitation and RAS activation in adriamycin-induced heart failure. Treatment with COX-2 inhibitor attenuates sympathoexcitation and RAS activation in adriamycin-induced heart failure.

  16. [The value of terminal force of P wave in V1 lead in the diagnosis of coal-worker's pneumoconiosis with pulmonary heart disease complicated by left ventricular hypertrophy].

    Science.gov (United States)

    Bao, Ying

    2012-01-01

    To determine the value of terminal force of P wave in V1 lead (Ptf-V1) in the diagnosis of coal-workers' pneumoconiosis with pulmonary heart disease complicated by left ventricular hypertrophy. Select the coal-worker with pneumoconiosis postmortem examination cases which were pathologically diagnosed as pulmonary heart disease complicated by left ventricular hypertrophy and can measure Ptf-V1. Select 14 cases with ECG left axis deviation, no deviation and right axis deviation. Measure and analyze the Ptf-V1 value, the thickness of left and right ventricular wall. There's obvious discrepancy in ventricular wall thickness mean in ECG left axis deviation, no deviation and right axis deviation groups, the discrepancy have statistical significance (F1 = 32.18, P left ventricular wall is thicker in ECG left axis deviation group [(1.81 +/- 0.18) cm] than in no deviation [(1.47 +/- 0.15) cm] and right axis deviation groups [(1.39 +/- 0.10) cm], the discrepancy have statistical significance with (P left axis deviation group [(0.79 +/- 0.14) cm] than in no deviation group [(0.58 +/- 0.14) cm], the discrepancy have statistical significance with (P axis deviation group [(0.71 +/- 0.14) cm] than in no deviation group, the discrepancy have statistical significance with (P left axis deviation Ptf-V1 relevance ratio 85.71% is higher than in no deviation (35.70%) and right axis deviation groups (28.57%), the discrepancy have statistical significance with (P left ventricular wall thickness in ECG left axis deviation and no deviation groups (r1 = 0.92, P left ventricular morphosis and function especially left atrium loading change. ECG Ptf-V1 combined with ECG left axis deviation is valuable to the diagnosis of coal-workers with pneumoconiosis complicated by left ventricular hypertrophy.

  17. Vascular calcification abrogates the nicorandil mediated cardio-protection in ischemia reperfusion injury of rat heart.

    Science.gov (United States)

    Ravindran, Sriram; Murali, Jeyashri; Amirthalingam, Sunil Kumar; Gopalakrishnan, Senthilkumar; Kurian, Gino A

    2017-02-01

    The present study was aimed to determine the efficacy of nicorandil in treating cardiac reperfusion injury with an underlying co-morbidity of vascular calcification (VC). Adenine diet was used to induce VC in Wistar rat and the heart was isolated to induce global ischemia reperfusion (IR) by Langendorff method, with and without the nicorandil (7.5mg/kg) pre-treatment and compared with those fed on normal diet. The adenine-treated rats displayed abnormal ECG changes and altered mitochondrial integrity compared to a normal rat heart. These hearts, when subjected to IR increased the infarct size, cardiac injury (measured by lactate dehydrogenase and creatine kinase activity in the coronary perfusate) and significantly altered the hemodynamics compared to the normal perfused heart. Nicorandil pretreatment in rat fed on normal diet enhanced the hemodynamics significantly (Pcardio-protective effect of nicorandil was absent in rat heart with underlying calcification. Our results suggest that, the protective effect of nicorandil, a known mitochondrial ATP linked K + channel opener, against myocardial reperfusion injury was confined to normal rat heart. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Renal denervation in male rats with heart failure improves ventricular sympathetic nerve innervation and function.

    Science.gov (United States)

    Pinkham, Maximilian I; Loftus, Michael T; Amirapu, Satya; Guild, Sarah-Jane; Quill, Gina; Woodward, William R; Habecker, Beth A; Barrett, Carolyn J

    2017-03-01

    Heart failure is characterized by the loss of sympathetic innervation to the ventricles, contributing to impaired cardiac function and arrhythmogenesis. We hypothesized that renal denervation (RDx) would reverse this loss. Male Wistar rats underwent myocardial infarction (MI) or sham surgery and progressed into heart failure for 4 wk before receiving bilateral RDx or sham RDx. After additional 3 wk, left ventricular (LV) function was assessed, and ventricular sympathetic nerve fiber density was determined via histology. Post-MI heart failure rats displayed significant reductions in ventricular sympathetic innervation and tissue norepinephrine content (nerve fiber density in the LV of MI+sham RDx hearts was 0.31 ± 0.05% vs. 1.00 ± 0.10% in sham MI+sham RDx group, P heart failure. Our findings show denervating the renal nerves improves cardiac sympathetic innervation and function in the post-MI failing heart. Copyright © 2017 the American Physiological Society.

  19. Histochemical detection of glycogen phosphorylase activity as parameter for early ischemic damage in rat heart

    NARCIS (Netherlands)

    Frederiks, W. M.; Schellens, J. P.; Marx, F.; Bosch, K. S.; Vreeling-Sindelárová, H.

    1993-01-01

    In the present study we have investigated whether enzyme histochemical parameters can be applied to detect early ischemic damage in rat heart after ischemia without restoration of the blood flow. Ischemia was induced by incubating heart fragments for 0, 10, 20, 30, 60, 120 and 240 min at 37 degrees

  20. MORPHOLOGICAL ACTIVATION OF LYMPHOCYTES IN BLOOD DURING REJECTION OF HEART AND LUNG GRAFTS IN RATS

    NARCIS (Netherlands)

    WESTRA, AL; HEIJN, AA; UYAMA, T; PROP, J; WILDEVUUR, CRH

    We investigated morphologic activation of lymphocytes in blood in a standardized, infection-free rat model and compared lymphocyte activation during rejection of heart grafts and that of lung grafts with other parameters of rejection. For heart grafts the other parameters were histology and

  1. Cardiac Hypertrophy: An Introduction to Molecular and Cellular Basis

    OpenAIRE

    Samak, Mostafa; Fatullayev, Javid; Sabashnikov, Anton; Zeriouh, Mohamed; Schmack, Bastian; Farag, Mina; Popov, Aron-Frederik; Dohmen, Pascal M.; Choi, Yeong-Hoon; Wahlers, Thorsten; Weymann, Alexander

    2016-01-01

    Ventricular hypertrophy is an ominous escalation of hemodynamically stressful conditions such as hypertension and valve disease. The pathophysiology of hypertrophy is complex and multifactorial, as it touches on several cellular and molecular systems. Understanding the molecular background of cardiac hypertrophy is essential in order to protect the myocardium from pathological remodeling, or slow down the destined progression to heart failure. In this review we highlight the most important mo...

  2. Pressure load: the main factor for altered gene expression in right ventricular hypertrophy in chronic hypoxic rats.

    Directory of Open Access Journals (Sweden)

    Jonas D Baandrup

    Full Text Available BACKGROUND: The present study investigated whether changes in gene expression in the right ventricle following pulmonary hypertension can be attributed to hypoxia or pressure loading. METHODOLOGY/PRINCIPAL FINDINGS: To distinguish hypoxia from pressure-induced alterations, a group of rats underwent banding of the pulmonary trunk (PTB, sham operation, or the rats were exposed to normoxia or chronic, hypobaric hypoxia. Pressure measurements were performed and the right ventricle was analyzed by Affymetrix GeneChip, and selected genes were confirmed by quantitative PCR and immunoblotting. Right ventricular systolic blood pressure and right ventricle to body weight ratio were elevated in the PTB and the hypoxic rats. Expression of the same 172 genes was altered in the chronic hypoxic and PTB rats. Thus, gene expression of enzymes participating in fatty acid oxidation and the glycerol channel were downregulated. mRNA expression of aquaporin 7 was downregulated, but this was not the case for the protein expression. In contrast, monoamine oxidase A and tissue transglutaminase were upregulated both at gene and protein levels. 11 genes (e.g. insulin-like growth factor binding protein were upregulated in the PTB experiment and downregulated in the hypoxic experiment, and 3 genes (e.g. c-kit tyrosine kinase were downregulated in the PTB and upregulated in the hypoxic experiment. CONCLUSION/SIGNIFICANCE: Pressure load of the right ventricle induces a marked shift in the gene expression, which in case of the metabolic genes appears compensated at the protein level, while both expression of genes and proteins of importance for myocardial function and remodelling are altered by the increased pressure load of the right ventricle. These findings imply that treatment of pulmonary hypertension should also aim at reducing right ventricular pressure.

  3. 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

  4. Direct effect of cocaine on epigenetic regulation of PKCε gene repression in the fetal rat heart

    OpenAIRE

    Meyer, Kurt; Zhang, Haitao; Zhang, Lubo

    2009-01-01

    Maternal cocaine administration during gestation caused a down-regulation of PKCε expression in the heart of adult offspring resulting in an increased sensitivity to ischemia and reperfusion injury. The present study investigated the direct effect of cocaine in epigenetic modification of PKCε gene repression in the fetal heart. Hearts were isolated from gestational day 17 fetal rats and treated with cocaine in an ex vivo organ culture system. Cocaine treatment for 48 h resulted in significant...

  5. The role of autophagy in cardiac hypertrophy

    Science.gov (United States)

    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

  6. The role of autophagy in cardiac hypertrophy.

    Science.gov (United States)

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

    2016-06-01

    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. © The Author 2016. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  7. Early inflammatory response during the development of right ventricular heart failure in a rat model.

    Science.gov (United States)

    Campian, Maria E; Hardziyenka, Maxim; de Bruin, Kora; van Eck-Smit, Berthe L F; de Bakker, Jacques M T; Verberne, Hein J; Tan, Hanno L

    2010-07-01

    Inflammatory activation plays an important role in the pathogenesis and progression of left ventricular (LV) heart failure. In right ventricular (RV) heart failure, little is known about the role of inflammatory activation. We aimed to study the role of inflammatory activation in RV heart failure by serial monitoring during disease progression. Right ventricular heart failure was induced in male Wistar rats by intraperitoneal injection of monocrotaline (MCT). Two groups were studied: MCT-treated rats (MCT-rats), and age-matched controls (CON-rats). Serial echocardiography and in vivo 67-Gallium ((67)Ga) scintigraphy were performed. Local inflammation in the RV was assessed by (i) ex vivo semi-quantitative (67)Ga autoradiography, (ii) immunohistochemistry of myeloperoxidase (MPO), a marker of neutrophil activity, and (iii) mRNA assays of tumour necrosis factor-alpha (TNF-alpha). In MCT-rats, (67)Ga scintigraphy showed increased myocardial uptake which started during the early stages of RV disease. (67)Ga autoradiography revealed that this increased (67)Ga uptake occurred in the RV and inter-ventricular septum, but not in the LV. The stage-dependent increases of in vivo (67)Ga RV myocardial uptake were paralleled by increases in mRNA gene expression for TNF-alpha in RV, and increased MPO staining in RV. Development and progression of RV heart failure is associated with an early increase in RV inflammation. (67)Ga scintigraphy may be used for the serial assessment of inflammation and monitoring of disease progression in RV heart failure.

  8. Association between Functional Variables and Heart Failure after Myocardial Infarction in Rats

    Energy Technology Data Exchange (ETDEWEB)

    Polegato, Bertha F.; Minicucci, Marcos F.; Azevedo, Paula S.; Gonçalves, Andréa F.; Lima, Aline F.; Martinez, Paula F.; Okoshi, Marina P.; Okoshi, Katashi; Paiva, Sergio A. R.; Zornoff, Leonardo A. M., E-mail: lzornoff@fmb.unesp.br [Faculdade de Medicina de Botucatu - Universidade Estadual Paulista ' Júlio de mesquita Filho' - UNESP Botucatu, SP (Brazil)

    2016-02-15

    Heart failure prediction after acute myocardial infarction may have important clinical implications. To analyze the functional echocardiographic variables associated with heart failure in an infarction model in rats. The animals were divided into two groups: control and infarction. Subsequently, the infarcted animals were divided into groups: with and without heart failure. The predictive values were assessed by logistic regression. The cutoff values predictive of heart failure were determined using ROC curves. Six months after surgery, 88 infarcted animals and 43 control animals were included in the study. Myocardial infarction increased left cavity diameters and the mass and wall thickness of the left ventricle. Additionally, myocardial infarction resulted in systolic and diastolic dysfunction, characterized by lower area variation fraction values, posterior wall shortening velocity, E-wave deceleration time, associated with higher values of E / A ratio and isovolumic relaxation time adjusted by heart rate. Among the infarcted animals, 54 (61%) developed heart failure. Rats with heart failure have higher left cavity mass index and diameter, associated with worsening of functional variables. The area variation fraction, the E/A ratio, E-wave deceleration time and isovolumic relaxation time adjusted by heart rate were functional variables predictors of heart failure. The cutoff values of functional variables associated with heart failure were: area variation fraction < 31.18%; E / A > 3.077; E-wave deceleration time < 42.11 and isovolumic relaxation time adjusted by heart rate < 69.08. In rats followed for 6 months after myocardial infarction, the area variation fraction, E/A ratio, E-wave deceleration time and isovolumic relaxation time adjusted by heart rate are predictors of heart failure onset.

  9. Hipertrofia ventricular esquerda do atleta: resposta adaptativa fisiológica do coração Left ventricular hypertrophy of athletes: adaptative physiologic response of the heart

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    Nabil Ghorayeb

    2005-09-01

    Full Text Available OBJETIVO: Verificar se a hipertrofia ventricular esquerda (HVE de atletas competitivos de resistência (maratonistas representa processo adaptativo, puramente fisiológico, ou se pode envolver aspectos patológicos em suas características anatômicas e funcionais. MÉTODOS: De novembro de 1999 a dezembro de 2000, foram separados consecutivamente de 30 maratonistas em atividade esportiva plena, idade inferior a 50 anos, com HVE, previamente documentada, e sem cardiopatia subjacente. Foram submetidos aos exames: clínico, eletrocardiograma, ecodopplercardiograma, e teste ergométrico (TE. Quinze foram sorteados para realizar, também, teste ergoespirométrico e ressonância magnética (RM do coração. RESULTADOS: Nos TE, todos apresentavam boa capacidade física cardiopulmonar, sem evidências de resposta isquêmica ao exercício, sintomas ou arritmias. No ecodopplercardiograma, os valores do diâmetro e espessura diastólica da parede posterior do ventrículo esquerdo (VE, do septo interventricular, massa do VE e diâmetro do átrio esquerdo, foram significativamente maiores que os do grupo de não atletas, com idades e medidas antropométricas semelhantes. A média da massa do VE dos atletas indexada à superfície corpórea (126 g/m2 foi significativamente maior que a do grupo controle (70 g/m2 (pOBJECTIVE: To verify whether left ventricular hypertrophy (LVH of elite competition athletes (marathoners represents a purely physiological, adaptative process, or it may involve pathological aspects in its anatomical and functional characteristics. METHODS: From November 1999 to December 2000, consecutive samples from 30 under 50-year-old marathoners in full sportive activity, with previously documented LVH and absence of cardiopathy were selected. They were submitted to clinical exams, electrocardiogram, color Doppler echocardiogram and exercise treadmill test (ETT. Fifteen were assorted to be also submitted to ergoespirometric test and heart

  10. ENDURANCE TRAINING AND GLUTATHIONE-DEPENDENT ANTIOXIDANT DEFENSE MECHANISM IN HEART OF THE DIABETIC RATS

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    Mustafa Atalay

    2003-06-01

    Full Text Available Regular physical exercise beneficially influences cardiac antioxidant defenses in normal rats. The aim of this study was to test whether endurance training can strengthen glutathione-dependent antioxidant defense mechanism and decrease lipid peroxidation in heart of the streptozotocin-induced diabetic rats. Redox status of glutathione in blood of diabetic rats in response to training and acute exercise was also examined. Eight weeks of treadmill training increased the endurance in streptozotocin-induced diabetic rats. It did not affect glutathione level in heart tissue at rest and also after exercise. On the other hand, endurance training decreased glutathione peroxidase activity in heart, while glutathione reductase and glutathione S-transferase activities were not affected either by acute exhaustive exercise or endurance training. Reduced and oxidized glutathione levels in blood were not affected by either training or acute exercise. Conjugated dienes levels in heart tissue were increased by acute exhaustive exercise and also 8 weeks treadmill training. Longer duration of exhaustion in trained group may have contributed to the increased conjugated dienes levels in heart after acute exercise. Our results suggest that endurance type exercise may make heart more susceptible to oxidative stress. Therefore it may be wise to combine aerobic exercise with insulin treatment to prevent its adverse effects on antioxidant defense in heart in patients with diabetes mellitus

  11. Long-term physiological T3 supplementation in hypertensive heart disease in rats.

    Science.gov (United States)

    Weltman, Nathan Y; Pol, Christine J; Zhang, Youhua; Wang, Yibo; Koder, Adrienne; Raza, Sarah; Zucchi, Riccardo; Saba, Alessandro; Colligiani, Daria; Gerdes, A Martin

    2015-09-15

    Animal studies suggest that hypertension leads to cardiac tissue hypothyroidism, a condition that can by itself lead to heart failure. We have previously shown that short-term thyroid hormone treatment in Spontaneously Hypertensive Heart Failure (SHHF) rats near heart failure is beneficial. This study tested the hypothesis that therapeutic, long-term T3 treatment in SHHF rats can prevent or attenuate cardiac dysfunction. Female SHHF rats were treated orally with a physiological T3 dose (0.04 μg/ml) from 12 to 24 mo of age. Age-matched female SHHF and Wistar-Kyoto rats served as hypertensive and normotensive controls, respectively. SHHF rats had reduced serum free thyroid hormone levels and cardiac tissue T3 levels, LV dysfunction, and elevated LV collagen content compared with normotensive controls. Restoration of serum and cardiac tissue thyroid hormone levels in T3-treated rats was associated with no change in heart rate, but strong trends for improvement in LV systolic function and collagen levels. For instance, end-systolic diameter, fractional shortening, systolic wall stress, and LV collagen levels were no longer significantly different from controls. In conclusion, longstanding hypertension in rats led to chronic low serum and cardiac tissue thyroid hormone levels. Long-term treatment with low-dose T3 was safe. While cardiac dysfunction could not be completely prevented in the absence of antihypertensive treatment, T3 may offer additional benefits as an adjunct therapy with possible improvement in diastolic function. Copyright © 2015 the American Physiological Society.

  12. Role of hypoxia-inducible factor in diabetic myocardial hypertrophy

    African Journals Online (AJOL)

    elevation of hypoxia inducible factor (HIF), which in turn leads to increases in levels of VEGF and other angiogenic factors. This adaptive response delays progression from pathological cardiac hypertrophy to heart failure. In early cardiac hypertrophy, stability of HIF-1 promotes glycolysis, which improves glucose utilization ...

  13. Coronary blood flow and thallium 201 uptake in rejecting rat heart transplantations

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    Bergsland, J.; Hwang, K.; Driscoll, R.; Carr, E.A.; Wright, J.R.; Curran-Everett, D.C.; Carroll, M.; Krasney, E.; Krasney, J.A. (Veterans Administration Medical Center, Buffalo, NY (USA))

    1989-03-01

    The effects of rejection on coronary flow (CAF) in heart allografts are unclear, although previous evidence with cardiac imaging agents indicates impaired flow during advanced rejection. The purpose of this study was to measure CAF in heterotopically placed heart grafts. Lewis rats (LEW) received grafts from either syngeneic Lewis rats (LEW/LEW group) or allogeneic ACI rats (ACI/LEW group). CAF was measured in both the transplanted and native hearts with radiolabeled microspheres. Rejection was measured histologically (grades 0 (absent) to 4+ (severe)). In addition systemic blood pressure and cardiac outputs of the native hearts were determined with microspheres. Different animals were studied during relatively early (4 days) and late (6 days) rejection. Among the 4-day animals a cyclosporine-treated group was included (ACI/LEW CyA). In 6-day rats CAF in allografts was lower (0.56 +/- .06 ml/gm/min) compared with syngeneic grafts (1.72 +/- 0.4 ml/gm/min) (p less than 0.05). The CAF in the native hearts did not differ significantly but was higher than in the grafts in both groups. Heart rates were reduced in allografts (p less than 0.05). It is interesting that arterial pressure and cardiac output were significantly lower in animals bearing allogeneic than syngeneic grafts. In rats studied at 4 days graft CAF was lower than in the native heart in both the LEW/LEW and ACI/LEW groups, but there was no significant difference in behavior between groups. The same was true for a cyclosporine-treated group. Graft heart rates were similar in all 4-day rats.

  14. Perinatal hypothyroidism modulates antioxidant defence status in the developing rat liver and heart.

    Science.gov (United States)

    Zhang, Hongmei; Dong, Yan; Su, Qing

    2017-02-01

    In the present study, we investigated oxidative stress parameters and antioxidant defence status in perinatal hypothyroid rat liver and heart. We found that the proteincarbonyl content did not differ significantly between the three groups both in the pup liver and in the heart. The OH˙ level was significantly decreased in the hypothyroid heart but not in the liver compared with controls. A slight but not significant decrease in SOD activity was observed in both perinatal hypothyroid liver and heart. A significantly increased activity of CAT was observed in the liver but not in the heart of hypothyroid pups. The GPx activity was considerably increased compared with controls in the perinatal hypothyroid heart and was unaltered in the liver of hypothyroid pups. We also found that vitamin E levels in the liver decreased significantly in hypothyroidism and were unaltered in the heart of perinatal hypothyroid rats. The GSH content was elevated significantly in both hypothyroid liver and heart. The total antioxidant capacity was higher in the liver of the hypothyroid group but not in the hypothyroid heart. Thyroxine replacement could not repair the above changes to normal. In conclusion, perinatal hypothyroidism modulates the oxidative stress status of the perinatal liver and heart.

  15. The Effect of Treadmill Exercise on Antioxidant Status in the Hearts of the Diabetic Rats

    Directory of Open Access Journals (Sweden)

    I. Salehi

    2009-07-01

    Full Text Available Introduction & Objective: Diabetes is a metabolic disorder caused by low secretion or resistance to the insulin action. Oxidative stress, as a result of imbalance between the free radical production and antioxidant defense systems is strongly related to diabetes and its complications. The aim of the present study is to evaluate the effect of experimental diabetes and forced treadmill exercise on oxidative stress indexes in heart tissue.Materials & Methods: 40 male wistar rats (20020g were divided into four groups(n=10: control, control with exercise, diabetic, diabetic with exercise. Diabetes was induced by a single dose injection of streptozotocin (50 mg/Kg-1, i.p. Treadmill was performed for 1 hour, 5 days in 8 weeks. At the end of the experiments, the rats were anesthetized by sodium pentobarbital (50 mg/Kg-1, i.p and left ventricle dissociate from heart and maintenance in -80 ºC. Supernatant from homogenization were used to determine the superoxide dismutase (SOD, gluthatione peroxidase (GPX, gluthatione reductase (GR and catalase (CAT activities as enzymatic antioxidant status. Also Maolnyldealdehyde (MDA level as index of lipid peroxidation and total glutathione (T.GSH of the heart tissue were measured.Results: Diabetes significantly reduced CAT and GR activities in diabetic rats compared with control rats. SOD and GPX activities weren't changed in the hearts of the diabetic rats. MDA level, as a lipid peroxidation index, increased in non exercised diabetic rats. In response to exercise, MDA level, CAT, GR and SOD activities showed a significant increase in exercise diabetic rats compared with non exercise diabetic rats.Conclusion: Forced treadmill with moderate severity has harmful effects on cardiovascular system in diabetes because it increases MDA level of heart tissue in exercised diabetic rats.

  16. Dose-dependent effects of a soluble dietary fibre (pectin on food intake, adiposity, gut hypertrophy and gut satiety hormone secretion in rats.

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    Clare L Adam

    Full Text Available Soluble fermentable dietary fibre elicits gut adaptations, increases satiety and potentially offers a natural sustainable means of body weight regulation. Here we aimed to quantify physiological responses to graded intakes of a specific dietary fibre (pectin in an animal model. Four isocaloric semi-purified diets containing 0, 3.3%, 6.7% or 10% w/w apple pectin were offered ad libitum for 8 or 28 days to young adult male rats (n = 8/group. Measurements were made of voluntary food intake, body weight, initial and final body composition by magnetic resonance imaging, final gut regional weights and histology, and final plasma satiety hormone concentrations. In both 8- and 28-day cohorts, dietary pectin inclusion rate was negatively correlated with food intake, body weight gain and the change in body fat mass, with no effect on lean mass gain. In both cohorts, pectin had no effect on stomach weight but pectin inclusion rate was positively correlated with weights and lengths of small intestine and caecum, jejunum villus height and crypt depth, ileum crypt depth, and plasma total glucagon-like peptide-1 (GLP-1 and peptide tyrosine tyrosine (PYY concentrations, and at 8 days was correlated with weight and length of colon and with caecal mucosal depth. Therefore, the gut's morphological and endocrine adaptations were dose-dependent, occurred within 8 days and were largely sustained for 28 days during continued dietary intervention. Increasing amounts of the soluble fermentable fibre pectin in the diet proportionately decreased food intake, body weight gain and body fat content, associated with proportionately increased satiety hormones GLP-1 and PYY and intestinal hypertrophy, supporting a role for soluble dietary fibre-induced satiety in healthy body weight regulation.

  17. Hypothyroidism and oxidative stress: differential effect on the heart of virgin and pregnant rats.

    Science.gov (United States)

    Carmona, Y V; Coria, M J; Oliveros, L B; Gimenez, M S

    2014-01-01

    The present study investigates the effects of hypothyroidism on both the redox state and the thyroid hormone receptors expression in the heart ventricle of virgin and pregnant rats.Hypothyroid state was induced by 6-n-propyl-2-thiouracil in drinking water given to Wistar rats starting 8 days before mating until day 21 of pregnancy or for 30 days in virgin rats. Serum paraoxonase-1 (PON-1) activity, serum and heart nitrites, and thiobarbituric acid-reactive substances (TBARS) were analyzed. Heart protein oxidation, as carbonyls, and copper-zinc superoxide dismutase (CuZnSOD), glutathione peroxidase (GPx), and catalase (CAT) activities, were determined. In addition, heart expressions of NADPH oxidase (NOX-2), CAT, SOD, GPx, and thyroid receptors (TRα and TRβ) mRNA were assessed by RT-PCR. Inducible and endothelial Nitric Oxide Synthase (iNOS and eNOS) were determined by Western blot. Hypothyroidism in the heart of virgin rats decreased TRα and TRβ expressions, and induced oxidative stress, leading to a decrease of nitrites and an increase of carbonyls, NOX-2 mRNA, and GPx activity. A decreased PON-1 activity suggested low protection against oxidative stress in blood circulation. Pregnancy reduced TRα and TRβ mRNA expressions and induced oxidative stress by increasing nitrite and TBARS levels, SOD and CAT activities and NOX-2, eNOS and iNOS expressions, while hypothyroidism, emphasized the decreases of TRα mRNA levels and did not alter the redox state in the heart. TR expressions and redox balance of rat hearts depend on the physiological state. Pregnancy per se seems to protect the heart against oxidative stress induced by hypothyroidism. Supporting Information for this article is available online at http://www.thieme-connect.de/ejournals/toc/hmr. © Georg Thieme Verlag KG Stuttgart · New York.

  18. The Regulatory Role of Nuclear Factor Kappa B in the Heart of Hereditary Hypertriglyceridemic Rat.

    Science.gov (United States)

    Vranková, Stanislava; Barta, Andrej; Klimentová, Jana; Dovinová, Ima; Líšková, Silvia; Dobešová, Zdenka; Pecháňová, Oľga; Kuneš, Jaroslav; Zicha, Josef

    2016-01-01

    Activation of nuclear factor-κB (NF-κB) by increased production of reactive oxygen species (ROS) might induce transcription and expression of different antioxidant enzymes and also of nitric oxide synthase (NOS) isoforms. Thus, we aimed at studying the effect of NF-κB inhibition, caused by JSH-23 (4-methyl-N (1)-(3-phenyl-propyl)-benzene-1,2-diamine) injection, on ROS and NO generation in hereditary hypertriglyceridemic (HTG) rats. 12-week-old, male Wistar and HTG rats were treated with JSH-23 (bolus, 10 μmol, i.v.). After one week, blood pressure (BP), superoxide dismutase (SOD) activity, SOD1, endothelial NOS (eNOS), and NF-κB (p65) protein expressions were higher in the heart of HTG rats compared to control rats. On the other hand, NOS activity was decreased. In HTG rats, JSH-23 treatment increased BP and heart conjugated dienes (CD) concentration (measured as the marker of tissue oxidative damage). Concomitantly, SOD activity together with SOD1 expression was decreased, while NOS activity and eNOS protein expression were increased significantly. In conclusion, NF-κB inhibition in HTG rats led to decreased ROS degradation by SOD followed by increased oxidative damage in the heart and BP elevation. In these conditions, increased NO generation may represent rather a counterregulatory mechanism activated by ROS. Nevertheless, this mechanism was not sufficient enough to compensate BP increase in HTG rats.

  19. The Regulatory Role of Nuclear Factor Kappa B in the Heart of Hereditary Hypertriglyceridemic Rat

    Directory of Open Access Journals (Sweden)

    Stanislava Vranková

    2016-01-01

    Full Text Available Activation of nuclear factor-κB (NF-κB by increased production of reactive oxygen species (ROS might induce transcription and expression of different antioxidant enzymes and also of nitric oxide synthase (NOS isoforms. Thus, we aimed at studying the effect of NF-κB inhibition, caused by JSH-23 (4-methyl-N1-(3-phenyl-propyl-benzene-1,2-diamine injection, on ROS and NO generation in hereditary hypertriglyceridemic (HTG rats. 12-week-old, male Wistar and HTG rats were treated with JSH-23 (bolus, 10 μmol, i.v.. After one week, blood pressure (BP, superoxide dismutase (SOD activity, SOD1, endothelial NOS (eNOS, and NF-κB (p65 protein expressions were higher in the heart of HTG rats compared to control rats. On the other hand, NOS activity was decreased. In HTG rats, JSH-23 treatment increased BP and heart conjugated dienes (CD concentration (measured as the marker of tissue oxidative damage. Concomitantly, SOD activity together with SOD1 expression was decreased, while NOS activity and eNOS protein expression were increased significantly. In conclusion, NF-κB inhibition in HTG rats led to decreased ROS degradation by SOD followed by increased oxidative damage in the heart and BP elevation. In these conditions, increased NO generation may represent rather a counterregulatory mechanism activated by ROS. Nevertheless, this mechanism was not sufficient enough to compensate BP increase in HTG rats.

  20. 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.

  1. 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.

  2. Proteção miocárdica ao coração hipertrofiado: o eterno desafio Myocardial protection to the hypertrophied heart: the eternal challenge

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    Elthon Silveira Cressoni

    2008-03-01

    Full Text Available A proteção miocárdica permitiu enorme avanço na moderna cirurgia cardíaca, reduzindo a mortalidade e permitindo que operações cada vez mais complexas pudessem ser realizadas. A alteração na população eleita para procedimentos cirúrgicos cardiológicos mudou significativamente nas últimas décadas, com o aumento de pacientes mais idosos, com função ventricular deprimida e miocárdio hipertrofiado. Essa última condição, desde os primórdios da cirurgia cardíaca, constituiu-se em grande desafio. Diversas técnicas de proteção ao miocárdio hipertrofiado foram descritas, porém com resultados não alentadores. As características da hipertrofia miocárdica no adulto com cardiopatia cirúrgica apresentam particularidades desafiadoras. Nesse artigo, procuramos atualizar o estado da arte sobre a proteção miocárdica ao coração hipertrofiado.The myocardial protection allowed great advance in cardiac surgery, decreasing the mortality and making more feasible complex surgeries. Latterly, the patient population elected for cardiac procedures has been changing towards elderly patients with ventricular function depressed and myocardial hypertrophy. The myocardial hypertrophy condition represents a great challenge since the beginning of the cardiac surgery. Several techniques have been described to protect the myocardial hypertrophy, however with no satisfactory results. In this manuscript we present the state of the art technique of myocardial protection.

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

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    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

  4. Delayed Repolarization Underlies Ventricular Arrhythmias in Rats With Heart Failure and Preserved Ejection Fraction.

    Science.gov (United States)

    Cho, Jae Hyung; Zhang, Rui; Kilfoil, Peter J; Gallet, Romain; de Couto, Geoffrey; Bresee, Catherine; Goldhaber, Joshua I; Marbán, Eduardo; Cingolani, Eugenio

    2017-11-21

    Heart failure with preserved ejection fraction (HFpEF) represents approximately half of heart failure, and its incidence continues to increase. The leading cause of mortality in HFpEF is sudden death, but little is known about the underlying mechanisms. Dahl salt-sensitive rats were fed a high-salt diet (8% NaCl) from 7 weeks of age to induce HFpEF (n=38). Rats fed a normal-salt diet (0.3% NaCl) served as controls (n=13). Echocardiograms were performed to assess systolic and diastolic function from 14 weeks of age. HFpEF-verified and control rats underwent programmed electrical stimulation. Corrected QT interval was measured by surface ECG. The mechanisms of ventricular arrhythmias (VA) were probed by optical mapping, whole-cell patch clamp to measure action potential duration and ionic currents, and quantitative polymerase chain reaction and Western blotting to investigate changes in ion channel expression. After 7 weeks of a high-salt diet, 31 of 38 rats showed diastolic dysfunction and preserved ejection fraction along with signs of heart failure and hence were diagnosed with HFpEF. Programmed electric stimulation demonstrated increased susceptibility to VA in HFpEF rats ( P hearts demonstrated prolonged action potentials ( P hearts. Susceptibility to VA was markedly increased in rats with HFpEF. Underlying abnormalities include QT prolongation, delayed repolarization from downregulation of potassium currents, and multiple reentry circuits during VA. Our findings are consistent with the hypothesis that potassium current downregulation leads to abnormal repolarization in HFpEF, which in turn predisposes to VA and sudden cardiac death. © 2017 American Heart Association, Inc.

  5. Effects of Ischemic Postconditioning on the Hemodynamic Parameters and Heart Nitric Oxide Levels of Hypothyroid Rats

    Directory of Open Access Journals (Sweden)

    Sajad Jeddi

    2015-02-01

    Full Text Available Background: Ischemic postconditioning (IPost is a method of protecting the heart against ischemia-reperfusion (IR injury. However, the effectiveness of IPost in cases of ischemic heart disease accompanied by co-morbidities such as hypothyroidism remains unclear. Objective: The aim of this study was to determine the effect of IPost on myocardial IR injury in hypothyroid male rats. Methods: Propylthiouracil in drinking water (500 mg/L was administered to male rats for 21 days to induce hypothyroidism. The hearts from control and hypothyroid rats were perfused in a Langendorff apparatus and exposed to 30 min of global ischemia, followed by 120 min of reperfusion. IPost was induced immediately following ischemia. Results: Hypothyroidism and IPost significantly improved the left ventricular developed pressure (LVDP and peak rates of positive and negative changes in left ventricular pressure (±dp/dt during reperfusion in control rats (p < 0.05. However, IPost had no add-on effect on the recovery of LVDP and ±dp/dt in hypothyroid rats. Furthermore, hypothyroidism significantly decreased the basal NO metabolite (NOx levels of the serum (72.5 ± 4.2 vs. 102.8 ± 3.7 μmol/L; p < 0.05 and heart (7.9 ± 1.6 vs. 18.8 ± 3.2 μmol/L; p < 0.05. Heart NOx concentration in the hypothyroid groups did not change after IR and IPost, whereas these were significantly (p < 0.05 higher and lower after IR and IPost, respectively, in the control groups. Conclusion: Hypothyroidism protects the heart from IR injury, which may be due to a decrease in basal nitric oxide (NO levels in the serum and heart and a decrease in NO after IR. IPost did not decrease the NO level and did not provide further cardioprotection in the hypothyroid group.

  6. Effects of Ischemic Postconditioning on the Hemodynamic Parameters and Heart Nitric Oxide Levels of Hypothyroid Rats

    Energy Technology Data Exchange (ETDEWEB)

    Jeddi, Sajad; Zaman, Jalal; Ghasemi, Asghar, E-mail: ghasemi@endocrine.ac.ir [Endocrine Physiology Research Center - Research Institute for Endocrine Sciences - Shahid Beheshti University of Medical Sciences, Tehran (Iran, Islamic Republic of); Endocrine Research Center - Research Institute for Endocrine Sciences - Shahid Beheshti University of Medical Sciences, Tehran (Iran, Islamic Republic of)

    2015-02-15

    Ischemic postconditioning (IPost) is a method of protecting the heart against ischemia-reperfusion (IR) injury. However, the effectiveness of IPost in cases of ischemic heart disease accompanied by co-morbidities such as hypothyroidism remains unclear. The aim of this study was to determine the effect of IPost on myocardial IR injury in hypothyroid male rats. Propylthiouracil in drinking water (500 mg/L) was administered to male rats for 21 days to induce hypothyroidism. The hearts from control and hypothyroid rats were perfused in a Langendorff apparatus and exposed to 30 min of global ischemia, followed by 120 min of reperfusion. IPost was induced immediately following ischemia. Hypothyroidism and IPost significantly improved the left ventricular developed pressure (LVDP) and peak rates of positive and negative changes in left ventricular pressure (±dp/dt) during reperfusion in control rats (p < 0.05). However, IPost had no add-on effect on the recovery of LVDP and ±dp/dt in hypothyroid rats. Furthermore, hypothyroidism significantly decreased the basal NO metabolite (NO{sub x}) levels of the serum (72.5 ± 4.2 vs. 102.8 ± 3.7 μmol/L; p < 0.05) and heart (7.9 ± 1.6 vs. 18.8 ± 3.2 μmol/L; p < 0.05). Heart NO{sub x} concentration in the hypothyroid groups did not change after IR and IPost, whereas these were significantly (p < 0.05) higher and lower after IR and IPost, respectively, in the control groups. Hypothyroidism protects the heart from IR injury, which may be due to a decrease in basal nitric oxide (NO) levels in the serum and heart and a decrease in NO after IR. IPost did not decrease the NO level and did not provide further cardioprotection in the hypothyroid group.

  7. Effect of acute nitric oxide synthase inhibition in the modulation of heart rate in rats

    Directory of Open Access Journals (Sweden)

    A.L. Fellet

    2003-05-01

    Full Text Available Acute nitric oxide synthase inhibition with N G-nitro-L-arginine methyl ester (L-NAME on chronotropic and pressor responses was studied in anesthetized intact rats and rats submitted to partial and complete autonomic blockade. Blood pressure and heart rate were monitored intra-arterially. Intravenous L-NAME injection (7.5 mg/kg elicited the same hypertensive response in intact rats and in rats with partial (ganglionic and parasympathetic blockade and complete autonomic blockade (38 ± 3, 55 ± 6, 54 ± 5, 45 ± 5 mmHg, respectively; N = 9, P = NS. L-NAME-induced bradycardia at the time when blood pressure reached the peak plateau was similar in intact rats and in rats with partial autonomic blockade (43 ± 8, 38 ± 5, 46 ± 6 bpm, respectively; N = 9, P = NS. Rats with combined autonomic blockade showed a tachycardic response to L-NAME (10 ± 3 bpm, P<0.05 vs intact animals, N = 9. Increasing doses of L-NAME (5.0, 7.5 and 10 mg/kg, N = 9 caused a similar increase in blood pressure (45 ± 5, 38 ± 3, 44 ± 9 mmHg, respectively; P = NS and heart rate (31 ± 4, 34 ± 3, 35 ± 4 bpm, respectively; P = NS. Addition of L-NAME (500 µM to isolated atria from rats killed by cervical dislocation and rats previously subjected to complete autonomic blockade did not affect spontaneous beating or contractile strength (N = 9. In vivo results showed that L-NAME promoted a tachycardic response in rats with complete autonomic blockade, whereas the in vitro experiments showed no effect on intrinsic heart rate, suggesting that humoral mechanisms may be involved in the L-NAME-induced cardiac response.

  8. Adaptations to iron deficiency: cardiac functional responsiveness to norepinephrine, arterial remodeling, and the effect of beta-blockade on cardiac hypertrophy

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    Walker LeeAnn

    2002-01-01

    Full Text Available Abstract Background Iron deficiency (ID results in ventricular hypertrophy, believed to involve sympathetic stimulation. We hypothesized that with ID 1 intravenous norepinephrine would alter heart rate (HR and contractility, 2 abdominal aorta would be larger and more distensible, and 3 the beta-blocker propanolol would reduce hypertrophy. Methods 1 30 CD rats were fed an ID or replete diet for 1 week or 1 month. Norepinephrine was infused via jugular vein; pressure was monitored at carotid artery. Saline infusions were used as a control. The pressure trace was analyzed for HR, contractility, systolic and diastolic pressures. 2 Abdominal aorta catheters inflated the aorta, while digital microscopic images were recorded at stepwise pressures to measure arterial diameter and distensibility. 3 An additional 10 rats (5 ID, 5 control were given a daily injection of propanolol or saline. After 1 month, the hearts were excised and weighed. Results Enhanced contractility, but not HR, was associated with ID hypertrophic hearts. Systolic and diastolic blood pressures were consistent with an increase in arterial diameter associated with ID. Aortic diameter at 100 mmHg and distensibility were increased with ID. Propanolol was associated with an increase in heart to body mass ratio. Conclusions ID cardiac hypertrophy results in an increased inotropic, but not chronotropic response to the sympathetic neurotransmitter, norepinephrine. Increased aortic diameter is consistent with a flow-dependent vascular remodeling; increased distensibility may reflect decreased vascular collagen content. The failure of propanolol to prevent hypertrophy suggests that ID hypertrophy is not mediated via beta-adrenergic neurotransmission.

  9. Overexpression of microRNA-99a Attenuates Cardiac Hypertrophy

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    Li, Ran; Bai, Jian; Ding, Liang; Gu, Rong; Wang, Lian; Xu, Biao

    2016-01-01

    Pathological cardiomyocyte hypertrophy is associated with significantly increased risk of heart failure, one of the leading medical causes of mortality worldwide. MicroRNAs are known to be involved in pathological cardiac remodeling. However, whether miR-99a participates in the signaling cascade leading to cardiac hypertrophy is unknown. To evaluate the role of miR-99a in cardiac hypertrophy, we assessed the expression of miR-99a in hypertrophic cardiomyocytes induced by isoprenaline (ISO)/angiotensin-II (Ang II) and in mice model of cardiac hypertrophy induced by transverse aortic constriction (TAC). Expression of miR-99a was evaluated in these hypertrophic cells and hearts. We also found that miR-99a expression was highly correlated with cardiac function of mice with heart failure (8 weeks after TAC surgery). Overexpression of miR-99a attenuated cardiac hypertrophy in TAC mice and cellular hypertrophy in stimuli treated cardiomyocytes through down-regulation of expression of mammalian target of rapamycin (mTOR). These results indicate that miR-99a negatively regulates physiological hypertrophy through mTOR signaling pathway, which may provide a new therapeutic approach for pressure-overload heart failure. PMID:26914935

  10. Overexpression of microRNA-99a Attenuates Cardiac Hypertrophy.

    Science.gov (United States)

    Li, Qiaoling; Xie, Jun; Wang, Bingjian; Li, Ran; Bai, Jian; Ding, Liang; Gu, Rong; Wang, Lian; Xu, Biao

    2016-01-01

    Pathological cardiomyocyte hypertrophy is associated with significantly increased risk of heart failure, one of the leading medical causes of mortality worldwide. MicroRNAs are known to be involved in pathological cardiac remodeling. However, whether miR-99a participates in the signaling cascade leading to cardiac hypertrophy is unknown. To evaluate the role of miR-99a in cardiac hypertrophy, we assessed the expression of miR-99a in hypertrophic cardiomyocytes induced by isoprenaline (ISO)/angiotensin-II (Ang II) and in mice model of cardiac hypertrophy induced by transverse aortic constriction (TAC). Expression of miR-99a was evaluated in these hypertrophic cells and hearts. We also found that miR-99a expression was highly correlated with cardiac function of mice with heart failure (8 weeks after TAC surgery). Overexpression of miR-99a attenuated cardiac hypertrophy in TAC mice and cellular hypertrophy in stimuli treated cardiomyocytes through down-regulation of expression of mammalian target of rapamycin (mTOR). These results indicate that miR-99a negatively regulates physiological hypertrophy through mTOR signaling pathway, which may provide a new therapeutic approach for pressure-overload heart failure.

  11. Raf-mediated cardiac hypertrophy in adult Drosophila

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    Yu, Lin; Daniels, Joseph; Glaser, Alex E.; Wolf, Matthew J.

    2013-01-01

    SUMMARY In response to stress and extracellular signals, the heart undergoes a process called cardiac hypertrophy during which cardiomyocytes increase in size. If untreated, cardiac hypertrophy can progress to overt heart failure that causes significant morbidity and mortality. The identification of molecular signals that cause or modify cardiomyopathies is necessary to understand how the normal heart progresses to cardiac hypertrophy and heart failure. Receptor tyrosine kinase (RTK) signaling is essential for normal human cardiac function, and the inhibition of RTKs can cause dilated cardiomyopathies. However, neither investigations of activated RTK signaling pathways nor the characterization of hypertrophic cardiomyopathy in the adult fly heart has been previously described. Therefore, we developed strategies using Drosophila as a model to circumvent some of the complexities associated with mammalian models of cardiovascular disease. Transgenes encoding activated EGFRA887T, Ras85DV12 and Ras85DV12S35, which preferentially signal to Raf, or constitutively active human or fly Raf caused hypertrophic cardiomyopathy as determined by decreased end diastolic lumen dimensions, abnormal cardiomyocyte fiber morphology and increased heart wall thicknesses. There were no changes in cardiomyocyte cell numbers. Additionally, activated Raf also induced an increase in cardiomyocyte ploidy compared with control hearts. However, preventing increases in cardiomyocyte ploidy using fizzy-related (Fzr) RNAi did not rescue Raf-mediated cardiac hypertrophy, suggesting that Raf-mediated polyploidization is not required for cardiac hypertrophy. Similar to mammals, the cardiac-specific expression of RNAi directed against MEK or ERK rescued Raf-mediated cardiac hypertrophy. However, the cardiac-specific expression of activated ERKD334N, which promotes hyperplasia in non-cardiac tissues, did not cause myocyte hypertrophy. These results suggest that ERK is necessary, but not sufficient, for

  12. Exposure to AT1 Receptor Autoantibodies during Pregnancy Increases Susceptibility of the Maternal Heart to Postpartum Ischemia-Reperfusion Injury in Rats

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    Hui-Ping Wang

    2014-06-01

    Full Text Available Epidemiological studies have demonstrated that women with a history of preeclampsia have a two-fold increased risk of developing cardiovascular diseases in later life. It is not known whether or not this risk is associated with angiotensin II receptor type 1 autoantibody (AT1-AA, an agonist acting via activation of AT1 receptor (AT1R, which is believed to be involved in the pathogenesis of preeclampsia. The objective of the present study was to confirm the hypothesis that AT1-AA exposure during pregnancy may change the maternal cardiac structure and increase the susceptibility of the postpartum heart to ischemia/reperfusion injury (IRI. In the present study, we first established a preeclampsia rat model by intravenous injection of AT1-AA extracted from the plasma of rats immunized with AT1R, observed the susceptibility of the postpartum maternal heart to IRI at 16 weeks postpartum using the Langendorff preparation, and examined the cardiac structure using light and transmission electron microscopy. The modeled animals presented with symptoms very similar to the clinical symptoms of human preeclampsia during pregnancy, including hypertension and proteinuria. The left ventricular weight (LVW and left ventricular mass index (LVMI in AT1-AA treatment group were significantly increased as compared with those of the control group (p < 0.01, although there was no significant difference in final weight between the two groups. AT1-AA acting on AT1R not only induced myocardial cell hypertrophy, mitochondrial swelling, cristae disorganization and collagen accumulation in the interstitium but affected the left ventricular (LV function and delayed recovery from IRI. In contrast, co-treatment with AT1-AA + losartan completely blocked AT1-AA-induced changes in cardiac structure and function. These data indicate that the presence of AT1-AA during pregnancy was strongly associated with the markers of LV geometry changes and remodeling, and increased the cardiac

  13. Premenarchal labia minora hypertrophy

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    Karoon Agrawal

    2016-01-01

    Full Text Available Labia minora hypertrophy is a relatively uncommon surgical entity being popularised in the realm of vulvovaginal plastic surgeries. Apart from the unaesthetic appearance of the hypertrophied minora, these cases are also associated with itching, hygiene problem, pain while sitting down, sports activities, difficulty in wearing tight clothing, bleeding and discomfort while or after sexual intercourse, social embarrassment, insecurity and psychological diminution of confidence and self-esteem. In a country like India, due to sociocultural reasons, patients hesitate to consult a doctor for such deformities. Most of the patients suffer in silence for years. Although common in the west, very few surgeons in the country perform this simple and rewarding surgery. Here, we are presenting a case of premenarchal juvenile labia minora hypertrophy (JLMH in an 8-year-old child. Labial hypertrophy in this age group is uncommon. We were unable to find hypertrophy of labia minora in the eight-year-old child on English literature search.

  14. Effect of zinc supplements in the attenuated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat heart.

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    Kansal, Sunil Kumar; Jyoti, Uma; Sharma, Samridhi; Kaura, Arun; Deshmukh, Rahul; Goyal, Sandeep

    2015-06-01

    Hyperlipidemia is regarded as independent risk factor in the development of ischemic heart disease, and it can increase the myocardial susceptibility to ischemia-/reperfusion (I/R)-induced injury. Hyperlipidemia attenuates the cardioprotective response of ischemic preconditioning (IPC). The present study investigated the effect of zinc supplements in the attenuated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat hearts. Hyperlipidemia was induced in rat by feeding high-fat diet (HFD) for 6 weeks then the serum lipid profile was observed. In experiment, the isolated Langendorff rat heart preparation was subjected to 4 cycles of ischemic preconditioning (IPC), then 30 min of ischemia followed by 120 min of reperfusion. Myocardial infarct size was elaborated morphologically by triphenyltetrazolium chloride (TTC) staining and biochemically by lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) release from coronary effluent and left ventricular collagen content. However, the effect of zinc supplement, i.e., zinc pyrithione (10 μM) perfused during reperfusion for 120 min, significantly abrogated the attenuated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat heart whereas administration of chelator of this zinc ionophore, i.e., N,N,N',N'-tetrakis(2-pyridylmethyl)ethylene diamine (TPEN; 10 μM), perfused during reperfusion 2 min before the perfusion of zinc pyrithione abrogated the cardioprotective effect of zinc supplement during experiment in hyperlipidemic rat heart. Thus, the administration of zinc supplements limits the infarct size, LDH, and CK-MB and enhanced the collagen level which suggests that the attenuated cardioprotective effect of IPC in hyperlipidemic rat is due to zinc loss during reperfusion caused by ischemia/reperfusion.

  15. Increased deposition of von Willebrand factor in the rat heart after local ionizing irradiation

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    Boerma, M.; Loenen, M.M. van; Klein, H.R.; Bart, C.I.; Wondergem, J. [Dept. of Clinical Oncology (K1-P), Leiden Univ. Medical Center (Netherlands); Kruse, J.J.C.M. [Dept. of Clinical Oncology (K1-P), Leiden Univ. Medical Center (Netherlands); Dept. of Experimental Therapy (H6), Netherlands Cancer Inst., Amsterdam (Netherlands); Zurcher, C. [Dept. of Clinical Oncology (K1-P), Leiden Univ. Medical Center (Netherlands); Dept. of Pathology, Faculty of Veterinary Medicine, Univ. of Utrecht (Netherlands)

    2004-02-01

    Background and purpose: von willebrand factor (vWf), a glycoprotein involved in blood coagulation, is synthesized by endothelial cells. Increased amounts of vWf in blood plasma or tissue samples are indicative of damaged endothelium. In the present study, mRNA expression and localization of vWf were determined in irradiated rat heart tissue. Material and methods: sprague-dawley rats received local heart irradiation with a single dose of 0, 15, or 20 Gy. Hearts were dissected at different time points (up to 16 months) after irradiation. In a second experiment, rats were injected with the radioprotector amifostine (160 mg/kg, i.p.) 15-20 min before irradiation and sacrificed after 6 months. Immunohistochemistry was performed using a polyclonal anti-vWf antibody. Serial sections were subjected to a general rat endothelial cell immunostaining (RECA-1) or a collagen staining (picrosirius red). mRNA expression was determined by using PCR. Results: in control tissue, all endothelial cells lining the lumen of the endocardium and coronary arteries, but not capillary endothelial cells, were stained for vWf. 1 month after irradiation with both 15 and 20 Gy, myocardial capillaries became immunoreactive. From 3 months onward, staining was observed also within the extracellular matrix (ECM) of fibrotic areas. At mRNA level, no changes in vWf could be observed at all time points after irradiation, suggesting that vWf deposition was not due to increased biosynthesis of the protein. In sections of amifostine-treated rat hearts, vWf staining was increased to a lesser extent. Conclusion: these dose- and time-dependent increases in deposition of vWf indicate the presence of damaged endothelium in the irradiated rat heart. These increases in vWf accumulation precede development of fibrosis in the subendocardial layer and myocardium of the left ventricles, right ventricles, and atria. (orig.)

  16. 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

  17. Effect of high fructose administration on histopathology of kidney, heart and aorta of rats

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    Rasha Saleh

    2017-03-01

    Results: Nephropathy was achieved in fructose group after one month as indicated by biochemical assay. Pathological observation showed that high fructose administration decreased size of cardio-myocytes, increased cardiac interstitial fibrosis score and aortic wall thickness. In kidneys, high fructose administration decreased glomerular tuft area and corpuscular area, increased percentage in the rats affected with interstitial renal fibrosis score 1 and percentage of rats had glomerular sclerosis score 2. Conclusion: High fructose in diet should be avoided because it can damage kidney, heart and aorta in rats. [J Adv Vet Anim Res 2017; 4(1.000: 71-79

  18. The Effects of Diabetes Induction on the Rat Heart: Differences in Oxidative Stress, Inflammatory Cells, and Fibrosis between Subendocardial and Interstitial Myocardial Areas.

    Science.gov (United States)

    Guido, Maria C; Marques, Alyne F; Tavares, Elaine R; Tavares de Melo, Marcelo D; Salemi, Vera M C; Maranhão, Raul C

    2017-01-01

    Diabetic cardiomyopathy (DCM) is characterized by cardiac remodeling and impaired diastolic function that may lead to heart failure. The aim of this study was to evaluate oxidative stress, inflammatory cells, and fibrosis in both subendocardial (SEN) and interstitial (INT) areas of the myocardium. Male Wistar rats were allocated to 2 groups of 9 animals, a control (CT) group and streptozotocin-induced diabetes (DM). After 8 weeks, echocardiography morphometry, protein expression, and confocal microscopy in SEN and INT areas of the left ventricle (LV) were performed. The echocardiographic analysis showed that diabetes induction leads to cardiac dilation, hypertrophy, and LV diastolic dysfunction. As compared to CT, the induction of diabetes increased inflammatory cells and fibrosis in both SEN and INT areas of DM myocardium and increased ROS generation only in SEN. Comparing the SEN and INT areas in the DM group, inflammatory cells and fibrosis in SEN were greater than in INT. In conclusion, diabetic myocardium SEN area, wherein oxidative stress was more pronounced, is more susceptible to cardiac dysfunction than INT area. This finding can be important for the understanding of the heart remodeling process occurring in DCM and perhaps to engender targeted therapies to attenuate or revert DCM-related diastolic dysfunction.

  19. The Effects of Diabetes Induction on the Rat Heart: Differences in Oxidative Stress, Inflammatory Cells, and Fibrosis between Subendocardial and Interstitial Myocardial Areas

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    Maria C. Guido

    2017-01-01

    Full Text Available Diabetic cardiomyopathy (DCM is characterized by cardiac remodeling and impaired diastolic function that may lead to heart failure. The aim of this study was to evaluate oxidative stress, inflammatory cells, and fibrosis in both subendocardial (SEN and interstitial (INT areas of the myocardium. Male Wistar rats were allocated to 2 groups of 9 animals, a control (CT group and streptozotocin-induced diabetes (DM. After 8 weeks, echocardiography morphometry, protein expression, and confocal microscopy in SEN and INT areas of the left ventricle (LV were performed. The echocardiographic analysis showed that diabetes induction leads to cardiac dilation, hypertrophy, and LV diastolic dysfunction. As compared to CT, the induction of diabetes increased inflammatory cells and fibrosis in both SEN and INT areas of DM myocardium and increased ROS generation only in SEN. Comparing the SEN and INT areas in the DM group, inflammatory cells and fibrosis in SEN were greater than in INT. In conclusion, diabetic myocardium SEN area, wherein oxidative stress was more pronounced, is more susceptible to cardiac dysfunction than INT area. This finding can be important for the understanding of the heart remodeling process occurring in DCM and perhaps to engender targeted therapies to attenuate or revert DCM-related diastolic dysfunction.

  20. Choice of cell-delivery route for skeletal myoblast transplantation for treating post-infarction chronic heart failure in rat.

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    Satsuki Fukushima

    2008-08-01

    Full Text Available Intramyocardial injection of skeletal myoblasts (SMB has been shown to be a promising strategy for treating post-infarction chronic heart failure. However, insufficient therapeutic benefit and occurrence of ventricular arrhythmias are concerns. We hypothesised that the use of a retrograde intracoronary route for SMB-delivery might favourably alter the behaviour of the grafted SMB, consequently modulating the therapeutic effects and arrhythmogenicity.Three weeks after coronary artery ligation in female wild-type rats, 5x10(6 GFP-expressing SMB or PBS only (control were injected via either the intramyocardial or retrograde intracoronary routes. Injection of SMB via either route similarly improved cardiac performance and physical activity, associated with reduced cardiomyocyte-hypertrophy and fibrosis. Grafted SMB via either route were only present in low numbers in the myocardium, analysed by real-time PCR for the Y-chromosome specific gene, Sry. Cardiomyogenic differentiation of grafted SMB was extremely rare. Continuous ECG monitoring by telemetry revealed that only intramyocardial injection of SMB produced spontaneous ventricular tachycardia up to 14 days, associated with local myocardial heterogeneity generated by clusters of injected SMB and accumulated inflammatory cells. A small number of ventricular premature contractions with latent ventricular tachycardia were detected in the late-phase of SMB injection regardless of the injection-route.Retrograde intracoronary injection of SMB provided significant therapeutic benefits with attenuated early-phase arrhythmogenicity in treating ischaemic cardiomyopathy, indicating the promising utility of this route for SMB-delivery. Late-phase arrhythmogenicity remains a concern, regardless of the delivery route.

  1. Energy Deregulation Precedes Alteration in Heart Energy Balance in Young Spontaneously Hypertensive Rats: A Non Invasive In Vivo31P-MR Spectroscopy Follow-Up Study.

    Science.gov (United States)

    Deschodt-Arsac, Veronique; Arsac, Laurent; Magat, Julie; Naulin, Jerome; Quesson, Bruno; Dos Santos, Pierre

    2016-01-01

    Gradual alterations in cardiac energy balance, as assessed by the myocardial PCr/ATP-ratio, are frequently associated with the development of cardiac disease. Despite great interest for the follow-up of myocardial PCr and ATP content, cardiac MR-spectroscopy in rat models in vivo is challenged by sensitivity issues and cross-contamination from other organs. Here we combined MR-Imaging and MR-Spectroscopy (Bruker BioSpec 9.4T) to follow-up for the first time in vivo the cardiac energy balance in the SHR, a genetic rat model of cardiac hypertrophy known to develop early disturbances in cytosolic calcium dynamics. We obtained consistent 31P-spectra with high signal/noise ratio from the left ventricle in vivo by using a double-tuned (31P/1H) surface coil. Reasonable acquisition time (energy regulation possibly due to calcium-mediated abnormalities in the SHR heart. Of note, defects in energy regulation were present before detectable abnormalities in cardiac energy balance at rest.

  2. Canola oil rich in oleic acid improves diastolic heart function in diet-induced obese rats.

    Science.gov (United States)

    Thandapilly, Sijo Joseph; Raj, Pema; Louis, Xavier Lieben; Perera, Danielle; Yamanagedara, Prasanga; Zahradka, Peter; Taylor, Carla G; Netticadan, Thomas

    2017-05-01

    Obesity is a leading cause of cardiovascular disease. It directly affects heart structure and function and contributes to heart failure. Diet is a major factor involved in the development of obesity along with genetic factors. We examined the effects of monounsaturated and polyunsaturated fatty acid-rich oils on cardiac structure and function in the diet-induced rodent model of obesity (DIO). Obese prone (OP) rats were fed a high-fat diet (HF; 55% of kcal) for 12 weeks; Sprague-Dawley rats fed commercial chow served as control. Echocardiography was performed to assess the cardiac structure and function in all rats at 12 weeks. OP rats fed the HF diet showed significant impairment in diastolic function compared to control rats. The HF diet containing high oleic canola oil significantly improved diastolic function of OP rats compared to the HF diet with lard. In conclusion, canola oil rich in oleic acid, when incorporated into an HF diet, prevents the development of diastolic dysfunction in DIO rats.

  3. Low-intensity exercise training delays onset of decompensated heart failure in spontaneously hypertensive heart failure rats.

    Science.gov (United States)

    Emter, Craig A; McCune, Sylvia A; Sparagna, Genevieve C; Radin, M Judith; Moore, Russell L

    2005-11-01

    Data regarding the effectiveness of chronic exercise training in improving survival in patients with congestive heart failure (CHF) are inconclusive. Therefore, we conducted a study to determine the effect of exercise training on survival in a well-defined animal model of heart failure (HF), using the lean male spontaneously hypertensive HF (SHHF) rat. In this model, animals typically present with decompensated, dilated HF between approximately 18 and 23 mo of age. SHHF rats were assigned to sedentary or exercise-trained groups at 9 and 16 mo of age. Exercise training consisted of 6 mo of low-intensity treadmill running. Exercise training delayed the onset of overt HF and improved survival (P effects on the hypertensive status of the rats. Training delayed the myosin heavy chain (MyHC) isoform shift from alpha- to beta-MyHC that was seen in sedentary animals that developed HF. Exercise was associated with a concurrent increase in cardiomyocyte length (approximately 6%), width, and area and prevented the increase in the length-to-width ratio seen in sedentary animals in HF. The increases in proteinuria, plasma atrial natriuretic peptide, and serum leptin levels observed in rats with HF were suppressed by low-intensity exercise training. No significant alterations in sarco(endo)plasmic reticulum Ca2+ ATPase, phospholamban, or Na+/Ca2+ exchanger protein expression were found in response to training. Our results indicate that 6 mo of low-intensity exercise training delays the onset of decompensated HF and improves survival in the male SHHF rat. Similarly, exercise intervention prevented or suppressed alterations in several key variables that normally occur with the development of overt CHF. These data support the idea that exercise may be a useful and inexpensive intervention in the treatment of HF.

  4. Energy Deregulation Precedes Alteration in Heart Energy Balance in Young Spontaneously Hypertensive Rats: A Non Invasive In Vivo31P-MR Spectroscopy Follow-Up Study.

    Directory of Open Access Journals (Sweden)

    Veronique Deschodt-Arsac

    Full Text Available Gradual alterations in cardiac energy balance, as assessed by the myocardial PCr/ATP-ratio, are frequently associated with the development of cardiac disease. Despite great interest for the follow-up of myocardial PCr and ATP content, cardiac MR-spectroscopy in rat models in vivo is challenged by sensitivity issues and cross-contamination from other organs.Here we combined MR-Imaging and MR-Spectroscopy (Bruker BioSpec 9.4T to follow-up for the first time in vivo the cardiac energy balance in the SHR, a genetic rat model of cardiac hypertrophy known to develop early disturbances in cytosolic calcium dynamics.We obtained consistent 31P-spectra with high signal/noise ratio from the left ventricle in vivo by using a double-tuned (31P/1H surface coil. Reasonable acquisition time (<3.2min allowed assessing the PCr/ATP-ratio comparatively in SHR and age-matched control rats (WKY: i weekly from 12 to 21 weeks of age; ii in response to a bolus injection of the ß-adrenoreceptor agonist isoproterenol at age 21 weeks.Along weeks, the cardiac PCr/ATP-ratio was highly reproducible, steady and similar (2.35±0.06 in SHR and WKY, in spite of detectable ventricular hypertrophy in SHR. At the age 21 weeks, PCr/ATP dropped more markedly (-17.1%±0.8% vs. -3,5%±1.4%, P<0.001 after isoproterenol injection in SHR and recovered slowly thereafter (time constant 21.2min vs. 6.6min, P<0.05 despite similar profiles of tachycardia among rats.The exacerbated PCr/ATP drop under ß-adrenergic stimulation indicates a defect in cardiac energy regulation possibly due to calcium-mediated abnormalities in the SHR heart. Of note, defects in energy regulation were present before detectable abnormalities in cardiac energy balance at rest.

  5. Influence of monoamine oxidase inhibitor on contractility of isolated rat hearts

    NARCIS (Netherlands)

    Meijler, F.L.; Durrer, D.

    1962-01-01

    Following the suggestion that monoamine oxidase inhibitor might interfere with potentiation of cardiac contractions, the influence of 1-iso-nicotinyl-2-isopropyl-hydrazide and 1-pivaloyl-2-benzyl-hydrazine on postextrasystolic increase of isotonic contractions in isolated perfused rat hearts was

  6. Myocardial enzyme activities in plasma after whole-heart irradiation in rats

    NARCIS (Netherlands)

    Franken, N. A.; Strootman, E.; Hollaar, L.; van der Laarse, A.; Wondergem, J.

    2000-01-01

    Plasma levels of myocardial enzymes present after local heart irradiation were studied in a rat model. The purpose was to investigate whether, within days after irradiation, these enzyme levels change to such an extent that they may be helpful in assessing the severity of cardiac damage after

  7. Thyroid hormone modulates inotropic responses, alpha-adrenoceptor density and catecholamine concentrations in the rat heart

    NARCIS (Netherlands)

    Zwaveling, J.; Batink, H. D.; de Jong, J.; Winkler Prins, E. A.; Pfaffendorf, M.; van Zwieten, P. A.

    1996-01-01

    We investigated the influence of hyper- and hypothyroidism on basal parameters of isolated perfused hearts of rats. In addition the effects of different extracellular calcium concentrations ([Ca2+]o), the calcium entry promoter Bay K8644 and the alpha 1-adrenoceptor agonist methoxamine were

  8. Extraneuronal accumulation of isoproterenol in atria and ventricle of perfused rat heart

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    Magaribuchi, T.; Kurahashi, K.; Akimoto, Y.; Fujiwara, M.

    1988-01-01

    Extraneuronal accumulation of isoproterenol in atria and ventricle of perfused rat heart was investigated. Rat hearts were perfused with various concentrations of /sup 3/H-isoproterenol for 30 min in the absence and the presence of catechol-O-methyltransferase (COMT) inhibitor (tropolone). When COMT was intact, the accumulation of /sup 3/H-isoproterenol in both atria and ventricle after perfusion with low concentration of /sup 3/H-isopreterenol was less than that of perfusing concentration; the tissue/medium ratio (T/M) of isoproterenol for atria was lower than that for ventricle. The T/M of isoproterenol after perfusion with 10 and 20 ..mu..mol/1 of /sup 3/H-isoproterenol were 0.94 and 1.76 for atria and 3.25 and 2.95 for ventricle, respectively. When COMT was inhibited by tropolone, the T/M increased 6.3 - 9.0 folds for atria and 5.1 - 6.7 folds for ventricle after perfusion with /sup 3/H-isoproterenol. From these results, it was concluded that both atria and ventricle of the rat heart have an extraneuronal O-methylating system as reported in rat whole heart, and was suggested that there might be different capacities of extraneuronal uptake and COMT between them. 10 references, 1 figure.

  9. Myocardial infarction with aortic banding - A combined rat model of heart failure

    NARCIS (Netherlands)

    Anthonio, RL; vanVeldhuisen, DJ; vanBekkum, C; deBoer, E; vanGilst, WH

    The effect of additional abdominal aortic banding on parameters of heart failure was studied in male Wistar rats with myocardial infarction. Contractile function was studied 8-9 weeks after operation, with an isoprenaline dose response protocol, in a retrograde Langendorff perfusion. Also, plasma

  10. 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

  11. 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.

  12. Incorporation of radioiodinated IPPA and BMIPP fatty acid analogues into complex lipids from isolated rat hearts.

    Science.gov (United States)

    Kropp, J; Ambrose, K R; Knapp, F F; Nissen, H P; Biersack, H J

    1992-04-01

    Heart lipids were extracted by the Folch technique from Langendorff-perfused rat hearts after administration of 15-(p-[131I]iodophenyl)pentadecanoic acid and 15-(p-[125I]iodophenyl)-3-R,S-methylpentadecanoic acid. Techniques utilizing successive high performance liquid chromatographic (HPLC) analyses have been developed for the evaluation of the uptake of the tracers into neutral lipids and phospholipids of the rat hearts. Phospholipids were separated on a SiO2 column eluted with a gradient of acetonitrile/water (97.5/2.5) and acetonitrile/water (85/15) followed by separation of the neutral lipids on a C-18 reversed phase column with a gradient consisting of acetonitrile and 2-propanol/hexane (60/40) containing 1 N H2SO4 (5 microL/100 mL). Both tracers show the incorporation into the expected major lipid classes.

  13. Polyol pathway and modulation of ischemia-reperfusion injury in Type 2 diabetic BBZ rat hearts

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    Guberski Dennis

    2008-10-01

    Full Text Available Abstract We investigated the role of polyol pathway enzymes aldose reductase (AR and sorbitol dehydrogenase (SDH in mediating injury due to ischemia-reperfusion (IR in Type 2 diabetic BBZ rat hearts. Specifically, we investigated, (a changes in glucose flux via cardiac AR and SDH as a function of diabetes duration, (b ischemic injury and function after IR, (c the effect of inhibition of AR or SDH on ischemic injury and function. Hearts isolated from BBZ rats, after 12 weeks or 48 weeks diabetes duration, and their non-diabetic littermates, were subjected to IR protocol. Myocardial function, substrate flux via AR and SDH, and tissue lactate:pyruvate (L/P ratio (a measure of cytosolic NADH/NAD+, and lactate dehydrogenase (LDH release (a marker of IR injury were measured. Zopolrestat, and CP-470,711 were used to inhibit AR and SDH, respectively. Myocardial sorbitol and fructose content, and associated changes in L/P ratios were significantly higher in BBZ rats compared to non-diabetics, and increased with disease duration. Induction of IR resulted in increased ischemic injury, reduced ATP levels, increases in L/P ratio, and poor cardiac function in BBZ rat hearts, while inhibition of AR or SDH attenuated these changes and protected hearts from IR injury. These data indicate that AR and SDH are key modulators of myocardial IR injury in BBZ rat hearts and that inhibition of polyol pathway could in principle be used as a therapeutic adjunct for protection of ischemic myocardium in Type 2 diabetic patients.

  14. Left Ventricular Hypertrophy: Major Risk Factor in Patients with Hypertension: Update and Practical Clinical Applications

    Directory of Open Access Journals (Sweden)

    Richard E. Katholi

    2011-01-01

    Full Text Available Left ventricular hypertrophy is a maladaptive response to chronic pressure overload and an important risk factor for atrial fibrillation, diastolic heart failure, systolic heart failure, and sudden death in patients with hypertension. Since not all patients with hypertension develop left ventricular hypertrophy, there are clinical findings that should be kept in mind that may alert the physician to the presence of left ventricular hypertrophy so a more definitive evaluation can be performed using an echocardiogram or cardiovascular magnetic resonance. Controlling arterial pressure, sodium restriction, and weight loss independently facilitate the regression of left ventricular hypertrophy. Choice of antihypertensive agents may be important when treating a patient with hypertensive left ventricular hypertrophy. Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers followed by calcium channel antagonists most rapidly facilitate the regression of left ventricular hypertrophy. With the regression of left ventricular hypertrophy, diastolic function and coronary flow reserve usually improve, and cardiovascular risk decreases.

  15. The Negative Chronotropic Effect in Rat Heart Stimulated by Ultrasonic Pulses: Role of Sex and Age.

    Science.gov (United States)

    Coiado, Olivia C; O'Brien, William D

    2017-04-01

    The goal of this study is to investigate the role of sex and age of the negative chronotropic effect after exposure of 3.5-MHz pulsed ultrasound (US) to the rat heart. Forty F344 rats were exposed transthoracically to ultrasonic pulses at a duty factor of approximately 1.0% at 2.0-MPa peak rarefactional pressure amplitude. The transthoracic ultrasonic bursts were delivered consecutively in five 10-s intervals, that is, 10 s of 6-Hz pulse repetition frequency (PRF), 10 s of 5-Hz PRF, 10 s of 4-Hz PRF, 10 s of 5-Hz PRF, and 10 s of 6-Hz, for a 50-s total exposure duration. The rats were divided into 8 groups (n = 5 each): US young male, control young male, US young female, control young female, US old male, control old male, US old female, and control old female. Two-way ANOVA for repeated measures was used to compare heart rate, cardiac output, arterial pressure, and other hemodynamic values (baseline) before and after US stimulation. Sex versus age versus US interaction was detected for heart rate. Cardiac output showed an age effect, and ejection fraction showed age and US effects. The arterial pressure showed a sex effect. A negative chronotropic effect (∼30% decrease in heart rate) was observed for young female rats. An hypothesis is that the US effect is weight (menopause) dependent, because the young (premenopausal) female rats weighed approximately 40 to 60% less than other groups of rats. It is likely that the ovarian hormones are responsible for different US-induced cardiac bioeffects in different ages and sexes. © 2017 by the American Institute of Ultrasound in Medicine.

  16. Dexamethasone Treatment of Newborn Rats Decreases Cardiomyocyte Endowment in the Developing Heart through Epigenetic Modifications.

    Directory of Open Access Journals (Sweden)

    Maresha S Gay

    Full Text Available The potential adverse effect of synthetic glucocorticoid, dexamethasone therapy on the developing heart remains unknown. The present study investigated the effects of dexamethasone on cardiomyocyte proliferation and binucleation in the developing heart of newborn rats and evaluated DNA methylation as a potential mechanism. Dexamethasone was administered intraperitoneally in a three day tapered dose on postnatal day 1 (P1, 2 and 3 to rat pups in the absence or presence of a glucocorticoid receptor antagonist Ru486, given 30 minutes prior to dexamethasone. Cardiomyocytes from P4, P7 or P14 animals were analyzed for proliferation, binucleation and cell number. Dexamethasone treatment significantly increased the percentage of binucleated cardiomyocytes in the hearts of P4 pups, decreased myocyte proliferation in P4 and P7 pups, reduced cardiomyocyte number and increased the heart to body weight ratio in P14 pups. Ru486 abrogated the effects of dexamethasone. In addition, 5-aza-2'-deoxycytidine (5-AZA blocked the effects of dexamethasone on binucleation in P4 animals and proliferation at P7, leading to recovered cardiomyocyte number in P14 hearts. 5-AZA alone promoted cardiomyocyte proliferation at P7 and resulted in a higher number of cardiomyocytes in P14 hearts. Dexamethasone significantly decreased cyclin D2, but not p27 expression in P4 hearts. 5-AZA inhibited global DNA methylation and blocked dexamethasone-mediated down-regulation of cyclin D2 in the heart of P4 pups. The findings suggest that dexamethasone acting on glucocorticoid receptors inhibits proliferation and stimulates premature terminal differentiation of cardiomyocytes in the developing heart via increased DNA methylation in a gene specific manner.

  17. Dexamethasone Treatment of Newborn Rats Decreases Cardiomyocyte Endowment in the Developing Heart through Epigenetic Modifications

    Science.gov (United States)

    Gay, Maresha S.; Li, Yong; Xiong, Fuxia; Lin, Thant; Zhang, Lubo

    2015-01-01

    The potential adverse effect of synthetic glucocorticoid, dexamethasone therapy on the developing heart remains unknown. The present study investigated the effects of dexamethasone on cardiomyocyte proliferation and binucleation in the developing heart of newborn rats and evaluated DNA methylation as a potential mechanism. Dexamethasone was administered intraperitoneally in a three day tapered dose on postnatal day 1 (P1), 2 and 3 to rat pups in the absence or presence of a glucocorticoid receptor antagonist Ru486, given 30 minutes prior to dexamethasone. Cardiomyocytes from P4, P7 or P14 animals were analyzed for proliferation, binucleation and cell number. Dexamethasone treatment significantly increased the percentage of binucleated cardiomyocytes in the hearts of P4 pups, decreased myocyte proliferation in P4 and P7 pups, reduced cardiomyocyte number and increased the heart to body weight ratio in P14 pups. Ru486 abrogated the effects of dexamethasone. In addition, 5-aza-2'-deoxycytidine (5-AZA) blocked the effects of dexamethasone on binucleation in P4 animals and proliferation at P7, leading to recovered cardiomyocyte number in P14 hearts. 5-AZA alone promoted cardiomyocyte proliferation at P7 and resulted in a higher number of cardiomyocytes in P14 hearts. Dexamethasone significantly decreased cyclin D2, but not p27 expression in P4 hearts. 5-AZA inhibited global DNA methylation and blocked dexamethasone-mediated down-regulation of cyclin D2 in the heart of P4 pups. The findings suggest that dexamethasone acting on glucocorticoid receptors inhibits proliferation and stimulates premature terminal differentiation of cardiomyocytes in the developing heart via increased DNA methylation in a gene specific manner. PMID:25923220

  18. Cardiovascular differentiation of imatinib and bosutinib in the rat.

    Science.gov (United States)

    Heyen, Jonathan R; Hu, Wenyue; Jamieson, Joseph; Thibault, Stephane; Batugo, Minerva; Loi, Cho-Ming; Burns-Naas, Leigh Ann; McHarg, Aileen D; Jessen, Bart

    2013-11-01

    Imatinib and bosutinib were administered to rats for up to 6 months at clinically relevant exposures to investigate the effects on the cardiovascular system. Imatinib treatment resulted in increased volume, wall thickness and mass suggesting a hypertrophic heart in male and female rats at one and fivefold clinical exposures, respectively. Bosutinib treatment resulted in milder cardiac hypertrophy in female rats only at fivefold clinical exposures. Analysis of excised hearts and cultured myocytes demonstrated increased expression of hypertrophic genes with imatinib or analogs, but not bosutinib or c-Abl RNAi treatment. The current dataset suggests that cardiovascular liability of imatinib and bosutinib are differentiated preclinically and c-Abl independent.

  19. Pathological alterations in liver injury following congestive heart failure induced by volume overload in rats.

    Directory of Open Access Journals (Sweden)

    Mohammed Shaqura

    Full Text Available Heart failure has emerged as a disease with significant public health implications. Following progression of heart failure, heart and liver dysfunction are frequently combined in hospitalized patients leading to increased morbidity and mortality. Here, we investigated the underlying pathological alterations in liver injury following heart failure. Heart failure was induced using a modified infrarenal aortocaval fistula (ACF in male Wistar rats. Sham operated and ACF rats were compared for their morphometric and hemodynamic data, for histopathological and ultrastructural changes in the liver as well as differences in the expression of apoptotic factors. ACF-induced heart failure is associated with light microscopic signs of apparent congestion of blood vessels, increased apoptosis and breakdown of hepatocytes and inflammatory cell inifltration were observed. The glycogen content depletion associated with the increased hepatic fibrosis, lipid globule formation was observed in ACF rats. Moreover, cytoplasmic organelles are no longer distinguishable in many ACF hepatocytes with degenerated fragmented rough endoplasmic reticulum, shrunken mitochondria and heavy cytoplasm vacuolization. ACF is associated with the upregulation of the hepatic TUNEL-positive cells and proapoptotic factor Bax protein concomitant with the mitochondrial leakage of cytochrome C into the cell cytoplasm and the transfer of activated caspase 3 from the cytoplasm into the nucleus indicating intrinsic apoptotic events. Taken together, the results demonstrate that ACF-induced congestive heart failure causes liver injury which results in hepatocellular apoptotic cell death mediated by the intrinsic pathway of mitochondrial cytochrome C leakage and subsequent transfer of activated caspase 3 into to the nucleus to initiate overt DNA fragmentation and cell death.

  20. Left Ventricular Hypertrophy

    Science.gov (United States)

    ... need to restrict certain physical activities, such as weightlifting, which may temporarily raise your blood pressure. The ... Accessed April 6, 2015. Chatterjee S, et al. Meta-analysis of left ventricular hypertrophy and sustained arrhythmias. American ...

  1. Metabolic Gene Remodeling and Mitochondrial Dysfunction in Failing Right Ventricular Hypertrophy due to Pulmonary Arterial Hypertension

    Science.gov (United States)

    Gomez-Arroyo, Jose; Mizuno, Shiro; Szczepanek, Karol; Van Tassell, Benjamin; Natarajan, Ramesh; dos Remedios, Cristobal G.; Drake, Jennifer I.; Farkas, Laszlo; Kraskauskas, Donatas; Wijesinghe, Dayanjan S.; Chalfant, Charles E.; Bigbee, John; Abbate, Antonio; Lesnefsky, Edward J.; Bogaard, Harm J.; Voelkel, Norbert F.

    2013-01-01

    Background Right ventricular dysfunction (RVD) is the most frequent cause of death in patients with pulmonary arterial hypertension. Whereas abnormal energy substrate utilization has been implicated in the development of chronic left heart failure, data describing such metabolic remodeling in RVD remain incomplete. Thus, we sought to characterize metabolic gene expression changes and mitochondrial dysfunction in functional and dysfunctional RV hypertrophy. Methods and Results Two different rat models of RV hypertrophy were studied. The model of RVD (SU5416/hypoxia) exhibited a significantly decreased gene expression of PPAR-gamma coactivator-1 alpha (PGC-1α), PPAR-α and ERR-α. The expression of multiple PCG-1α target genes required for fatty acid oxidation (FAO) was similarly decreased. Decreased PGC-1α expression was also associated with a net loss of mitochondrial protein and oxidative capacity. Reduced mitochondrial number was associated with a downregulation of TFAM and other genes required for mitochondrial biogenesis. Electron microscopy demonstrated that in RVD tissue, mitochondria had abnormal shape and size. Lastly, respirometric analysis demonstrated that mitochondria isolated from RVD-tissue had a significantly reduced ADP-stimulated (state 3) rate for complex I. Conversely, functional RV hypertrophy in the pulmonary artery banding (PAB) model showed normal expression of PGC-1α, whereas the expression of FAO genes was either preserved or unregulated. Moreover, PAB-RV tissue exhibited preserved TFAM expression and mitochondrial respiration despite elevated RV pressure-overload. Conclusions Right ventricular dysfunction, but not functional RV hypertrophy in rats, demonstrates a gene expression profile compatible with a multilevel impairment of fatty acid metabolism and significant mitochondrial dysfunction, partially independent of chronic pressure-overload. PMID:23152488

  2. Heart dysfunction and fibrosis in rat treated with myocardial ...

    African Journals Online (AJOL)

    use

    2011-11-16

    Nov 16, 2011 ... damage and death associated with myocardial cells. (Thygesen et al., 2007). Even if other heart tissue ... good material for regenerative medicine and cell therapy research in MI and reperfusion. Thus, the aim of .... improve the condition of myocardial ischemia, stem cell therapy research, and regenerative ...

  3. Heart failure decreases passive tension generation of rat diaphragm fibers.

    NARCIS (Netherlands)

    Hees, H.W.H. van; Ottenheijm, C.A.C.; Granzier, H.L.; Dekhuijzen, P.N.R.; Heunks, L.M.A.

    2010-01-01

    BACKGROUND: Diaphragm dysfunction is well-known to limit quality of life and prognosis of patients with heart failure (HF), but its underlying mechanisms are not well understood. In an animal model for HF we recently showed that impaired diaphragm contractility arises at the single fiber level and

  4. Hypertrophy signaling pathways in experimental chronic aortic regurgitation

    DEFF Research Database (Denmark)

    Olsen, Niels Thue; Dimaano, Veronica L; Fritz-Hansen, Thomas

    2013-01-01

    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......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...... 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....

  5. Neonatal hyperthyroidism on rat heart: interrelation with nitric oxide and sex.

    Science.gov (United States)

    Rodríguez, L; Detomaso, F; Braga, P; Prendes, M; Perosi, F; Cernadas, G; Balaszczuk, A; Fellet, A

    2015-06-01

    To clarify the mechanism mediating the effect of hyperthyroidism on cardiac function during the second month of life in rats. Male and female Sprague-Dawley rats were assigned to a control or to a triiodothyronine (T3)-treated group. Treatment of each group was started on the third day after birth. Control rats (Eut) received 0.9 NaCl [0.1 ml/100 g body weight (BW)] every second day during 60 days and T3-treated rats (Hyper) received subcutaneous (SC) T3 injections every second day during 60 days. Hyperthyroidism decreased left ventricle volume only in male rats. Female euthyroid rats presented higher atrial nitric oxide synthase (NOS) activity than male rats and hormonal treatment decreased this enzyme's activity in both sexes. Euthyroid male and female rats had similar atrial NOS protein levels, but females had higher caveolin (cav) 3 protein levels. T3 treatment increased this protein only in males. Female rats had lower ventricular NOS activity than male rats; hyperthyroidism increased NOS activity in both sexes but this effect was associated with lower cav 3 protein levels. Hyperthyroidism did not change cav 1 protein levels in both male and female rats. The results of this study demonstrating clinically relevant sex-related differences in the pathophysiology of the hyperthyroid heart have raised new questions regarding the mechanisms responsible for the observed differences. This study suggests that sex-related intrinsic factors such as nitric oxide may modulate the response to hyperthyroidism that leads to cardiovascular dysfunction.

  6. [Expression of L-type calcium channel alpha1C subunit in adult rat heart].

    Science.gov (United States)

    Ou, Yan; Niu, Xiao-lin; Ren, Fu-xian; Zhang, Ying; Ling, Feng-dong

    2005-11-01

    To investigate the expression and distribution of L-type calcium channel alpha1C subunits in adult rat heart. HE staining was applied on the frozen sections of adult rat heart to identify the sinoatrial node (SAN), atrioventricular node (AVN), and posterior nodal extension (PNE). The protein expression of L-type calcium channel alpha1C in adult rat heart and its cellular localization were examined by Western blotting and immunohistochemistry, respectively. L-type calcium channel alpha1C subunit was immunolocalized on the membrane of the myocardial cells, and its expression increased gradually in the SAN, AVN, PNE, right atrium and right ventricle. The protein level of L-type calcium channel alpha1C in the AVN was similar to that in the PNE (P>0.05), and its level in the right atrium and ventricle were significantly higher than those in the SAN and AVN (Pchannel alpha1C subunit may play a role in the electrophysiological functions of the heart.

  7. Cardioprotective properties of citicoline against hyperthyroidism-induced reperfusion damage in rat hearts.

    Science.gov (United States)

    Hernández-Esquivel, Luz; Pavón, Natalia; Buelna-Chontal, Mabel; González-Pacheco, Héctor; Belmont, Javier; Chávez, Edmundo

    2015-06-01

    Hyperthyroidism represents an increased risk factor for cardiovascular morbidity, especially when the heart is subjected to an ischemia/reperfusion process. The aim of this study was to explore the possible protective effect of the nucleotide citicoline on the susceptibility of hyperthyroid rat hearts to undergo reperfusion-induced damage, which is associated with mitochondrial dysfunction. Hence, we analyzed the protective effect of citicoline on the electrical behavior and on the mitochondrial function in rat hearts. Hyperthyroidism was established after a daily i.p. injection of triiodothyronine (at 2 mg/kg of body weight) during 5 days. Thereafter, citicoline was administered i.p. (at 125 mg/kg of body weight) for 5 days. In hyperthyroid rat hearts, citicoline protected against reperfusion-induced ventricular arrhythmias. Moreover, citicoline maintained the accumulation of mitochondrial Ca(2+), allowing mitochondria to reach a high transmembrane electric gradient that protected against the release of cytochrome c. It also preserved the activity of the enzyme aconitase that inhibited the release of cytokines. The protection also included the inhibition of oxidative stress-induced mDNA disruption. We conclude that citicoline protects against the reperfusion damage that is found in the hyperthyroid myocardium. This effect might be due to its inhibitory action on the permeability transition in mitochondria.

  8. Histopathological Changes in the Kidney following Congestive Heart Failure by Volume Overload in Rats

    Directory of Open Access Journals (Sweden)

    Noureddin B. Aboryag

    2017-01-01

    Full Text Available Background. This study investigated histopathological changes and apoptotic factors that may be involved in the renal damage caused by congestive heart failure in a rat model of infrarenal aortocaval fistula (ACF. Methods. Heart failure was induced using a modified approach of ACF in male Wistar rats. Sham-operated controls and ACF rats were characterized by their morphometric and hemodynamic parameters and investigated for their histopathological, ultrastructural, and apoptotic factor changes in the kidney. Results. ACF-induced heart failure is associated with histopathological signs of congestion and glomerular and tubular atrophy, as well as nuclear and cellular degeneration in the kidney. In parallel, overexpression of proapoptotic Bax protein, release of cytochrome C from the outer mitochondrial membrane into cell cytoplasm, and nuclear transfer of activated caspase 3 indicate apoptotic events. This was confirmed by electron microscopic findings of apoptotic signs in the kidney such as swollen mitochondria and degenerated nuclei in renal tubular cells. Conclusions. This study provides morphological evidence of renal injury during heart failure which may be due to caspase-mediated apoptosis via overexpression of proapoptotic Bax protein, subsequent mitochondrial cytochrome C release, and final nuclear transfer of activated caspase 3, supporting the notion of a cardiorenal syndrome.

  9. [Sodium hydrosulfide improves cardiac functions and structures in rats with chronic heart failure].

    Science.gov (United States)

    Li, Xiao-hui; Zhang, Chao-ying; Zhang, Ting

    2011-11-22

    To explore the effects of sodium hydrosulfide (NaHS), a hydrogen sulphide (H(2)S) donor, on cardiac functions and structures in rats with chronic heart failure induced by volume overload and examine its influence on cardiac remodelling. A total of 47 SD rats (120 - 140 g) were randomly divided into 5 groups:shunt group (n = 11), sham group (n = 8), shunt + NaHS group (n = 10), sham + NaHS group (n = 8) and shunt + phentolamine group (n = 10). The rat model of chronic heart failure was induced by abdominal aorta-inferior vena cava puncture. At Week 8 post-operation, hemodynamic parameters, microstructures and ultrastructures of myocardial tissues were analyzed. Extracellular collagen content in myocardial tissues was analyzed after Sirius red staining. Right ventricular hydroxyproline concentration was determined and compared. At Week 8 post-operation, compared with the sham operation and shunt + NaHS groups, the shunt group showed significantly increased right ventricular systolic pressure (RVSP) and right ventricular end diastolic pressure (RVEDP) (mm Hg: 35.2 ± 3.9 vs 21.4 ± 3.7 and 28.1 ± 2.7, 32 ± 5 vs 21 ± 4 and 26 ± 4, all P cardiac functions and ameliorate cardiac structures in rats with chronic heart failure probably through dilating the blood vessels and affecting the extracellular collagen metabolism.

  10. The Protection of Salidroside of the Heart against Acute Exhaustive Injury and Molecular Mechanism in Rat

    Directory of Open Access Journals (Sweden)

    Yunru Wang

    2013-01-01

    Full Text Available Objective. To investigate the protection of salidroside of the heart against acute exhaustive injury and its mechanism of antioxidative stress and MAPKs signal transduction. Method. Adult male SD rats were divided into four groups randomly. Cardiomyocytes ultrastructure was observed by optical microscopy and transmission electron microscopy. The contents of CK, CK-MB, LDH, MDA, and SOD were determined by ELISA method, and the phosphorylation degrees of ERK and p38 MAPK were assayed by Western blotting. Cardiac function of isolated rat heart ischemia/reperfusion was detected by Langendorff technique. Results. Salidroside reduced the myocardium ultrastructure injury caused by exhaustive swimming, decreased the contents of CK, CK-MB, and LDH, improved the LVDP, ±LV dp/dtmax under the basic condition, reduced the content of MDA and the phosphorylation degree of p38 MAPK, and increased the content of SOD and the phosphorylation degree of ERK in acute exhaustive rats. Conclusion. Salidroside has the protection of the heart against acute exhaustive injury. The cardioprotection is mainly mediated by antioxidative stress and MAPKs signal transduction through reducing the content of MDA, increasing the content of SOD, and increasing p-ERK and decreasing p-p38 protein expressions in rat myocardium, which might be the mechanisms of the cardioprotective effect of salidroside.

  11. The Protection of Salidroside of the Heart against Acute Exhaustive Injury and Molecular Mechanism in Rat

    Science.gov (United States)

    Wang, Yunru; Xu, Peng; Wang, Yang; Liu, Haiyan; Zhou, Yuwen; Cao, Xuebin

    2013-01-01

    Objective. To investigate the protection of salidroside of the heart against acute exhaustive injury and its mechanism of antioxidative stress and MAPKs signal transduction. Method. Adult male SD rats were divided into four groups randomly. Cardiomyocytes ultrastructure was observed by optical microscopy and transmission electron microscopy. The contents of CK, CK-MB, LDH, MDA, and SOD were determined by ELISA method, and the phosphorylation degrees of ERK and p38 MAPK were assayed by Western blotting. Cardiac function of isolated rat heart ischemia/reperfusion was detected by Langendorff technique. Results. Salidroside reduced the myocardium ultrastructure injury caused by exhaustive swimming, decreased the contents of CK, CK-MB, and LDH, improved the LVDP, ±LV dp/dt max under the basic condition, reduced the content of MDA and the phosphorylation degree of p38 MAPK, and increased the content of SOD and the phosphorylation degree of ERK in acute exhaustive rats. Conclusion. Salidroside has the protection of the heart against acute exhaustive injury. The cardioprotection is mainly mediated by antioxidative stress and MAPKs signal transduction through reducing the content of MDA, increasing the content of SOD, and increasing p-ERK and decreasing p-p38 protein expressions in rat myocardium, which might be the mechanisms of the cardioprotective effect of salidroside. PMID:24454984

  12. [Testosterone therapy improves cardiac function of male rats with right heart failure].

    Science.gov (United States)

    Li, Zong-Bin; Wang, Jing; Wang, Ju-Xiang; Chen, Xun-Min; Jiang, Shi-Sen

    2009-11-01

    Clinical studies have shown decreased levels of sexual hormones, particularly testosterone deficiency, in men with chronic heart failure (CHF). The authors aimed to investigate the effect of testosterone on cardiac function and the possible mechanism of androgen protecting the heart in male rats. Forty-three male SD rats were randomly divided into 3 groups: right heart failure (RHF, n = 15), physiologic testosterone treatment (TT, n = 15) and control (n = 13). The RHF group was given intraperitoneal injection of monocrotaline at 60 mg/kg to make RHF models; the TT group was injected with testosterone at 5 mg/kg 3 days after monocrotaline administration; and the control group received equal volume of saline. The CD34+ cells in the peripheral blood of each rat were counted by flow cytometry. The levels of serum testosterone and tumor necrosis factor alpha (TNF-alpha) were measured by chemiluminescence immunoassay and enzyme linked immunosorbent assay, respectively. The hearts, lungs and livers of all the surviving rats were excised at 6 weeks for pathological and immunohistochemical examinations. The level of serum testosterone was gradually decreased, while that of TNF-alpha obviously increased in the RHF group. After testosterone treatment, the TT group showed a remarkable improvement of cardiac performance and a significant decrease in the level of serum TNF-alpha as compared with the RHF group. Statistically significant differences were observed neither in the CD34+ cell count in the peripheral blood nor in the CD34+ expression of the myocardial cells between the TT and RHF groups. Physiological supplementation of testosterone can improve the cardiac function of RHF male rats, probably through its inhibition of TNF-alpha rather than by autologous mobilization of bone marrow stem cells.

  13. Cardioprotection provided by Echinatin against ischemia/reperfusion in isolated rat hearts.

    Science.gov (United States)

    Tian, Xing-Han; Liu, Chao-Liang; Jiang, Hai-Li; Zhang, Yan; Han, Ji-Chun; Liu, Ju; Chen, Meng

    2016-05-31

    This study evaluated the protective effect of Echinatin against myocardial ischemia/reperfusion (I/R) injury in rats. The effect of Echinatin on cardiac function in rats subjected to I/R was demonstrated through improved Langendorff retrograde perfusion technology. Adult Sprague-Dawley rats were randomly divided into five groups, and myocardial infarct size was macroscopically estimated through 2,3,5-triphenyltetrazolium chloride staining. The coronary effluent was analyzed for the release of lactate dehydrogenase (LDH) and creatine kinase (CK) to assess the degree of cardiac injury. The concentrations of malondialdehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were determined along with superoxide dismutase (SOD) activity using ELISA. Finally, cardiomyocyte apoptosis analysis was conducted with POD, an in situ cell death detection kit. Echinatin (0.5 and 2.5 μg/mL) pretreatment enhanced the maximum up/down rate of the left ventricular pressure (±dp/dtmax), improved the heart rate, increased the left ventricular developed pressure (LVDP), enhanced the coronary flow, and reduced the CK and LDH levels in the coronary flow of the treated group compared with the I/R group. Echinatin limited the contents of CK and LDH, improved the LVDP, reduced the contents of MDA, IL-6, and TNF-α, and increased the SOD activity. The infarct size and cell apoptosis in the hearts of the rats in the Echinatin-treated group were smaller and lower, respectively, than those in the hearts of the rats in the I/R control group. Echinatin exerts a protective effect against I/R-induced myocardial injury on hearts. This effect may be attributed to the antioxidant and anti-inflammatory activities of this compound.

  14. Connective tissue growth factor overexpression in cardiomyocytes promotes cardiac hypertrophy and protection against pressure overload.

    Directory of Open Access Journals (Sweden)

    Anna N Panek

    Full Text Available Connective tissue growth factor (CTGF is a secreted protein that is strongly induced in human and experimental heart failure. CTGF is said to be profibrotic; however, the precise function of CTGF is unclear. We generated transgenic mice and rats with cardiomyocyte-specific CTGF overexpression (CTGF-TG. To investigate CTGF as a fibrosis inducer, we performed morphological and gene expression analyses of CTGF-TG mice and rat hearts under basal conditions and after stimulation with angiotensin II (Ang II or isoproterenol, respectively. Surprisingly, cardiac tissues of both models did not show increased fibrosis or enhanced gene expression of fibrotic markers. In contrast to controls, Ang II treated CTGF-TG mice displayed preserved cardiac function. However, CTGF-TG mice developed age-dependent cardiac dysfunction at the age of 7 months. CTGF related heart failure was associated with Akt and JNK activation, but not with the induction of natriuretic peptides. Furthermore, cardiomyocytes from CTGF-TG mice showed unaffected cellular contractility and an increased Ca(2+ reuptake from sarcoplasmatic reticulum. In an ischemia/reperfusion model CTGF-TG hearts did not differ from controls.Our data suggest that CTGF itself does not induce cardiac fibrosis. Moreover, it is involved in hypertrophy induction and cellular remodeling depending on the cardiac stress stimulus. Our new transgenic animals are valuable models for reconsideration of CTGF's profibrotic function in the heart.

  15. Neonatal Lipopolysaccharide Exposure Gender-Dependently Increases Heart Susceptibility to Ischemia/Reperfusion Injury in Male Rats.

    Science.gov (United States)

    Zhang, Peng; Lv, Juanxiu; Li, Yong; Zhang, Lubo; Xiao, Daliao

    2017-01-01

    Background: Adverse stress exposure during the early neonatal period has been shown to cause aberrant development, resulting in an increased risk of adult disease. We tested the hypothesis that neonatal exposure to lipopolysaccharide (LPS) does not alter heart function at rest condition but causes heart dysfunction under stress stimulation later in life. Methods: Saline control or LPS were administered to neonatal rats via intraperitoneal injection. Experiments were conducted in 6 week-old male and female rats. Isolated hearts were perfused in a Langendorff preparation. Results: Neonatal LPS exposure exhibited no effects on the body weight of the developing rats, but induced decreases in the left ventricle (LV) to the body weight ratio in male rats. Neonatal LPS exposure showed no effects on the baseline heart function determined by in vivo and ex vivo experiments, but caused decreases in the post-ischemic recovery of the LV function in male but not female rats. Neonatal LPS-mediated LV dysfunction was associated with an increase in myocardial infarct size and the LDH release in the male rats. Conclusion: The present study provides novel evidence that neonatal immune challenges could induce gender-dependent long-term effects on cardiac development and heart function, which reinforces the notion that adverse stress exposure during the early neonatal period can aggravate heart functions and the development of a heart ischemia-sensitive phenotype later in life.

  16. Compensatory renal hypertrophy following uninephrectomy is calcineurin-independent.

    Science.gov (United States)

    Williams, Clintoria R; Wynne, Brandi M; Walker, Makeeva; Hoover, Robert S; Gooch, Jennifer L

    2014-12-01

    Calcineurin is a calcium-dependent phosphatase that is involved in many cellular processes including hypertrophy. Inhibition or genetic loss of calcineurin blocks pathological cardiac hypertrophy and diabetic renal hypertrophy. However, calcineurin does not appear to be involved in physiological cardiac hypertrophy induced by exercise. The role of calcineurin in a compensatory, non-pathological model of renal hypertrophy has not been tested. Therefore, in this study, we examined activation of calcineurin and the effect of calcineurin inhibition or knockout on compensatory hypertrophy following uninephrectomy (UNX). UNX induces ~15% increase in the size of the remaining kidney; the data show no change in the generation of reactive oxygen species (ROS), Nox4 or transforming growth factor-β expression confirming the model as one of compensatory hypertrophy. Next, analyses of the remaining kidney reveal that total calcineurin activity is increased, and, to a lesser extent, transcriptional activity of the calcineurin substrate nuclear factor of activated T cell is up-regulated following UNX. However, inhibition of calcineurin with cyclosporine failed to prevent compensatory renal hypertrophy. Likewise, hypertrophy was comparable to WT in mice lacking either isoform of the catalytic subunit of calcineurin (CnAα-/- or CnAβ-/-). In conclusion, similar to its role in the heart, calcineurin is required for pathological but not compensatory renal hypertrophy. This separation of signalling pathways could therefore help further define key factors necessary for pathological hypertrophy including diabetic nephropathy. © 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  17. Discrepant uptake of the radiolabeled norepinephrine analogues hydroxyephedrine (HED) and metaiodobenzylguanidine (MIBG) in rat hearts

    Energy Technology Data Exchange (ETDEWEB)

    Rischpler, Christoph [Johns Hopkins University, Division of Nuclear Medicine, The Russell H. Morgan Department of Radiology, Baltimore, MD (United States); Klinikum rechts der Isar, Nuklearmedizinische Klinik und Poliklinik, Munich (Germany); Fukushima, Kenji; Isoda, Takuro; Javadi, Mehrbod S.; Dannals, Robert F.; Wahl, Richard [Johns Hopkins University, Division of Nuclear Medicine, The Russell H. Morgan Department of Radiology, Baltimore, MD (United States); Abraham, Roselle [Johns Hopkins University, Division of Cardiology, Department of Medicine, Baltimore, MD (United States); Bengel, Frank M. [Johns Hopkins University, Division of Nuclear Medicine, The Russell H. Morgan Department of Radiology, Baltimore, MD (United States); Hannover Medical School, Department of Nuclear Medicine, Hannover (Germany); Higuchi, Takahiro [Johns Hopkins University, Division of Nuclear Medicine, The Russell H. Morgan Department of Radiology, Baltimore, MD (United States); Wuerzburg University, CHFC/Department of Nuclear Medicine, Wuerzburg (Germany); Universitaetsklinikum Wuerzburg, Nuklearmedizinische Klinik und Poliklinik, Wuerzburg (Germany)

    2013-07-15

    {sup 11}C-Hydroxyephedrine (HED) and radioiodinated metaiodobenzylguanidine ({sup 123}I/{sup 131}I-MIBG) are catecholamine analogue tracers for sympathetic nerve positron emission tomography/single photon emission computed tomography (PET/SPECT) imaging. In contrast to humans, rat hearts demonstrate high nonneural catecholamine uptake-2 in addition to neural uptake-1, the contributions of which to tracer accumulation are not fully elucidated. Wistar rats were studied using the following pretreatments: uptake-1 blockade with desipramine 2 mg/kg IV, both uptake-1 and -2 blockade with phenoxybenzamine 50 mg/kg IV, or control with saline IV. HED or {sup 123}I-MIBG was injected 10 min after pretreatment, and rats were sacrificed 10 min later. Heart to blood tissue count ratio (H/B ratio) was obtained using a gamma counter. To determine regional tracer uptake, dual-tracer autoradiography was performed with HED and {sup 131}I-MIBG in Wistar rats with chronic infarction by transient coronary occlusion and reperfusion and in healthy control rats. Local tracer distributions were analyzed, and the infarcted rats' local tracer distributions were compared with histology. The H/B ratios in control hearts were 34.4 {+-} 1.7 and 25.5 {+-} 2.1 for HED and {sup 123}I-MIBG, respectively. Desipramine led to a significant decrease in HED (3.2 {+-} 0.5, p < 0.0001), while there was no change in {sup 123}I-MIBG (25.5 {+-} 6.4, p = n.s.). Phenoxybenzamine led to a significant decrease in both HED and {sup 123}I-MIBG (3.5 {+-} 0.02, 4.3 {+-} 0.7, p < 0.0001). Only HED showed a subepicardium-subendocardium gradient in healthy control hearts which is consistent with physiological innervation, while {sup 131}I-MIBG was evenly distributed throughout the myocardium. {sup 131}I-MIBG uptake defect closely matched the scar area determined by histology [3.8 {+-} 2.3 % ({sup 131}I-MIBG defect) vs 4.0 {+-} 2.4 % (scar)]. However, the scar area was clearly exceeded by the HED uptake defect (9

  18. Interaction between pre- and postconditioning in the in vivo rat heart.

    Science.gov (United States)

    Manintveld, Olivier C; Hekkert, Maaike te Lintel; van der Ploeg, Nathalie T; Verdouw, Pieter D; Duncker, Dirk J

    2009-11-01

    Patients with an impending myocardial infarction may be preconditioned by pre-infarct angina. Hence, it is important to establish whether ischemic postconditioning is still effective in preconditioned hearts. We therefore studied in anesthetized rats the effect of postconditioning after coronary artery occlusions (CAO) of 60 min in control hearts, hearts preconditioned by a single 15-min CAO (1IPC15) or a triple 3-min CAO (3IPC3). Furthermore, we studied the effect of postconditioning in hearts that had been pharmacologically preconditioned with intravenous adenosine and in hearts that had become tolerant to 1IPC15. Postconditioning limited infarct size in control hearts, but did not afford additional protection in preconditioned hearts, irrespective of the IPC stimulus. NO synthase inhibition abolished the cardioprotection by postconditioning, both IPC stimuli, and the combination of postconditioning and either IPC stimulus. Postconditioning also failed to afford cardioprotection in hearts protected by adenosine, and in hearts that had become tolerant to cardioprotection by 1IPC15. In accordance with previous observations, postconditioning paradoxically increased infarct size following a 30-min CAO. This detrimental effect was prevented by either IPC stimulus, in a NO synthase-dependent manner. In conclusion, postconditioning does not afford additional protection in preconditioned hearts, irrespective of the preconditioning stimulus and the presence of tolerance to preconditioning. Lack of additional protection may be related to the observation that postconditioning and preconditioning are both mediated via NO synthase. In contrast, the increase in infarct size by postconditioning following a 30-min CAO is abolished by either IPC stimulus. These findings indicate that the interaction between preconditioning and postconditioning is highly dependent on the duration of index ischemia, but independent of the preconditioning stimulus.

  19. Effects of ischemia and omeprazole preconditioning on functional recovery of isolated rat heart.

    Science.gov (United States)

    Jeremic, Nevena; Petkovic, Anica; Srejovic, Ivan; Zivkovic, Vladimir; Djuric, Dragan; Jakovljevic, Vladimir

    2015-01-01

    The aim of this study was to compare protective effects of ischemic and potential protective effects of pharmacological preconditioning with omeprazole on isolated rat heart subjected to ischemia/reperfusion. The hearts of male Wistar albino rats were excised and perfused on a Langendorff apparatus. In control group (CG) after stabilization period, hearts were subjected to global ischemia (perfusion was totally stopped) for 20 minutes and 30 minutes of reperfusion. Hearts of group II (IPC) were submitted to ischemic preconditioning lasting 5 minutes before 20 minutes of ischemia and 30 minutes of reperfusion. In third group (OPC) hearts first underwent preconditioning lasting 5 minutes with 100 μM omeprazole, and then submitted 20 minutes of ischemia and 30 minutes of reperfusion. Administration of omeprazole before ischemia induction had protective effect on myocardium function recovery especially regarding to values of systolic left ventricular pressure and dp/dt max. Also our findings are that values of coronary flow did not change between OPC and IPC groups in last point of reperfusion. Based on our results it seems that ischemic preconditioning could be used as first window of protection after ischemic injury especially because all investigated parameters showed continuous trend of recovery of myocardial function. On the other hand, preconditioning with omeprazole induced sudden trend of recovery with positive myocardium protection, although less effective than results obtained with ischemic preconditioning not withstand, we must consider that omeprazole may be used in many clinical circumstances where direct coronary clamping for ischemic preconditioning is not possible.

  20. Role of the bradykinin B2 receptor in a rat model of local heart irradiation.

    Science.gov (United States)

    Lieblong, Benjamin J; Sridharan, Vijayalakshmi; Srivastava, Anup K; Moros, Eduardo G; Sharma, Sunil K; Boerma, Marjan

    2015-08-01

    Radiation-induced heart disease (RIHD) is a delayed effect of radiotherapy for cancers of the chest, such as breast, esophageal, and lung. Kinins are small peptides with cardioprotective properties. We previously used a rat model that lacks the precursor kininogen to demonstrate that kinins are involved in RIHD. Here, we examined the role of the kinin B2 receptor (B2R) in early radiation-induced signaling in the heart. Male Brown Norway rats received the B2R-selective antagonist HOE-140 (icatibant) via osmotic minipump from 5 days before until 4 weeks after 21 Gy local heart irradiation. At 4 weeks, signaling events were measured in left ventricular homogenates and nuclear extracts using western blotting and real-time polymerase chain reaction. Numbers of CD68-positive (monocytes/macrophages), CD2-positive (T-lymphocytes), and mast cells were measured using immunohistochemistry. Radiation-induced c-Jun phosphorylation and nuclear translocation were enhanced by HOE-140. HOE-140 did not modify endothelial nitric oxide synthase (eNOS) phosphorylation or alter numbers of CD2-positive or mast cells, but enhanced CD68-positive cell counts in irradiated hearts. B2R signaling may regulate monocyte/macrophage infiltration and c-Jun signals in the irradiated heart. Although eNOS is a main target for kinins, the B2R may not regulate eNOS phosphorylation in response to radiation.

  1. Comparative proteomic analysis reveals heart toxicity induced by chronic arsenic exposure in rats.

    Science.gov (United States)

    Huang, Qingyu; Xi, Guochen; Alamdar, Ambreen; Zhang, Jie; Shen, Heqing

    2017-10-01

    Arsenic is a widespread metalloid in the environment, which poses a broad spectrum of adverse effects on human health. However, a global view of arsenic-induced heart toxicity is still lacking, and the underlying molecular mechanisms remain unclear. By performing a comparative quantitative proteomic analysis, the present study aims to investigate the alterations of proteome profile in rat heart after long-term exposure to arsenic. As a result, we found that the abundance of 81 proteins were significantly altered by arsenic treatment (35 up-regulated and 46 down-regulated). Among these, 33 proteins were specifically associated with cardiovascular system development and function, including heart development, heart morphology, cardiac contraction and dilation, and other cardiovascular functions. It is further proposed that the aberrant regulation of 14 proteins induced by arsenic would disturb cardiac contraction and relaxation, impair heart morphogenesis and development, and induce thrombosis in rats, which is mediated by the Akt/p38 MAPK signaling pathway. Overall, these findings will augment our knowledge of the involved mechanisms and develop useful biomarkers for cardiotoxicity induced by environmental arsenic exposure. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Hypertrophic cardiomyopathy and left ventricular hypertrophy in hypertensive heart disease with mildly reduced or preserved ejection fraction: insight from altered mechanics and native T1 mapping.

    Science.gov (United States)

    Wu, L-M; An, D-A L; Yao, Q-Y; Ou, Y-R Z; Lu, Q; Jiang, M; Xu, J-R

    2017-10-01

    To explore the relationship between extracellular volume (ECV), native T1, and systolic strain in hypertrophic cardiomyopathy (HCM) and hypertensive patients with left ventricular hypertrophy (HTN LVH) with mildly reduced or preserved ejection fraction. T1 mapping was performed in 45 patients with late gadolinium enhancement positive (LGE+) HCM (mean age, 53±6 years), 11 patients with LGE- (LGE-) HCM (mean age, 56±5 years), and 20 patients with HTN LVH (mean age, 55±6 years) on at 3 T magnetic resonance imaging (MRI) using the modified look-locker inversion-recovery (MOLLI) pulse sequence. Mean T1 value, ECV and circumferential strain parameters were determined for each patient. Overall, the HCM patients had higher native T1 values (1242.92±68.94) and ECV (0.31±0.05) in comparison to those of the HTN LVH patients (1197±46.80, 0.27±0.04; p<0.05). In the subgroup analysis, the HCM LGE+ patients had the highest native T1 values among the three groups. The HCM LGE+ patients had higher ECV than the LGE- patients. HCM LGE- patients had higher ECV than HTN LVH patients (p<0.05). Peak systolic circumferential strain and early diastolic strain rates were reduced in the HCM LGE+ patients in comparison to the HCM LGE- and HTN LVH patients (p<0.05). Reduced peak systolic and early diastolic circumferential strain rates were associated with increased levels of ECV and native T1 values among all the patients. HCM LGE+ patients had higher native T1 values, higher ECV, and an associated reduction in early diastolic strain rates and peak systolic circumferential strains when compared to the HCM LGE- and HTN LVH patients with mildly reduced or preserved ejection fraction. Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

  3. Cardiac Hypertrophy: An Introduction to Molecular and Cellular Basis

    Science.gov (United States)

    Samak, Mostafa; Fatullayev, Javid; Sabashnikov, Anton; Zeriouh, Mohamed; Schmack, Bastian; Farag, Mina; Popov, Aron-Frederik; Dohmen, Pascal M.; Choi, Yeong-Hoon; Wahlers, Thorsten; Weymann, Alexander

    2016-01-01

    Ventricular hypertrophy is an ominous escalation of hemodynamically stressful conditions such as hypertension and valve disease. The pathophysiology of hypertrophy is complex and multifactorial, as it touches on several cellular and molecular systems. Understanding the molecular background of cardiac hypertrophy is essential in order to protect the myocardium from pathological remodeling, or slow down the destined progression to heart failure. In this review we highlight the most important molecular aspects of cardiac hypertrophic growth in light of the currently available published research data. PMID:27450399

  4. A novel experimental model of erectile dysfunction in rats with heart failure using volume overload.

    Directory of Open Access Journals (Sweden)

    Fábio Henrique Silva

    Full Text Available Patients with heart failure (HF display erectile dysfunction (ED. However, the pathophysiology of ED during HF remains poorly investigated.This study aimed to characterize the aortocaval fistula (ACF rat model associated with HF as a novel experimental model of ED. We have undertaken molecular and functional studies to evaluate the alterations of the nitric oxide (NO pathway, autonomic nervous system and oxidative stress in the penis.Male rats were submitted to ACF for HF induction. Intracavernosal pressure in anesthetized rats was evaluated. Concentration-response curves to contractile (phenylephrine and relaxant agents (sodium nitroprusside; SNP, as well as to electrical field stimulation (EFS, were obtained in the cavernosal smooth muscle (CSM strips from sham and HF rats. Protein expression of endothelial NO synthase (eNOS and neuronal NO synthase (nNOS and phosphodiestarese-5 in CSM were evaluated, as well as NOX2 (gp91phox and superoxide dismutase (SOD mRNA expression. SOD activity and thiobarbituric acid reactive substances (TBARs were also performed in plasma.HF rats display erectile dysfunction represented by decreased ICP responses compared to sham rats. The neurogenic contractile responses elicited by EFS were greater in CSM from the HF group. Likewise, phenylephrine-induced contractions were greater in CSM from HF rats. Nitrergic response induced by EFS were decreased in the cavernosal tissue, along with lower eNOS, nNOS and phosphodiestarese-5 protein expressions. An increase of NOX2 and SOD mRNA expression in CSM and plasma TBARs of HF group were detected. Plasma SOD activity was decreased in HF rats.ED in HF rats is associated with decreased NO bioavailability in erectile tissue due to eNOS/nNOS dowregulation and NOX2 upregulation, as well as hypercontractility of the penis. This rat model of ACF could be a useful tool to evaluate the molecular alterations of ED associated with HF.

  5. Is rate-pressure product of any use in the isolated rat heart? Assessing cardiac 'effort' and oxygen consumption in the Langendorff-perfused heart.

    Science.gov (United States)

    Aksentijević, Dunja; Lewis, Hannah R; Shattock, Michael J

    2016-02-01

    What is the central question of this study? Rate-pressure product (RPP) is commonly used as an index of cardiac 'effort'. In canine and human hearts (which have a positive force-frequency relationship), RPP is linearly correlated with oxygen consumption and has therefore been widely adopted as a species-independent index of cardiac work. However, given that isolated rodent hearts demonstrate a negative force-frequency relationship, its use in this model requires validation. What is the main finding and its importance? Despite its widespread use, RPP is not correlated with oxygen consumption (or cardiac 'effort') in the Langendorff-perfused isolated rat heart. This lack of correlation was also evident when perfusions included a range of metabolic substrates, insulin or β-adrenoceptor stimulation. Langendorff perfusion of hearts isolated from rats and mice has been used extensively for physiological, pharmacological and biochemical studies. The ability to phenotype these hearts reliably is, therefore, essential. One of the commonly used indices of function is rate-pressure product (RPP); a rather ill-defined index of 'work' or, more correctly, 'effort'. Rate-pressure product, as originally described in dog or human hearts, was shown to be correlated with myocardial oxygen consumption (MV̇O2). Despite its widespread use, the application of this index to rat or mouse hearts (which, unlike the dog or human, have a negative force-frequency relationship) has not been characterized. The aim of this study was to examine the relationship between RPP and MV̇O2 in Langendorff-perfused rat hearts. Paced hearts (300-750 beats min(-1)) were perfused either with Krebs-Henseleit (KH) buffer (11 mm glucose) or with buffer supplemented with metabolic substrates and insulin. The arteriovenous oxygen consumption (MV̇O2) was recorded. Metabolic status was assessed using (31) P magnetic resonance spectroscopy and lactate efflux. Experiments were repeated in the presence of

  6. Is rate–pressure product of any use in the isolated rat heart? Assessing cardiac ‘effort’ and oxygen consumption in the Langendorff‐perfused heart

    Science.gov (United States)

    Aksentijević, Dunja; Lewis, Hannah R.

    2016-01-01

    New Findings What is the central question of this study? Rate–pressure product (RPP) is commonly used as an index of cardiac ‘effort’. In canine and human hearts (which have a positive force–frequency relationship), RPP is linearly correlated with oxygen consumption and has therefore been widely adopted as a species‐independent index of cardiac work. However, given that isolated rodent hearts demonstrate a negative force–frequency relationship, its use in this model requires validation. What is the main finding and its importance? Despite its widespread use, RPP is not correlated with oxygen consumption (or cardiac ‘effort’) in the Langendorff‐perfused isolated rat heart. This lack of correlation was also evident when perfusions included a range of metabolic substrates, insulin or β‐adrenoceptor stimulation. Langendorff perfusion of hearts isolated from rats and mice has been used extensively for physiological, pharmacological and biochemical studies. The ability to phenotype these hearts reliably is, therefore, essential. One of the commonly used indices of function is rate–pressure product (RPP); a rather ill‐defined index of ‘work’ or, more correctly, ‘effort’. Rate–pressure product, as originally described in dog or human hearts, was shown to be correlated with myocardial oxygen consumption (MV˙O2). Despite its widespread use, the application of this index to rat or mouse hearts (which, unlike the dog or human, have a negative force–frequency relationship) has not been characterized. The aim of this study was to examine the relationship between RPP and MV˙O2 in Langendorff‐perfused rat hearts. Paced hearts (300–750 beats min−1) were perfused either with Krebs–Henseleit (KH) buffer (11 mm glucose) or with buffer supplemented with metabolic substrates and insulin. The arteriovenous oxygen consumption (MV˙O2) was recorded. Metabolic status was assessed using 31P magnetic resonance spectroscopy and lactate efflux

  7. The Effects of Velvet Antler of Deer on Cardiac Functions of Rats with Heart Failure following Myocardial Infarction

    Directory of Open Access Journals (Sweden)

    Ming-Jing Shao

    2012-01-01

    Full Text Available Velvet antler of deer (VAD is a commonly-used kidney-Yang supplementing traditional Chinese medication. According to the heart-kidney-related theory, heart Yang originates in kidney Yang and heart failure due to heart Yang deficiency can be treated by tonifying kidney Yang. In this study, we investigated therapeutic effects of VAD on cardiac functions in rats with heart failure following myocardial infarction. Forty-eight male Wistar rats were subjected either to left coronary artery ligation (N=36 or to sham operation (N=12. One week after the surgery, rats with heart failure received daily treatment of double-distilled water, captopril or VAD by gavage for consecutively four weeks, while sham-operated animals were given double-distilled water. Ultrasonic echocardiography was adopted to examine cardiac structural and functional parameters and serum brain natriuretic peptide (BNP concentration was measured using radioimmunoassay. We found that VAD partially reversed changes in cardiac functional parameters and serum BNP levels in rats with heart failure. These results provide further evidence for the heart-kidney-related theory and suggest that VAD might be a potentially alternative and complementary medicine for the treatment of heart failure.

  8. Cytophotometric analysis of reaction rates of succinate and lactate dehydrogenase activity in rat liver, heart muscle and tracheal epithelium

    NARCIS (Netherlands)

    van Noorden, C. J.; Vogels, I. M.

    1989-01-01

    Reaction rates of succinate and lactate dehydrogenase activity in cryostat sections of rat liver, tracheal epithelium and heart muscle were monitored by continuous measurement of formazan formation by cytophotometry at room temperature. Incubation media contained polyvinyl alcohol as tissue

  9. [Effect of implantation of cardiosphere-derived cells combined with rat heart tissue-derived extracellular matrix on acute myocardial infarction in rats].

    Science.gov (United States)

    Jiang, Da-Qing; Gu, Tian-Xiang; Xu, Zhao-Fa; Liu, Shuang; Li, Xue-Yuan

    2016-10-20

    To investigate whether heart tissue-derived extracellular matrix (ECM) promotes the differentiation of cardiosphere-derived cells (CDCs) implanted in rat infracted myocardium to improve the cardiac structure and function. Rat CDCs were cultured by cardiac explant methods, and ECM was prepared by decelluariztion method. In a Wistar rat model of acute myocardial infarction established by ligating the left anterior descending branch, IMDM solution, ECM suspension, 10 6 CDCs in IMDM solution, or 10 6 CDCs in ECM suspension were injected into the infracted rat myocardium (6 rats in each group). The cardiac function of the rats was evaluated by cardiac ultrasonography, and the percentage of positive heart fibrosis area after infarction was determined with Masson staining. The differentiation of implanted CDCs in the infarcted myocardium was detected using immunofluorescence assay for the markers of cardiac muscle cells (α-SA), vascular endothelial cells (vWF) and smooth muscle cells (α-SMA). Three weeks after acute myocardial infarction, the rats with injection of CDCs in ECM showed the highest left ventricular ejection fraction (LVEF) and percentage of fraction shortening with the lowest percentage of positive heart fibrosis area; implantation of CDCs with ECM resulted in significantly higher rates of CDC differentiation into cardiac muscle cells, vascular endothelial cells and smooth muscle cell (P<0.05). Heart-tissue derived ECM significantly promotes the differentiation of CDCs implanted in the infracted myocardium into cardiac muscle cells, vascular endothelial cells and smooth muscle cells to improve the cardiac structure and cardiac functions in rats.

  10. Glucose Transporters in Cardiac Metabolism and Hypertrophy

    Science.gov (United States)

    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

  11. Cardiac effects of cupping: myocardial infarction, arrhythmias, heart rate and mean arterial blood pressure in the rat heart.

    Science.gov (United States)

    Shekarforoush, Shahnaz; Foadoddini, Mohsen

    2012-08-31

    This study was carried out to determine the effects of cupping on hemodynamic parameters, arrhythmias and infarct size (IS) after myocardial ischemic reperfusion injury in male rats. Rats were randomly subjected to dry or wet cupping. While dry cupping simply involved stimulation of the skin by suction, in wet cupping, scarification of the back skin was also carried out with a surgical blade and 0.5 ml blood was sucked out in each session. For ischemic reperfusion injury, rats were subjected to 30 min of left anterior descending coronary artery occlusion and 120 min of reperfusion. Our results show that cupping did not change the baseline heart rate or mean arterial blood pressure. Ischemic reperfusion injury caused an IS of 50 ± 5%, whereas dry cupping, single and repeated wet cupping significantly reduced IS to 28 ± 3%, 35 ± 3% and 22 ± 2% of area at risk, respectively. The rate of ischemic induced arrhythmias was significantly modified by wet cupping (P cupping might be cardioprotective in the ischemic reperfusion injury model.

  12. Higher prevalence of left ventricular hypertrophy in two Māori cohorts: findings from the Hauora Manawa/Community Heart Study.

    Science.gov (United States)

    Whalley, Gillian A; Pitama, Suzanne; Troughton, Richard W; Doughty, Rob N; Gamble, Greg D; Gillies, Tawhirimatea; Wells, J Elisabeth; Faatoese, Allamanda; Huria, Tania; Richards, Mark; Cameron, Vicky A

    2015-02-01

    Cardiovascular disease (CVD) is the leading cause of mortality in New Zealand with a disproportionate burden of disease in the Māori population. The Hauora Manawa Project investigated the prevalence of cardiovascular risk factors and CVD in randomly selected Māori and non-Māori participants. This paper reports the prevalence of structural changes in the heart. A total of 252 rural Māori, 243 urban Māori; and 256 urban non-Māori underwent echocardiography to assess cardiac structure and function. Multivariable logistic regression was used to determine variables associated with heart size. Left ventricular (LV) mass measurements were largest in the rural Māori cohort (183.5,sd 61.4), intermediate in the urban Māori cohort (169.7,sd 57.1) and smallest in the non-Māori cohort (152.6,sd 46.7; pMaori cohorts (highest in the rural cohort). There were three significant predictors of LVH: rural Māori (p=0.0001); age (p<0.0001); and gender (p=0.0048). Structural and functional heart abnormalities are more prevalent in Māori compared to non-Māori, and especially rural Māori. Early identification should lead to better management, ultimately improving life expectancy and quality of life. © 2014 Public Health Association of Australia.

  13. 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

  14. 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.

  15. Effect of angiotensin-(1-7 on reperfusion arrhythmias in isolated rat hearts

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    L.A.A. Neves

    1997-06-01

    Full Text Available There is increasing evidence that angiotensin-(1-7 (Ang-(1-7 is an endogenous biologically active component of the renin-angiotensin system (RAS. In the present study, we investigated the effects of Ang-(1-7 on reperfusion arrhythmias in isolated rat hearts. Isolated rat hearts were perfused with two different media, i.e., Krebs-Ringer (2.52 mM CaCl2 and low-Ca2+ Krebs-Ringer (1.12 mM CaCl2. In hearts perfused with Krebs-Ringer, Ang-(1-7 produced a concentration-dependent (27-210 nM reduction in coronary flow (25% reduction at highest concentration, while only slight and variable changes in contraction force and heart rate were observed. Under the same conditions, angiotensin II (Ang II; 27 and 70 nM produced a significant reduction in coronary flow (39% and 48%, respectively associated with a significant increase in force. A decrease in heart rate was also observed. In low-Ca2+ Krebs-Ringer solution, perfusion with Ang-(1-7 or Ang II at 27 nM concentration produced similar changes in coronary flow, contraction force and heart rate. In isolated hearts perfused with normal Krebs-Ringer, Ang-(1-7 produced a significant enhancement of reperfusion arrhythmias revealed by an increase in the incidence and duration of ventricular tachycardia and ventricular fibrillation (more than 30-min duration. The facilitation of reperfusion arrhythmias by Ang-(1-7 was associated with an increase in the magnitude of the decreased force usually observed during the post-ischemic period. The effects of Ang-(1-7 were abolished in isolated rat hearts perfused with low-Ca2+ Krebs-Ringer. The effect of Ang II (27 nM was similar but less pronounced than that of Ang-(1-7 at the same concentration. These results indicate that the heart is a site of action for Ang-(1-7 and suggest that this heptapeptide may be involved in the mediation of the cardiac effects of the RAS

  16. 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

  17. The effects of clobazam treatment in rats on the expression of genes and proteins encoding glucronosyltransferase 1A/2B (UGT1A/2B) and multidrug resistance‐associated protein-2 (MRP2), and development of thyroid follicular cell hypertrophy

    Energy Technology Data Exchange (ETDEWEB)

    Miyawaki, Izuru, E-mail: izuru-miyawaki@ds-pharma.co.jp; Tamura, Akitoshi; Matsumoto, Izumi; Inada, Hiroshi; Kunimatsu, Takeshi; Kimura, Juki; Funabashi, Hitoshi

    2012-12-15

    Clobazam (CLB) is known to increase hepatobiliary thyroxine (T4) clearance in Sprague–Dawley (SD) rats, which results in hypothyroidism followed by thyroid follicular cell hypertrophy. However, the mechanism of the acceleration of T4-clearance has not been fully investigated. In the present study, we tried to clarify the roles of hepatic UDP-glucronosyltransferase (UGT) isoenzymes (UGT1A and UGT2B) and efflux transporter (multidrug resistance–associated protein-2; MRP2) in the CLB-induced acceleration of T4-clearance using two mutant rat strains, UGT1A-deficient mutant (Gunn) and MRP2-deficient mutant (EHBR) rats, especially focusing on thyroid morphology, levels of circulating hormones (T4 and triiodothyronine (T3)) and thyroid-stimulating hormone (TSH), and mRNA or protein expressions of UGTs (Ugt1a1, Ugt1a6, and Ugt2b1/2) and MRP2 (Mrp). CLB induced thyroid morphological changes with increases in TSH in SD and Gunn rats, but not in EHBR rats. T4 was slightly decreased in SD and Gunn rats, and T3 was decreased in Gunn rats, whereas these hormones were maintained in EHBR rats. Hepatic Ugt1a1, Ugt1a6, Ugt2b1/2, and Mrp2 mRNAs were upregulated in SD rats. In Gunn rats, UGT1A mRNAs (Ugt1a1/6) and protein levels were quite low, but UGT2B mRNAs (Ugt2b1/2) and protein were prominently upregulated. In SD and Gunn rats, MRP2 mRNA and protein were upregulated to the same degree. These results suggest that MRP2 is an important contributor in development of the thyroid cellular hypertrophy in CLB-treated rats, and that UGT1A and UGT2B work in concert with MRP2 in the presence of MRP2 function to enable the effective elimination of thyroid hormones. -- Highlights: ► Role of UGT and MRP2 in thyroid pathology was investigated in clobazam-treated rats. ► Clobazam induced thyroid cellular hypertrophy in SD and Gunn rats, but not EHBR rats. ► Hepatic Mrp2 gene and protein were upregulated in SD and Gunn rats, but not EHBR rats. ► Neither serum thyroid hormones (T3/T4

  18. hHGF overexpression in myoblast sheets enhances their angiogenic potential in rat chronic heart failure.

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    Antti Siltanen

    Full Text Available After severe myocardial infarction (MI, heart failure results from ischemia, fibrosis, and remodeling. A promising therapy to enhance cardiac function and induce therapeutic angiogenesis via a paracrine mechanism in MI is myoblast sheet transplantation. We hypothesized that in a rat model of MI-induced chronic heart failure, this therapy could be further improved by overexpression of the antiapoptotic, antifibrotic, and proangiogenic hepatocyte growth factor (HGF in the myoblast sheets. We studied the ability of wild type (L6-WT and human HGF-expressing (L6-HGF L6 myoblast sheet-derived paracrine factors to stimulate cardiomyocyte, endothelial cell, or smooth muscle cell migration in culture. Further, we studied the autocrine effect of hHGF-expression on myoblast gene expression profiles by use of microarray analysis. We induced MI in Wistar rats by left anterior descending coronary artery (LAD ligation and allowed heart failure to develop for 4 weeks. Thereafter, we administered L6-WT (n = 15 or L6-HGF (n = 16 myoblast sheet therapy. Control rats (n = 13 underwent LAD ligation and rethoracotomy without therapy, and five rats underwent a sham operation in both surgeries. We evaluated cardiac function with echocardiography at 2 and 4 weeks after therapy, and analyzed cardiac angiogenesis and left ventricular architecture from histological sections at 4 weeks. Paracrine mediators from L6-HGF myoblast sheets effectively induced migration of cardiac endothelial and smooth muscle cells but not cardiomyocytes. Microarray data revealed that hHGF-expression modulated myoblast gene expression. In vivo, L6-HGF sheet therapy effectively stimulated angiogenesis in the infarcted and non-infarcted areas. Both L6-WT and L6-HGF therapies enhanced cardiac function and inhibited remodeling in a similar fashion. In conclusion, L6-HGF therapy effectively induced angiogenesis in the chronically failing heart. Cardiac function, however, was not further

  19. X-ray intravital microscopy for functional imaging in rat hearts using synchrotron radiation coronary microangiography

    Science.gov (United States)

    Umetani, K.; Fukushima, K.

    2013-03-01

    An X-ray intravital microscopy technique was developed to enable in vivo visualization of the coronary, cerebral, and pulmonary arteries in rats without exposure of organs and with spatial resolution in the micrometer range and temporal resolution in the millisecond range. We have refined the system continually in terms of the spatial resolution and exposure time. X-rays transmitted through an object are detected by an X-ray direct-conversion type detector, which incorporates an X-ray SATICON pickup tube. The spatial resolution has been improved to 6 μm, yielding sharp images of small arteries. The exposure time has been shortened to around 2 ms using a new rotating-disk X-ray shutter, enabling imaging of beating rat hearts. Quantitative evaluations of the X-ray intravital microscopy technique were extracted from measurements of the smallest-detectable vessel size and detection of the vessel function. The smallest-diameter vessel viewed for measurements is determined primarily by the concentration of iodinated contrast material. The iodine concentration depends on the injection technique. We used ex vivo rat hearts under Langendorff perfusion for accurate evaluation. After the contrast agent is injected into the origin of the aorta in an isolated perfused rat heart, the contrast agent is delivered directly into the coronary arteries with minimum dilution. The vascular internal diameter response of coronary arterial circulation is analyzed to evaluate the vessel function. Small blood vessels of more than about 50 μm diameters were visualized clearly at heart rates of around 300 beats/min. Vasodilation compared to the control was observed quantitatively using drug manipulation. Furthermore, the apparent increase in the number of small vessels with diameters of less than about 50 μm was observed after the vasoactive agents increased the diameters of invisible small blood vessels to visible sizes. This technique is expected to offer the potential for direct

  20. Enhanced Electrical Integration of Engineered Human Myocardium via Intramyocardial versus Epicardial Delivery in Infarcted Rat Hearts.

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    Kaytlyn A Gerbin

    Full Text Available Cardiac tissue engineering is a promising approach to provide large-scale tissues for transplantation to regenerate the heart after ischemic injury, however, integration with the host myocardium will be required to achieve electromechanical benefits. To test the ability of engineered heart tissues to electrically integrate with the host, 10 million human embryonic stem cell (hESC-derived cardiomyocytes were used to form either scaffold-free tissue patches implanted on the epicardium or micro-tissue particles (~1000 cells/particle delivered by intramyocardial injection into the left ventricular wall of the ischemia/reperfusion injured athymic rat heart. Results were compared to intramyocardial injection of 10 million dispersed hESC-cardiomyocytes. Graft size was not significantly different between treatment groups and correlated inversely with infarct size. After implantation on the epicardial surface, hESC-cardiac tissue patches were electromechanically active, but they beat slowly and were not electrically coupled to the host at 4 weeks based on ex vivo fluorescent imaging of their graft-autonomous GCaMP3 calcium reporter. Histologically, scar tissue physically separated the patch graft and host myocardium. In contrast, following intramyocardial injection of micro-tissue particles and suspended cardiomyocytes, 100% of the grafts detected by fluorescent GCaMP3 imaging were electrically coupled to the host heart at spontaneous rate and could follow host pacing up to a maximum of 300-390 beats per minute (5-6.5 Hz. Gap junctions between intramyocardial graft and host tissue were identified histologically. The extensive coupling and rapid response rate of the human myocardial grafts after intramyocardial delivery suggest electrophysiological adaptation of hESC-derived cardiomyocytes to the rat heart's pacemaking activity. These data support the use of the rat model for studying electromechanical integration of human cardiomyocytes, and they

  1. Heart rate variability and inflammatory response in rats with lipopolysaccharide-induced endotoxemia.

    Science.gov (United States)

    Zila, I; Mokra, D; Kopincova, J; Kolomaznik, M; Javorka, M; Calkovska, A

    2015-01-01

    The aim of the study was to evaluate short-term heart rate variability (HRV) as an index of cardiac autonomic control in rats with lipopolysaccharide (LPS)-induced endotoxemia. Animals were injected intraperitoneally with LPS (100 microg/kg b.w.) and control group with an equivalent volume of saline. ECG recordings were done before (base) and 60, 120, 180, 240 and 300 min after LPS or saline administration. HRV magnitude was quantified by time and frequency-domain analysis (mean RR interval, SDRR, RMSSD, spectral powers in low (LF) and high frequency (HF) bands. Heart tissue homogenates and plasma were analyzed to determine interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha) and oxidative stress level (TBARS). Administration of lipopolysaccharide was followed by continuous rise in colonic body temperature compared to saline-treated controls. Endotoxemia in rats was accompanied by significant decrease in HRV spectral activity in high-frequency range at maximal body temperature (logHFpower: 1.2+/-0.5 vs. 1.9+/-0.6 ms(2), P<0.01). Increased IL-6 was found in heart tissue homogenates of LPS rats (8.0+/-0.6 vs. 26.4+/-4.8 pg/ml, (P<0.05). In conclusions, reduced HRV in HF band may indicate a decreased parasympathetic activity in LPS-induced endotoxemia as basic characteristics of altered cardiac control during response to endotoxemia.

  2. The Effect of Methanolic Soy Extract on Heart Tissue Changes in Ovariectomized Rats

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    Mohammad Reza Nasirzadeh

    2012-04-01

    Full Text Available Background & Objectives: Following to estrogen depletion in postmenopausal womens, its cardioprotective effect decreases. Stroke usually occurs in women during the menopause years. Estrogen hormone therapy is still controversial. Epidemiological data suggest that phytoestrogens have a preventive effect on various estrogen-related diseases/symptoms such as menopausal symptoms, cardiovascular diseases. Some studies suggest that genistein as an important component of soy have cardioprotection effects but its role on inflammation and cardiomyocte injury remained to be elucidated. So, this study was goaled to investigate the cardioprotective effect of methanolic soy extract on heart tissue injures.   Method: In this study 40 female rats were randomly allocated into 4 groups: 1 Control (intact animals, 2 sham surgery (without ovarictomy, 3 ovariectomized (ovx, and 4 treatment (ovx and soy gavage group that received 60mg/kg per day soy extract in drinking water for 28days (4 weeks. At the end of experiments, the rat heart tissue was processed histologically and the sections were stained with hematoxylin and eosin to examine under light microscope. Statistical analysis was performed using the wilcoxon test.   Results: The results showed that ovariectomy significantly increased inflammation and cardiomyocte injury and soy extract significantly promoted heart tissue recovery (p<0.05.   Conclosions: This study indicated that oral administration of soy extract has a positive effect on attenuation of inflammation and myocyte injury in ovariectomized rat.

  3. Loss of KCNK3 is a hallmark of RV hypertrophy/dysfunction associated with pulmonary hypertension.

    Science.gov (United States)

    Lambert, Mélanie; Boet, Angèle; Rucker-Martin, Catherine; Mendes-Ferreira, Pedro; Capuano, Véronique; Hatem, Stéphane; Adão, Rui; Brás-Silva, Carmen; Hautefort, Aurélie; Michel, Jean-Baptiste; Dorfmuller, Peter; Fadel, Elie; Kotsimbos, Tom; Price, Laura; Jourdon, Philippe; Montani, David; Humbert, Marc; Perros, Frédéric; Antigny, Fabrice

    2018-01-19

    Mutations in the KCNK3 gene, which encodes for an outward-rectifier K+ channel, have been identified in patients suffering from pulmonary arterial hypertension (PAH), and constitute the first described channelopathy in PAH. In human PAH and experimental pulmonary hypertension (PH), we demonstrated that KCNK3 expression and function are severely reduced in pulmonary vascular cells, promoting PH-like phenotype at the morphologic and hemodynamic levels. Since KCNK3 channel is also expressed in both the human and rodent heart, we aimed to elucidate the pathophysiological role of KCNK3 channel in right ventricular (RV) hypertrophy (RVH) related to PH. Using whole-cell Patch-clamp technique, we demonstrated that KCNK3 is predominantly expressed in adult rat RV cardiomyocytes compared to the left ventricle cardiomyocytes and participates in the repolarizing phase of the RV action potential. We revealed a reduction in KCNK3 function prior to development of RVH and the rise of pulmonary vascular resistance. KCNK3 function is severely reduced in RV cardiomyocytes during the development of RVH in several rat models of pulmonary hypertension (exposure to monocrotaline, chronic hypoxia and Sugen/hypoxia) and chronic RV pressure overload (pulmonary artery banding). In experimental PH, we revealed a reduction in KCNK3 function before any rise in pulmonary vascular resistance and the development of RVH. KCNK3 mRNA level is also reduced in human RV tissues from PAH patients compared to non PAH patients. The reduction of KCNK3 current also precedes the development of RVH. In line with these findings, chronic inhibition of KCNK3 in rats with the specific inhibitor (A293) induces RV hypertrophy which is associated with the re-expression of fetal genes, RV fibrosis, RV inflammation and subsequent loss of RV performance as assessed by echocardiography. Our data indicate that loss of KCNK3 function and expression is a hallmark of the RV hypertrophy/dysfunction associated with pulmonary

  4. Central inhibitory effect of α-methyldopa on blood pressure, heart rate and body temperature of renal hypertensive rats

    NARCIS (Netherlands)

    Nijkamp, F.P.; Ezer, Joseph; Jong, Wybren de

    The central inhibitory effect of α-methyldopa on blood pressure, heart rate and body temperature was studied in conscious renal hypertensive rats. Systemic administration of α-methyldopa decreased mean arterial blood pressure and body temperature and caused a short lasting increase in heart rate

  5. Bi-ventricular finite element model of right ventricle overload in the healthy rat heart.

    Science.gov (United States)

    Masithulela, Fulufhelo

    2016-11-25

    The recognition of RV overpressure is critical to human life, as this may signify morbidity and mortality. Right ventricle (RV) dysfunction is understood to have an impact on the performance of the left ventricle (LV), but the mechanisms remain poorly understood. It is understood that ventricular compliance has the ability to affect cardiac performance. In this study, a bi-ventricular model of the rat heart was used in preference to other, single-ventricle models. Finite element analysis (FEA) of the bi-ventricular model provides important information on the function of the healthy heart. The passive myocardium was modelled as a nearly incompressible, hyperelastic, transversely isotropic material using finite element (FE) methods. Bi-ventricular geometries of healthy rat hearts reconstructed from magnetic resonance images were imported in Abaqus©. In simulating the normal passive filling of the rat heart, pressures of 4.8 kPa and 0.0098 kPa were applied to the inner walls of the LV and RV respectively. In addition, to simulate the overpressure of the RV, pressures of 2.4 kPa and 4.8 kPa were applied to the endocardial walls of the LV and RV respectively. As boundary conditions, the circumferential and longitudinal displacements at the base were set to zero. The radial displacements at the base were left free. The results show that the average circumferential stress at the mid-wall in the overloaded model increased from 2.8 kPa to 18.2 kPa. The average longitudinal stress increased from 1.5 kPa to 9.7 kPa. Additionally, in the radial direction, the average stress increased from 0.1 kPa to 0.6 kPa in the mid-wall. The average circumferential strain was found to be 0.138 and 0.100 on the endocardium of the over pressured and healthy model respectively. The average circumferential stress at the epicardium, mid-wall and endocardium in the case of a normal heart is 10 times lower than in the overloaded heart model. The finite analysis method is able to provide

  6. Comparison of in vivo cardiac function with ex vivo cardiac performance of the rat heart after thoracic irradiation

    NARCIS (Netherlands)

    Franken, N. A.; Camps, J. A.; van Ravels, F. J.; van der Laarse, A.; Pauwels, E. K.; Wondergem, J.

    1997-01-01

    The aim of the study was to compare in vivo cardiac function with ex vivo cardiac performance after local heart irradiation in the same rat. Left ventricular ejection fraction (LVEF) was measured in vivo by radionuclide ventriculography in Sprague-Dawley rats up to 16 months after a single dose of

  7. Chronic exposure to zinc oxide nanoparticles increases ischemic-reperfusion injuries in isolated rat hearts

    Science.gov (United States)

    Milivojević, Tamara; Drobne, Damjana; Romih, Tea; Mali, Lilijana Bizjak; Marin, Irena; Lunder, Mojca; Drevenšek, Gorazd

    2016-10-01

    The use of zinc oxide nanoparticles (ZnO NPs) in numerous products is increasing, although possible negative implications of their long-term consumption are not known yet. Our aim was to evaluate the chronic, 6-week oral exposure to two different concentrations of ZnO NPs on isolated rat hearts exposed to ischemic-reperfusion injury and on small intestine morphology. Wistar rats of both sexes ( n = 18) were randomly divided into three groups: (1) 4 mg/kg ZnO NPs, (2) 40 mg/kg ZnO NPs, and (3) control. After 6 weeks of treatment, the hearts were isolated, the left ventricular pressure (LVP), the coronary flow (CF), the duration of arrhythmias and the lactate dehydrogenase release rate (LDH) were measured. A histological investigation of the small intestine was performed. Chronic exposure to ZnO NPs acted cardiotoxic dose-dependently. ZnO NPs in dosage 40 mg/kg maximally decreased LVP (3.3-fold) and CF (2.5-fold) and increased the duration of ventricular tachycardia (all P oral exposure to ZnO NPs dose-dependently increased heart injuries and caused irritation of the intestinal mucosa. A prolonged exposure to ZnO NPs might cause functional damage to the heart even with exposures to the recommended daily doses, which should be tested in future studies.

  8. The effects of calcium dobesilate on the mechanical function of rat hearts.

    Science.gov (United States)

    Cihan Ozbek, I; Arslan, C; Cantürk, E; Süzer, O

    2009-06-01

    Calcium dobesilate is an angio-protective agent that has positive effects on hemorheological parameters. It decreases blood and plasma viscosity, thrombocyte aggregation, and microvascular hyperpermeability. It is an antioxidant that increases endothelial-derived vasodilator substance secretion. In this experimental study, the effects of calcium dobesilate on myocardial ischemia reperfusion injury were investigated. Using the Langendorff setup, 24 adult Wistar albino rat hearts were perfused. MeanP (mean pressure perfusing the coronary arteries), PSP (maximum left ventricle pressure), +dp/dt(max) (change in contraction power over time), -dp/dt(max) (change in relaxing power over time), PP (peak systolic pressure-minimum balloon pressure) and bpm (number of heart beats per minute) were evaluated. The control group (N.=6) was perfused with Tyrode solution alone. The other three groups (N.=6 for each group) were perfused with the Tyrode solution and calcium dobesilate either before ischemia, during the ischemia reperfusion period, or during the reperfusion-only period. The meanP values were significantly higher in groups perfused by calcium dobesilate. For other parameters, calcium dobesilate did not demonstrate a positive effect. This study showed that calcium dobesilate may have cardio-protective effects in isolated, perfused rat hearts. In hearts perfused by calcium dobesilate, the increase in mean P may be explained by the increase in endothelium-derived vasodilator substances. Further studies are needed to better characterize the myocardial protective effects of calcium dobesilate.

  9. Myotoxic effects of clenbuterol in the rat heart and soleus muscle.

    Science.gov (United States)

    Burniston, Jatin G; Ng, Yeelan; Clark, William A; Colyer, John; Tan, Lip-Bun; Goldspink, David F

    2002-11-01

    Myocyte-specific necrosis in the heart and soleus muscle of adult male Wistar rats was investigated in response to a single subcutaneous injection of the anabolic beta(2)-adrenergic receptor agonist clenbuterol. Necrosis was immunohistochemically detected by administration of a myosin antibody 1 h before the clenbuterol challenge and quantified by using image analysis. Clenbuterol-induced myocyte necrosis occurred against a background of zero damage in control muscles. In the heart, the clenbuterol-induced necrosis was not uniform, being more abundant in the left subendocardium and peaking 2.4 mm from the apex. After position (2.4 mm from the apex), dose (5 mg clenbuterol/kg), and sampling time (12 h) were optimized, maximum cardiomyocyte necrosis was found to be 1.0 +/- 0.2%. In response to the same parameters (i.e., 5 mg of clenbuterol and sampled at 12 h), skeletal myocyte necrosis was 4.4 +/- 0.8% in the soleus. These data show significant myocyte-specific necrosis in the heart and skeletal muscle of the rat. Such irreversible damage in the heart suggests that clenbuterol may be damaging to long-term health.

  10. Voluntary exercise delays heart failure onset in rats with pulmonary artery hypertension.

    Science.gov (United States)

    Natali, Antonio J; Fowler, Ewan D; Calaghan, Sarah C; White, Ed

    2015-08-01

    Increased physical activity is recommended for the general population and for patients with many diseases because of its health benefits but can be contraindicated if it is thought to be a risk for serious cardiovascular events. One such condition is pulmonary artery hypertension (PAH). PAH and right ventricular failure was induced in rats by a single injection of monocrotaline (MCT). MCT rats with voluntary access to a running wheel ran on average 2 km/day. The time for half the animals to develop heart failure signs (median survival time) was 28 days (exercise failure group), significantly longer than sedentary animals (sedentary failure group, 23 days). The contractility of single failing myocytes in response to increasing demand (stimulation frequency) was significantly impaired compared with that in both sedentary control and exercising control myocytes. However, myocytes from exercising MCT rats, tested at 23 days (exercise + MCT group), showed responses intermediate to the control (sedentary control and exercising control) and failing (sedentary failure and exercise failure) groups. We conclude that voluntary exercise is beneficial to rats with heart failure induced by PAH, and this is evidence to support the consideration of appropriate exercise regimes for potentially vulnerable groups. Copyright © 2015 the American Physiological Society.

  11. Selective remodeling of cardiolipin fatty acids in the aged rat heart

    Directory of Open Access Journals (Sweden)

    Rapoport Stanley I

    2006-01-01

    Full Text Available Abstract Background The heart is rich in cardiolipin, a phospholipid acylated in four sites, predominately with linoleic acid. Whether or not aging alters the composition of cardiolipin acyl chains is controversial. We therefore measured the fatty acid concentration of cardiolipin in hearts of 4, 12 and 24 month old rats that consumed one diet, adequate in fatty acids for the duration of their life. Results The concentration (nmol/g of linoleic acid was decreased in 24 month old rats (3965 ± 617, mean ± SD vs 4 month old rats (5525 ± 656, while the concentrations of arachidonic and docosahexaenoic acid were increased in 24 month old rats (79 ± 9 vs 178 ± 27 and 104 ± 16 vs 307 ± 68 for arachidonic and docosahexaenoic acids, 4 months vs 24 months, respectively. Similar changes were not observed in ethanolamine glycerophospholipids or plasma unesterified fatty acids, suggesting specificity of these effects to cardiolipin. Conclusion These results demonstrate that cardiolipin remodeling occurs with aging, specifically an increase in highly unsaturated fatty acids.

  12. Chronic heart failure modifies respiratory mechanics in rats: a randomized controlled trial.

    Science.gov (United States)

    Pacheco, Deise M; Silveira, Viviane D; Thomaz, Alex; Nunes, Ramiro B; Elsner, Viviane R; Dal Lago, Pedro

    2016-01-01

    To analyze respiratory mechanics and hemodynamic alterations in an experimental model of chronic heart failure (CHF) following myocardial infarction. Twenty-seven male adult Wistar rats were randomized to CHF group (n=12) or Sham group (n=15). Ten weeks after coronary ligation or sham surgery, the animals were anesthetized and submitted to respiratory mechanics and hemodynamic measurements. Pulmonary edema as well as cardiac remodeling were measured. The CHF rats showed pulmonary edema 26% higher than the Sham group. The respiratory system compliance (Crs) and the total lung capacity (TLC) were lower (40% and 27%, respectively) in the CHF rats when compared to the Sham group (Prespiratory mechanics, which may be associated with alterations in cardiopulmonary interactions.

  13. Protection of Ischemic and Reperfused Rat Heart by Aqueous Extract of Urtica Dioica

    Directory of Open Access Journals (Sweden)

    D Shackebaei

    2010-09-01

    Full Text Available Background: Urtica dioica (U.D has widely been used in traditional medicine for its hypotensive and vasodilatory effects. The objective of this study was to clarify the effects of aqueous extract of Urtica dioica on isolated ischemia- reperfused heart.Methods: The heart of male wistar rats were isolated and perfused according to langendorff method. In the control group (n = 13 the hearts were subjected to three steps of stabilization (30 min, normothermic global ischemia (40 min and reperfusion (45 min. In addition, before and after ischemia, the aqueous extract of U.D (200 mg/ml was added to perfusion solution in the test group (n=14. Different cardiac variables including left ventricular pressure, heart rate and coronary flow were measured and rate pressure product was calculated.Results: Results showed that left ventricular pressure (59.11±4.7 and rate pressure product (13680±1136 in 45th minute of reperfusion in the test group were significantly (P=0.0187 and 0.0321 respectively greater than the control group (39.1±6.0, 9480±1480 respectively. These findings indicated decreased cardiac damage following ischemia in the test group, compared with that of control group.Conclusion: Results of the present study showed that the aqueous extract of U.D, increased the tolerance of isolated rat hearts against ischemic damage. This effect can be explained by potent antioxidant activity of the U.D extract, suggesting its clinical use in ischemic heart disease.

  14. Ubiquinol-cytochrome-c reductase 7.2 kDa protein of mitochondrial complex III is steroid-responsive and increases in cardiac hypertrophy and hypertension.

    Science.gov (United States)

    Huynh, Hung; Servant, Nicolas; Chalifour, Lorraine E

    2007-10-01

    Women and men do not respond identically to cardiac insults; premenopausal women are somewhat protected from cardiovascular disease. Our objective was to isolate and characterize hormone-responsive genes in the heart. Differential display identified an estrogen-inducible fragment that was found to encode the ubiquinol-cytochrome-c reductase (UCCR) 7.2 kDa protein of the mitochondrial respiratory complex III. We found UCCR7.2 mRNA to be highly expressed in the heart, and this expression increased in hearts of 4-, 10-, and 28-week-old spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto rats. Oral hydralazine treatment to reduce hypertension reduced SHR UCCR7.2 expression. Cardiac UCCR7.2 mRNA expression was also increased significantly after a 5/6 nephrectomy compared with mock surgery. Cardiac expression after ovariectomy was 50% that of intact rats. Supplementation of ovariectomized rats with estrogen had no effect, whereas progesterone increased cardiac expression, although not to intact levels. No change in cardiac UCCR7.2 expression was found when intact rats were treated with either tamoxifen or ICI 182780. Thus, UCCR7.2 expression is reduced in the absence of ovarian hormones, but is not directly regulated by estrogen in the heart. We conclude that UCCR7.2 is a steroid hormone-responsive gene in the heart, with expression increased in cardiac hypertrophy and in response to hypertension.

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

    DEFF Research Database (Denmark)

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

    2004-01-01

    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...... genes whose altered expression had previously been reported. We identified a single common gene program underlying hypertrophic remodelling, regardless of how the hypertrophy was induced. These genes constitute the molecular basis for the existence of one main form of cardiac hypertrophy and may...

  16. Expression of manganese superoxide dismutase in rat blood, heart and brain during induced systemic hypoxia

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    Septelia I. Wanandi

    2011-02-01

    Full Text Available Background: Hypoxia results in an increased generation of ROS. Until now, little is known about the role of MnSOD - a major endogenous antioxidant enzyme - on the cell adaptation response against hypoxia. The aim of this study was to  determine the MnSOD mRNA expression and levels of specific activity in blood, heart and brain of rats during induced systemic hypoxia.Methods: Twenty-five male Sprague Dawley rats were subjected to systemic hypoxia in an hypoxic chamber (at 8-10% O2 for 0, 1, 7, 14 and 21 days, respectively. The mRNA relative expression of MnSOD was analyzed using Real Time RT-PCR. MnSOD specific activity was determined using xanthine oxidase inhibition assay.Results: The MnSOD mRNA relative expression in rat blood and heart was decreased during early induced systemic hypoxia (day 1 and increased as hypoxia continued, whereas the mRNA expression in brain was increased since day 1 and reached its maximum level at day 7. The result of MnSOD specific activity during early systemic hypoxia was similar to the mRNA expression. Under very late hypoxic condition (day 21, MnSOD specific activity in blood, heart and brain was significantly decreased. We demonstrate a positive correlation between MnSOD mRNA expression and specific activity in these 3 tissues during day 0-14 of induced systemic hypoxia. Furthermore, mRNA expression and specific activity levels in heart strongly correlate with those in blood.Conclusion: The MnSOD expression at early and late phases of induced systemic hypoxia is distinctly regulated. The MnSOD expression in brain differs from that in blood and heart revealing that brain tissue can  possibly survive better from induced systemic hypoxia than heart and blood. The determination of MnSOD expression in blood can be used to describe its expression in heart under systemic hypoxic condition. (Med J Indones 2011; 20:27-33Keywords: MnSOD, mRNA expression, ROS, specific activity, systemic hypoxia

  17. Asymmetric left ventricular hypertrophy associated with morbid obesity mimicking familial hypertrophic cardiomyopathy.

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    Wong, Raymond Ching-Chiew; Tan, Kong Bing

    2014-12-01

    Asymmetric septal hypertrophy with systolic anterior motion of the mitral valve is frequently a phenotypic, but not pathognomonic, expression of genetic hypertrophic cardiomyopathy (HCM) with or without obstruction. It can, however, be associated nonspecifically with other forms of increased left ventricular (LV) afterload. We herein report the case of a young man with obesity cardiomyopathy and heart failure who presented with asymmetric septal hypertrophy and marked LV hypertrophy, and endomyocardial biopsy ruled out genetic HCM.

  18. T-tubule remodelling disturbs localized β2-adrenergic signalling in rat ventricular myocytes during the progression of heart failure.

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    Schobesberger, Sophie; Wright, Peter; Tokar, Sergiy; Bhargava, Anamika; Mansfield, Catherine; Glukhov, Alexey V; Poulet, Claire; Buzuk, Andrey; Monszpart, Aron; Sikkel, Markus; Harding, Sian E; Nikolaev, Viacheslav O; Lyon, Alexander R; Gorelik, Julia

    2017-06-01

    Cardiomyocyte β2-adrenergic receptor (β2AR) cyclic adenosine monophosphate (cAMP) signalling is regulated by the receptors' subcellular location within transverse tubules (T-tubules), via interaction with structural and regulatory proteins, which form a signalosome. In chronic heart failure (HF), β2ARs redistribute from T-tubules to the cell surface, which disrupts functional signalosomes and leads to diffuse cAMP signalling. However, the functional consequences of structural changes upon β2AR-cAMP signalling during progression from hypertrophy to advanced HF are unknown. Rat left ventricular myocytes were isolated at 4-, 8-, and 16-week post-myocardial infarction (MI), β2ARs were stimulated either via whole-cell perfusion or locally through the nanopipette of the scanning ion conductance microscope. cAMP release was measured via a Förster Resonance Energy Transfer-based sensor Epac2-camps. Confocal imaging of di-8-ANNEPS-stained cells and immunoblotting were used to determine structural alterations. At 4-week post-MI, T-tubule regularity, density and junctophilin-2 (JPH2) expression were significantly decreased. The amplitude of local β2AR-mediated cAMP in T-tubules was reduced and cAMP diffused throughout the cytosol instead of being locally confined. This was accompanied by partial caveolin-3 (Cav-3) dissociation from the membrane. At 8-week post-MI, the β2AR-mediated cAMP response was observed at the T-tubules and the sarcolemma (crest). Finally, at 16-week post-MI, the whole cell β2AR-mediated cAMP signal was depressed due to adenylate cyclase dysfunction, while overall Cav-3 levels were significantly increased and a substantial portion of Cav-3 dissociated into the cytosol. Overexpression of JPH2 in failing cells in vitro or AAV9.SERCA2a gene therapy in vivo did not improve β2AR-mediated signal compartmentation or reduce cAMP diffusion. Although changes in T-tubule structure and β2AR-mediated cAMP signalling are significant even at 4-week post

  19. Nitroxyl (HNO stimulates soluble guanylyl cyclase to suppress cardiomyocyte hypertrophy and superoxide generation.

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    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.

  20. Chronic exposure to zinc oxide nanoparticles increases ischemic-reperfusion injuries in isolated rat hearts

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    Milivojević, Tamara; Drobne, Damjana; Romih, Tea; Mali, Lilijana Bizjak [University of Ljubljana, Department of Biology, Biotechnical Faculty (Slovenia); Marin, Irena; Lunder, Mojca; Drevenšek, Gorazd, E-mail: gorazd.drevensek@mf.uni-lj.si [University of Ljubljana, Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine (Slovenia)

    2016-10-15

    The use of zinc oxide nanoparticles (ZnO NPs) in numerous products is increasing, although possible negative implications of their long-term consumption are not known yet. Our aim was to evaluate the chronic, 6-week oral exposure to two different concentrations of ZnO NPs on isolated rat hearts exposed to ischemic-reperfusion injury and on small intestine morphology. Wistar rats of both sexes (n = 18) were randomly divided into three groups: (1) 4 mg/kg ZnO NPs, (2) 40 mg/kg ZnO NPs, and (3) control. After 6 weeks of treatment, the hearts were isolated, the left ventricular pressure (LVP), the coronary flow (CF), the duration of arrhythmias and the lactate dehydrogenase release rate (LDH) were measured. A histological investigation of the small intestine was performed. Chronic exposure to ZnO NPs acted cardiotoxic dose-dependently. ZnO NPs in dosage 40 mg/kg maximally decreased LVP (3.3-fold) and CF (2.5-fold) and increased the duration of ventricular tachycardia (all P < 0.01) compared to control, whereas ZnO NPs in dosage 4 mg/kg acted less cardiotoxic. Goblet cells in the small intestine epithelium of rats, treated with 40 mg ZnO NPs/kg, were enlarged, swollen and numerous, the intestinal epithelium width was increased. Unexpectedly, ZnO NPs in both dosages significantly decreased LDH. A 6-week oral exposure to ZnO NPs dose-dependently increased heart injuries and caused irritation of the intestinal mucosa. A prolonged exposure to ZnO NPs might cause functional damage to the heart even with exposures to the recommended daily doses, which should be tested in future studies.

  1. 3D imaging of the mitochondrial redox state of rat hearts under normal and fasting conditions

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    He N. Xu

    2014-03-01

    Full Text Available The heart requires continuous ATP availability that is generated in the mitochondria. Although studies using the cell culture and perfused organ models have been carried out to investigate the biochemistry in the mitochondria in response to a change in substrate supply, mitochondrial bioenergetics of heart under normal feed or fasting conditions has not been studied at the tissue level with a sub-millimeter spatial resolution either in vivo or ex vivo. Oxidation of many food-derived metabolites to generate ATP in the mitochondria is realized through the NADH/NAD+ couple acting as a central electron carrier. We employed the Chance redox scanner — the low-temperature fluorescence scanner to image the three-dimensional (3D spatial distribution of the mitochondrial redox states in heart tissues of rats under normal feeding or an overnight starvation for 14.5 h. Multiple consecutive sections of each heart were imaged to map three redox indices, i.e., NADH, oxidized flavoproteins (Fp, including flavin adenine dinucleotide (FAD and the redox ratio NADH/Fp. The imaging results revealed the micro-heterogeneity and the spatial distribution of these redox indices. The quantitative analysis showed that in the fasted hearts the standard deviation of both NADH and Fp, i.e., SD_NADH and SD_Fp, significantly decreased with a p value of 0.032 and 0.045, respectively, indicating that the hearts become relatively more homogeneous after fasting. The fasted hearts contained 28.6% less NADH (p = 0.038. No significant change in Fp was found (p = 0.4. The NADH/Fp ratio decreased with a marginal p value (0.076. The decreased NADH in the fasted hearts is consistent with the cardiac cells' reliance of fatty acids consumption for energy metabolism when glucose becomes scarce. The experimental observation of NADH decrease induced by dietary restriction in the heart at tissue level has not been reported to our best knowledge. The Chance redox scanner demonstrated the

  2. 3D IMAGING OF THE MITOCHONDRIAL REDOX STATE OF RAT HEARTS UNDER NORMAL AND FASTING CONDITIONS.

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    Xu, He N; Zhou, Rong; Moon, Lily; Feng, Min; Li, Lin Z

    2014-03-01

    The heart requires continuous ATP availability that is generated in the mitochondria. Although studies using the cell culture and perfused organ models have been carried out to investigate the biochemistry in the mitochondria in response to a change in substrate supply, mitochondrial bioenergetics of heart under normal feed or fasting conditions has not been studied at the tissue level with a sub-millimeter spatial resolution either in vivo or ex vivo. Oxidation of many food-derived metabolites to generate ATP in the mitochondria is realized through the NADH/NAD(+) couple acting as a central electron carrier. We employed the Chance redox scanner - the low-temperature fluorescence scanner to image the three-dimensional (3D) spatial distribution of the mitochondrial redox states in heart tissues of rats under normal feeding or an overnight starvation for 14.5 h. Multiple consecutive sections of each heart were imaged to map three redox indices, i.e., NADH, oxidized flavoproteins (Fp, including flavin adenine dinucleotide (FAD)) and the redox ratio NADH/Fp. The imaging results revealed the micro-heterogeneity and the spatial distribution of these redox indices. The quantitative analysis showed that in the fasted hearts the standard deviation of both NADH and Fp, i.e., SD_NADH and SD_Fp, significantly decreased with a p value of 0.032 and 0.045, respectively, indicating that the hearts become relatively more homogeneous after fasting. The fasted hearts contained 28.6% less NADH (p = 0.038). No significant change in Fp was found (p = 0.4). The NADH/Fp ratio decreased with a marginal p value (0.076). The decreased NADH in the fasted hearts is consistent with the cardiac cells' reliance of fatty acids consumption for energy metabolism when glucose becomes scarce. The experimental observation of NADH decrease induced by dietary restriction in the heart at tissue level has not been reported to our best knowledge. The Chance redox scanner demonstrated the feasibility of 3D

  3. Factors influencing left ventricular hypertrophy in children and adolescents with or without family history of premature myocardial infarction

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    Seyyed Mohsen Hosseini

    2014-01-01

    Result : The results showed that among the studied variables, gender, age, body mass index, and blood pressure were associated with the left ventricular hypertrophy. Conclusion: Considering the results and previous studies in this field, it was observed that left ventricular hypertrophy exists at early ages, which is very dangerous and can lead to heart diseases at early ages. Factors such as being overweight, having high blood pressure, and being male cause left ventricular hypertrophy and lead to undiagnosable heart diseases.

  4. Qiliqiangxin Attenuates Phenylephrine-Induced Cardiac Hypertrophy through Downregulation of MiR-199a-5p

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    Haifeng Zhang

    2016-05-01

    Full Text Available Background/Aims: Qiliqiangxin (QL, a traditional Chinese medicine, has long been used to treat chronic heart failure. Previous studies demonstrated that QL could prevent cardiac remodeling and hypertrophy in response to hypertensive or ischemic stress. However, little is known about whether QL could modulate cardiac hypertrophy in vitro, and (if so whether it is through modulation of specific hypertrophy-related microRNA. Methods: The primary neonatal rat ventricular cardiomyocytes were isolated, cultured, and treated with phenylephrine (PE, 50 µmol/L, 48 h to induce hypertrophy in vitro, in the presence or absence of pretreatment with QL (0.5 µg/ml, 48 h. The cell surface area was determined by immunofluorescent staining for α-actinin. The mRNA levels of hypertrophic markers including atrial natriuretic peptide (ANP, brain natriuretic peptide (BNP, and β-myosin heavy chain (MYH7 were assayed by qRT-PCRs. The protein synthesis of cardiomyocytes was determined by the protein/DNA ratio. The miR-199a-5p expression level was quantified in PE-treated cardiomyocytes and heart samples from acute myocardial infarction (AMI mouse model. MiR-199a-5p overexpression was used to determine its role in the anti-hypertrophic effect of QL on cardiomyocytes. Results: PE induced obvious enlargement of cell surface in cardiomyocytes, paralleling with increased ANP, BNP, and MYH7 mRNA levels and elevated protein/DNA ratio. All these changes were reversed by the treatment with QL. Meanwhile, miR-199a-5p was increased in AMI mouse heart tissues. Of note, the increase of miR-199a-5p in PE-treated cardiomyocytes was reversed by the treatment with QL. Moreover, overexpression of miR-199a-5p abolished the anti-hypertrophic effect of QL on cardiomyocytes. Conclusion: QL prevents PE-induced cardiac hypertrophy. MiR-199a-5p is increased in cardiac hypertrophy, while reduced by treatment with QL. miR-199a-5p suppression is essential for the anti-hypertrophic effect of QL

  5. Intrinsic-mediated caspase activation is essential for cardiomyocyte hypertrophy

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    Putinski, Charis; Abdul-Ghani, Mohammad; Stiles, Rebecca; Brunette, Steve; Dick, Sarah A.; Fernando, Pasan; Megeney, Lynn A.

    2013-01-01

    Cardiomyocyte hypertrophy is the cellular response that mediates pathologic enlargement of the heart. This maladaptation is also characterized by cell behaviors that are typically associated with apoptosis, including cytoskeletal reorganization and disassembly, altered nuclear morphology, and enhanced protein synthesis/translation. Here, we investigated the requirement of apoptotic caspase pathways in mediating cardiomyocyte hypertrophy. Cardiomyocytes treated with hypertrophy agonists displayed rapid and transient activation of the intrinsic-mediated cell death pathway, characterized by elevated levels of caspase 9, followed by caspase 3 protease activity. Disruption of the intrinsic cell death pathway at multiple junctures led to a significant inhibition of cardiomyocyte hypertrophy during agonist stimulation, with a corresponding reduction in the expression of known hypertrophic markers (atrial natriuretic peptide) and transcription factor activity [myocyte enhancer factor-2, nuclear factor kappa B (NF-κB)]. Similarly, in vivo attenuation of caspase activity via adenoviral expression of the biologic effector caspase inhibitor p35 blunted cardiomyocyte hypertrophy in response to agonist stimulation. Treatment of cardiomyocytes with procaspase 3 activating compound 1, a small-molecule activator of caspase 3, resulted in a robust induction of the hypertrophy response in the absence of any agonist stimulation. These results suggest that caspase-dependent signaling is necessary and sufficient to promote cardiomyocyte hypertrophy. These results also confirm that cell death signal pathways behave as active remodeling agents in cardiomyocytes, independent of inducing an apoptosis response. PMID:24101493

  6. Effects of ischemia and omeprazole preconditioning on functional recovery of isolated rat heart

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    Nevena Jeremic

    2015-04-01

    Full Text Available AbstractObjective:The aim of this study was to compare protective effects of ischemic and potential protective effects of pharmacological preconditioning with omeprazole on isolated rat heart subjected to ischemia/reperfusion.Methods:The hearts of male Wistar albino rats were excised and perfused on a Langendorff apparatus. In control group (CG after stabilization period, hearts were subjected to global ischemia (perfusion was totally stopped for 20 minutes and 30 minutes of reperfusion. Hearts of group II (IPC were submitted to ischemic preconditioning lasting 5 minutes before 20 minutes of ischemia and 30 minutes of reperfusion. In third group (OPC hearts first underwent preconditioning lasting 5 minutes with 100μM omeprazole, and then submitted 20 minutes of ischemia and 30 minutes of reperfusion.Results:Administration of omeprazole before ischemia induction had protective effect on myocardium function recovery especially regarding to values of systolic left ventricular pressure and dp/dt max. Also our findings are that values of coronary flow did not change between OPC and IPC groups in last point of reperfusion.Conclusion:Based on our results it seems that ischemic preconditioning could be used as first window of protection after ischemic injury especially because all investigated parameters showed continuous trend of recovery of myocardial function. On the other hand, preconditioning with omeprazole induced sudden trend of recovery with positive myocardium protection, although less effective than results obtained with ischemic preconditioning not withstand, we must consider that omeprazole may be used in many clinical circumstances where direct coronary clamping for ischemic preconditioning is not possible.

  7. Measurement of Ca channel activity of isolated adult rat heart cells using /sup 54/Mn

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    Haworth, R.A.; Goknur, A.B.; Berkoff, H.A.

    1989-02-01

    Isolated adult rat heart cells incubated with 5 microM Mn in a medium with 1 mM Ca showed a rapid phase of Mn binding plus a slow phase of Mn uptake. The rapid phase was extracellular binding, as judged by its temperature-insensitive removal by ethylene glycol bis(beta-aminoethyl ether) N, N'-tetraacetic acid. The slow linear phase represented cellular uptake, as judged by its release with digitonin plus the ionophore A23187. Isoproterenol increased the linear rate of Mn uptake and induced spontaneous beating activity in some cells. Both effects were inhibited by nitrendipine. Electrical stimulation of the cells in suspension increased the linear rate of cellular Mn uptake. The increase was potentiated by isoproterenol, and inhibited by nitrendipine or verapamil. Stimulation-dependent Mn uptake (per milligram protein) was greater for cells from 5- to 6-week-old rats than for 8- to 9-month-old female retired breeder rats, in the presence of isoproterenol. Ryanodine increased the stimulation-dependent Mn uptake in the presence of isoproterenol, but not in its absence. We conclude: (i) that cellular uptake of /sup 54/Mn is a good probe of Ca channel function; (ii) that isoproterenol promotes Mn influx by the channel in isolated heart cells; (iii) that cells from young rats (5-6 weeks) have a higher beta-adrenergically induced Ca channel activity than cells from mature rats (8-9 months); and (iv) that ryanodine promotes Ca channel activity (perhaps indirectly) in the presence of isoproterenol.

  8. Increase of ATP-sensitive potassium (KATP channels in the heart of type-1 diabetic rats

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    Chen Zhih-Cherng

    2012-01-01

    Full Text Available Abstract Background An impairment of cardiovascular function in streptozotocin (STZ-diabetic rats has been mentioned within 5 days-to-3 months of induction. ATP-sensitive potassium (KATP channels are expressed on cardiac sarcolemmal membranes. It is highly responsive to metabolic fluctuations and can have effects on cardiac contractility. The present study attempted to clarify the changes of cardiac KATP channels in diabetic disorders. Methods Streptozotocin-induced diabetic rats and neonatal rat cardiomyocytes treated with a high concentration of glucose (a D-glucose concentration of 30 mM was used and cells were cultured for 24 hr were used to examine the effect of hyperglycemia on cardiac function and the expression of KATP channels. KATP channels expression was found to be linked to cardiac tonic dysfunction, and we evaluated the expression levels of KATP channels by Western blot and Northern blot analysis. Results The result shows diazoxide produced a marked reduction of heart rate in control group. Furthermore, the methods of Northern blotting and Western blotting were employed to identify the gene expression of KATP channel. Two subunits of cardiac KATP channel (SUR2A and kir 6.2 were purchased as indicators and showed significantly decreased in both diabetic rats and high glucose treated rat cardiac myocytes. Correction of hyperglycemia by insulin or phlorizin restored the gene expression of cardiac KATP in these diabetic rats. Conclusions Both mRNA and protein expression of cardiac KATP channels are decreased in diabetic rats induced by STZ for 8 weeks. This phenomenon leads to result in desensitization of some KATP channel drugs.

  9. Effects of DPP-4 inhibitors on the heart in a rat model of uremic cardiomyopathy.

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    Lyubov Chaykovska

    Full Text Available BACKGROUND: Uremic cardiomyopathy contributes substantially to mortality in chronic kidney disease (CKD patients. Glucagon-like peptide-1 (GLP-1 may improve cardiac function, but is mainly degraded by dipeptidyl peptidase-4 (DPP-4. METHODOLOGY/PRINCIPAL FINDINGS: In a rat model of chronic renal failure, 5/6-nephrectomized [5/6N] rats were treated orally with DPP-4 inhibitors (linagliptin, sitagliptin, alogliptin or placebo once daily for 4 days from 8 weeks after surgery, to identify the most appropriate treatment for cardiac dysfunction associated with CKD. Linagliptin showed no significant change in blood level AUC(0-∞ in 5/6N rats, but sitagliptin and alogliptin had significantly higher AUC(0-∞ values; 41% and 28% (p = 0.0001 and p = 0.0324, respectively. No correlation of markers of renal tubular and glomerular function with AUC was observed for linagliptin, which required no dose adjustment in uremic rats. Linagliptin 7 µmol/kg caused a 2-fold increase in GLP-1 (AUC 201.0 ng/l*h in 5/6N rats compared with sham-treated rats (AUC 108.6 ng/l*h (p = 0.01. The mRNA levels of heart tissue fibrosis markers were all significantly increased in 5/6N vs control rats and reduced/normalized by linagliptin. CONCLUSIONS/SIGNIFICANCE: DPP-4 inhibition increases plasma GLP-1 levels, particularly in uremia, and reduces expression of cardiac mRNA levels of matrix proteins and B-type natriuretic peptides (BNP. Linagliptin may offer a unique approach for treating uremic cardiomyopathy in CKD patients, with no need for dose-adjustment.

  10. Tumor necrosis factor receptor-associated factor 3 is a positive regulator of pathological cardiac hypertrophy.

    Science.gov (United States)

    Jiang, Xi; Deng, Ke-Qiong; Luo, Yuxuan; Jiang, Ding-Sheng; Gao, Lu; Zhang, Xiao-Fei; Zhang, Peng; Zhao, Guang-Nian; Zhu, Xueyong; Li, Hongliang

    2015-08-01

    Cardiac hypertrophy, a common early symptom of heart failure, is regulated by numerous signaling pathways. Here, we identified tumor necrosis factor receptor-associated factor 3 (TRAF3), an adaptor protein in tumor necrosis factor-related signaling cascades, as a key regulator of cardiac hypertrophy in response to pressure overload. TRAF3 expression was upregulated in hypertrophied mice hearts and failing human hearts. Four weeks after aortic banding, cardiac-specific conditional TRAF3-knockout mice exhibited significantly reduced cardiac hypertrophy, fibrosis, and dysfunction. Conversely, transgenic mice overexpressing TRAF3 in the heart developed exaggerated cardiac hypertrophy in response to pressure overload. TRAF3 also promoted an angiotensin II- or phenylephrine-induced hypertrophic response in isolated cardiomyocytes. Mechanistically, TRAF3 directly bound to TANK-binding kinase 1 (TBK1), causing increased TBK1 phosphorylation in response to hypertrophic stimuli. This interaction between TRAF3 and TBK1 further activated AKT signaling, which ultimately promoted the development of cardiac hypertrophy. Our findings not only reveal a key role of TRAF3 in regulating the hypertrophic response but also uncover TRAF3-TBK1-AKT as a novel signaling pathway in the development of cardiac hypertrophy and heart failure. This pathway may represent a potential therapeutic target for this pathological process. © 2015 American Heart Association, Inc.

  11. Systems Genetics Approach Identifies Gene Pathways and Adamts2 as Drivers of Isoproterenol-Induced Cardiac Hypertrophy and Cardiomyopathy in Mice.

    Science.gov (United States)

    Rau, Christoph D; Romay, Milagros C; Tuteryan, Mary; Wang, Jessica J-C; Santolini, Marc; Ren, Shuxun; Karma, Alain; Weiss, James N; Wang, Yibin; Lusis, Aldons J

    2017-01-25

    We previously reported a genetic analysis of heart failure traits in a population of inbred mouse strains treated with isoproterenol to mimic catecholamine-driven cardiac hypertrophy. Here, we apply a co-expression network algorithm, wMICA, to perform a systems-level analysis of left ventricular transcriptomes from these mice. We describe the features of the overall network but focus on a module identified in treated hearts that is strongly related to cardiac hypertrophy and pathological remodeling. Using the causal modeling algorithm NEO, we identified the gene Adamts2 as a putative regulator of this module and validated the predictive value of NEO using small interfering RNA-mediated knockdown in neonatal rat ventricular myocytes. Adamts2 silencing regulated the expression of the genes residing within the module and impaired isoproterenol-induced cellular hypertrophy. Our results provide a view of higher order interactions in heart failure with potential for diagnostic and therapeutic insights. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  12. 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

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    Hugo Celso Dutra de Souza

    2007-08-01

    Full Text Available OBJETIVO: O presente estudo avaliou as adaptações teciduais cardíacas em ratos submetidos a treinamento aeróbio, após o bloqueio da síntese de óxido nítrico (NO. MÉTODOS: Os animais (n = 48 foram divididos em quatro grupos: sedentários (grupo CONTROLE, hipertensos após administração de Ng-nitro-L-arginina metil éster durante sete dias (grupo L-NAME, treinados por meio de natação durante oito semanas (grupo TREINADO e treinados e tratados com L-NAME na última semana (grupo TREINADO L-NAME. Em todos os animais foi registrada a pressão arterial (PA e realizada a avaliação morfométrica cardíaca. RESULTADOS: Os grupos L-NAME e TREINADO L-NAME apresentaram-se hipertensos em relação aos demais (p OBJECTIVE: The objective of the present study was to evaluate cardiac tissue adaptations in rats submitted to aerobic training after nitric oxide (NO synthesis blockade. METHODS: The animals (n=48 were divided into four groups: sedentary (CONTROL group; hypertensive after administration of NG-nitro-L-arginine methyl ester for 7 days (L-NAME Group; trained for 8 weeks through swimming exercises (TRAINED Group;trained and treated with L-NAME during the last week (L-NAME TRAINED Group. All the animals were submitted to the experiment procedures for blood pressure (BP readings and cardiac morphometric evaluation. RESULTS: In comparison to the other groups, the L-NAME and L-NAME TRAINED groups were hypertensive (p<0.05; however, BP elevation in the L-NAME TRAINED group was significantly lower than the L-NAME group (p<0.05. The heart weight indexes for the TRAINED and L-NAME TRAINED groups were higher than the CONTROL and L-NAME groups (p<0.05. Also they had presented higher rates of macroscopic cardiac area and cardiac fibrosis in relation to the rest (p<0.05; comparisons revealed that the values for the L-NAME TRAINED group were significantly higher (p<0.05 than the others. CONCLUSION: Short term NO synthesis blockade in sedentary animals

  13. Effects Of The Direct Renin Inhibitor Aliskiren On Oxidative Stress In Isolated Rat Heart

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    Plecevic Sasa

    2015-09-01

    Full Text Available Increased activity of the renin-angiotensin-aldosterone system (RAAS plays a significant role in the development and progression of various cardio-metabolic diseases, such as hypertension, atherosclerosis and heart failure. Aliskiren is the newest antihypertensive drug and the first orally active direct renin inhibitor to become available for clinical use. This study investigated the acute and direct effects of Aliskiren on different parameters of oxidative stress on isolated rat heart. The hearts of male Wistar albino rats (n = 24, 8 per experimental group, age 8 weeks, body mass 180–200 g, were excised and retrogradely perfused according to the Langendorfftechnique at a gradually increasing perfusion pressure (40-120 cmH2O. Markers of oxidative stress (NO2−, TBARS, H2O2 and O2− were measured spectrophotometrically after perfusion with three different concentrations of Aliskiren (0.1 μM, 1 μM, and 10 μM. The results demonstrated possible dose-dependent cardioprotective properties of Aliskiren, particularly with higher CPP. Lipid peroxidation (TBARS levels decreased with the highest dose of Aliskiren and higher CPP, and the same trend was observed in nitrite (NO2− and hydrogen peroxide (H2O2 levels. These findings indicate that the acute effects of Aliskiren do not likely promote the production of reactive oxygen species upon higher pressure with the highest dose. Aliskiren may exert beneficial effects on oxidative stress biomarkers.

  14. Cardioprotective Effects of Astragalin against Myocardial Ischemia/Reperfusion Injury in Isolated Rat Heart.

    Science.gov (United States)

    Qu, Daoxu; Han, Jichun; Ren, Huanhuan; Yang, Wenxiao; Zhang, Xinjie; Zheng, Qiusheng; Wang, Dong

    2016-01-01

    This study aims to evaluate the cardioprotective effects of astragalin against myocardial ischemia/reperfusion (I/R) injury in isolated rat heart. The cardioprotective effects of astragalin on myocardial I/R injury were investigated on Langendorff apparatus. Adult male Sprague-Dawley rats were randomly divided into five groups. The results showed that astragalin pretreatment improved myocardial function. Compared with I/R group, lactate dehydrogenase (LDH) and creatine kinase (CK) activities in coronary flow decreased in astragalin pretreatment groups, whereas superoxide dismutase (SOD) activity and glutathione/glutathione disulfide (GSH/GSSG) ratio significantly increased. The levels of malondialdehyde (MDA), intracellular reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) decreased in astragalin-treated groups. The infarct size (IS) and apoptosis rate in hearts from astragalin-treated groups were lower than those in hearts from the I/R group. Western blot analysis also revealed that astragalin preconditioning significantly reduced Bax level, whereas Bcl-2 was increased in the myocardium. Therefore, astragalin exhibited cardioprotective effects via its antioxidative, antiapoptotic, and anti-inflammatory activities.

  15. Early combined treatment with sildenafil and adipose-derived mesenchymal stem cells preserves heart function in rat dilated cardiomyopathy

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    Fu Morgan

    2010-09-01

    Full Text Available Abstract Background We investigated whether early combined autologous adipose-derived mesenchymal stem cell (ADMSC and sildenafil therapy offers an additive benefit in preserving heart function in rat dilated cardiomyopathy (DCM. Methods Adult Lewis rats (n = 8 per group were divided into group 1 (normal control, group 2 (saline-treated DCM rats, group 3 [2.0 × 106 ADMSC implanted into left ventricular (LV myocardium of DCM rats], group 4 (DCM rats with sildenafil 30 mg/kg/day, orally, and group 5 (DCM rats with combined ADMSC-sildenafil. Treatment was started 1 week after DCM induction and the rats were sacrificed on day 90. Results The results showed that mitochondrial protein expressions of connexin43 and cytochrome-C were lowest in group 2, and lower in groups 3 and 4 than in group 5 (p Conclusion Early combined ADMSC/sildenafil is superior to either treatment alone in preserving LV function.

  16. Cardiovascular effects of Urtica dioica L. in isolated rat heart and aorta.

    Science.gov (United States)

    Legssyer, Abdelkhaleq; Ziyyat, Abderrahim; Mekhfi, Hassane; Bnouham, Mohamed; Tahri, Abdelhafid; Serhrouchni, Mohamed; Hoerter, Jacqueline; Fischmeister, Rodolphe

    2002-09-01

    Urtica dioica L. or Nettle (Urticaceae) is widely used in oriental Morocco to treat hypertension. Aqueous extract of Nettle (AEN) also exerts a hypotensive action in the rat in vivo. The aim of this work was to characterize the specific cardiac and vascular effects of AEN. In the isolated Langendorff perfused rat heart, AEN (1 and 2 g/l) markedly decreased heart rate and increased left ventricular pressure. Higher concentration (5 g/l) even led to cardiac arrest. Although carbachol mimicked the bradycardiac effect of AEN, atropine (a muscarinic receptor antagonist, 1 micro M) did not modify the response. Beside its action on myocardium, AEN also affected vascular contractility. Indeed, AEN (0.1-5 g/l) produced a dose-dependent increase in basal tone of isolated rat aorta. This effect was endothelium independent and was abolished by 1 micro M prazosin (an alpha1-adrenergic antagonist). AEN had little additional effects when the aorta was precontracted by noradrenaline (1 micro M) or KCl (40 mM). Our data indicate that AEN produces a vasoconstriction of the aorta which is due to activation of alpha1-adrenergic receptors. However, AEN also induces a strong bradycardia through non-cholinergic and non-adrenergic pathways which might compensate for its vascular effect and account for the hypotensive action of Urtica dioica L described in vivo. Copyright 2002 John Wiley & Sons, Ltd.

  17. Protective effects of Salvia miltiorrhizae on the hearts of rats with severe acute pancreatits or obstructive jaundice*

    Science.gov (United States)

    Zhang, Xi-ping; Feng, Guang-hua; Zhang, Jie; Cai, Yang; Tian, Hua; Zhang, Xiao-feng; Zhou, Yi-feng; Wang, Zhi-wei; Wang, Ke-yi

    2009-01-01

    Objective: To investigate the therapeutic effects and mechanisms of Salvia miltiorrhizae (Danshen) in the treatment of severe acute pancreatitis (SAP)- or obstructive jaundice (OJ)-induced heart injury. Methods: A total of 288 rats were used for SAP- (n=108) and OJ-associated (n=180) experiments. The rats were randomly divided into sham-operated, model control, and Salvia miltiorrhizae-treated groups. According to the difference of time points after operation, SAP rats in each group were subdivided into 3, 6 and 12 h subgroups (n=12), whereas OJ rats were subdivided into 7, 14, 21, and 28 d subgroups (n=15). At the corresponding time points after operation, the mortality rates of the rats, the contents of endotoxin and phospholipase A2 (PLA2) in blood, and pathological changes of the hearts were investigated. Results: The numbers of dead SAP and OJ rats in the treated groups declined as compared with those in the model control