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Sample records for nonpeptide ang ii

  1. Interaction of a non-peptide agonist with angiotensin II AT1 receptor mutants

    DEFF Research Database (Denmark)

    Costa-Neto, Claudio M; Miyakawa, Ayumi A; Pesquero, João B;

    2002-01-01

    To identify residues of the rat AT1A angiotensin II receptor involved with signal transduction and binding of the non-peptide agonist L-162,313 (5,7-dimethyl-2-ethyl-3-[[4-[2(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazol[4,5,6]-pyridine) we have performed ligand bindi...

  2. TGF-beta Inhibits Ang II-Induced MAPK p44/42 Signaling in Vascular Smooth Muscle Cells by Ang II Type 1 Receptor Downregulation

    NARCIS (Netherlands)

    Meijering, Bernadet D. M.; van der Wouden, Els A.; Pelgrom, Vincent; Henning, Robert H.; Sharma, Kumar; Deelman, Leo E.

    2009-01-01

    Vascular changes in diabetes are characterized by reduced vasoconstriction and vascular remodeling. Previously, we demonstrated that TGF-beta 1 impairs Ang II-induced contraction through reduced calcium mobilization. However, the effect of TGF-beta 1 on Ang II-induced vascular remodeling is unknown.

  3. ANG II is required for optimal overload-induced skeletal muscle hypertrophy

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    Gordon, S. E.; Davis, B. S.; Carlson, C. J.; Booth, F. W.

    2001-01-01

    ANG II mediates the hypertrophic response of overloaded cardiac muscle, likely via the ANG II type 1 (AT(1)) receptor. To examine the potential role of ANG II in overload-induced skeletal muscle hypertrophy, plantaris and/or soleus muscle overload was produced in female Sprague-Dawley rats (225-250 g) by the bilateral surgical ablation of either the synergistic gastrocnemius muscle (experiment 1) or both the gastrocnemius and plantaris muscles (experiment 2). In experiment 1 (n = 10/group), inhibiting endogenous ANG II production by oral administration of an angiotensin-converting enzyme (ACE) inhibitor during a 28-day overloading protocol attenuated plantaris and soleus muscle hypertrophy by 57 and 96%, respectively (as measured by total muscle protein content). ACE inhibition had no effect on nonoverloaded (sham-operated) muscles. With the use of new animals (experiment 2; n = 8/group), locally perfusing overloaded soleus muscles with exogenous ANG II (via osmotic pump) rescued the lost hypertrophic response in ACE-inhibited animals by 71%. Furthermore, orally administering an AT(1) receptor antagonist instead of an ACE inhibitor produced a 48% attenuation of overload-induced hypertrophy that could not be rescued by ANG II perfusion. Thus ANG II may be necessary for optimal overload-induced skeletal muscle hypertrophy, acting at least in part via an AT(1) receptor-dependent pathway.

  4. ANG II is required for optimal overload-induced skeletal muscle hypertrophy

    Science.gov (United States)

    Gordon, S. E.; Davis, B. S.; Carlson, C. J.; Booth, F. W.

    2001-01-01

    ANG II mediates the hypertrophic response of overloaded cardiac muscle, likely via the ANG II type 1 (AT(1)) receptor. To examine the potential role of ANG II in overload-induced skeletal muscle hypertrophy, plantaris and/or soleus muscle overload was produced in female Sprague-Dawley rats (225-250 g) by the bilateral surgical ablation of either the synergistic gastrocnemius muscle (experiment 1) or both the gastrocnemius and plantaris muscles (experiment 2). In experiment 1 (n = 10/group), inhibiting endogenous ANG II production by oral administration of an angiotensin-converting enzyme (ACE) inhibitor during a 28-day overloading protocol attenuated plantaris and soleus muscle hypertrophy by 57 and 96%, respectively (as measured by total muscle protein content). ACE inhibition had no effect on nonoverloaded (sham-operated) muscles. With the use of new animals (experiment 2; n = 8/group), locally perfusing overloaded soleus muscles with exogenous ANG II (via osmotic pump) rescued the lost hypertrophic response in ACE-inhibited animals by 71%. Furthermore, orally administering an AT(1) receptor antagonist instead of an ACE inhibitor produced a 48% attenuation of overload-induced hypertrophy that could not be rescued by ANG II perfusion. Thus ANG II may be necessary for optimal overload-induced skeletal muscle hypertrophy, acting at least in part via an AT(1) receptor-dependent pathway.

  5. Standardization of radioimmunoassay for dosage of angiotensin II (ang-II) and its methodological evaluation; Padronizacao do radioimunoensaio para dosagem de angiotensina II (ang-II) e sua validacao metodologica

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    Mantovani, Milene; Mecawi, Andre S.; Elias, Lucila L.K.; Antunes-Rodrigues, Jose, E-mail: llelias@fmrp.usp.b, E-mail: antunes@fmrp.usp.b [Universidade de Sao Paulo (FMRP/USP), Ribeirao Preto, SP (Brazil). Faculdade de Medicina

    2011-10-26

    This paper standardizes the radioimmunoassay (RIA) for dosage of ANG-II of rats, after experimental conditions of saline hypertonic (2%), treating with losartan (antagonist of ANG-II), hydric privation, and acute hemorrhage (25%). After that, the plasmatic ANG-II was extracted for dosage of RIA, whose sensitiveness was of 1.95 pg/m L, with detection of 1.95 to 1000 pg/m L. The treatment with saline reduced the concentration of ANG-II, while the administration pf losartan, the hydric administration and the hemorrhage increase the values, related to the control group. Those results indicate variations in the plasmatic concentration of ANG-II according to the experimental protocols, validating the method for evaluation of activity renin-angiotensin

  6. Drinking and arterial blood pressure responses to ANG II in young and old rats

    Science.gov (United States)

    Beltz, Terry G.; Johnson, Alan Kim

    2010-01-01

    We investigated water drinking and arterial blood pressure responses to intravenous infusions of ANG II in young (4 mo), middle-aged adult (12 mo), and old (29 mo) male Brown Norway rats. Infusions of ANG II began with arterial blood pressure either at control levels or at reduced levels following injection of the vasodilator minoxidil. Under control conditions, mean arterial pressure (MAP) in response to ANG II rose to the same level for all groups, and middle-aged and old rats drank as much or more water in response to ANG II compared with young rats, depending on whether intakes were analyzed using absolute or body weight-adjusted values. When arterial blood pressure first was reduced with minoxidil, MAP in response to ANG II stabilized at significantly lower levels compared with control conditions for all groups. Young rats drank significantly more water under reduced pressure conditions compared with control conditions, while middle-aged and old rats did not. Urine volume in response to ANG II was lower, while water balance was higher, under conditions of reduced pressure compared with control conditions. Baroreflex control of heart rate was substantially reduced in old rats compared with young and middle-aged animals. In summary, young rats appear to be more sensitive to the inhibitory effects of increased arterial blood pressure on water drinking than are older animals. PMID:20739604

  7. Chronic ANG II infusion induces sex-specific increases in renal T cells in Sprague-Dawley rats.

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    Zimmerman, Margaret A; Baban, Babak; Tipton, Ashlee J; O'Connor, Paul M; Sullivan, Jennifer C

    2015-04-01

    Recent studies suggest that sex of the animal and T cell impact ANG II hypertension in Rag(-/-) mice, with females being protected relative to males. This study tested the hypothesis that ANG II results in greater increases in proinflammatory T cells and cytokines in males than in females. Male and female Sprague-Dawley (SD) rats, aged 12 wk, were treated with vehicle or ANG II (200 ng·kg(-1)·min(-1)) for 2 wk. Renal CD4(+) T cells and Tregs were comparable between vehicle-treated males and females, although males expressed more Th17 and IL-17(+) T cells and fewer IL-10(+) T cells than females. ANG II resulted in greater increases in CD4(+) T cells, Th17 cells, and IL-17(+) cells in males; Tregs increased only in females. We previously showed that ANG (1-7) antagonizes ANG II-induced increases in blood pressure in females and ANG (1-7) has been suggested to be anti-inflammatory. Renal ANG (1-7) levels were greater in female SD at baseline and following ANG II infusion. Additional rats were treated with ANG II plus the ANG (1-7)-mas receptor antagonist A-779 (48 μg·kg(-1)·h(-1)) to test the hypothesis that greater ANG (1-7) in females results in more Tregs relative to males. Inhibition of ANG (1-7) did not alter renal T cells in either sex. In conclusion, ANG II induces a sex-specific effect on the renal T cell profile. Males have greater increases in proinflammatory T cells, and females have greater increases in anti-inflammatory Tregs; however, sex differences in the renal T cell profile are not mediated by ANG (1-7). Copyright © 2015 the American Physiological Society.

  8. Increased renal vascular reactivity to ANG II after unilateral nephrectomy in the rat involves 20-HETE.

    Science.gov (United States)

    Joly, E; Seqqat, R; Flamion, B; Caron, N; Michel, A; Imig, J D; Kramp, R

    2006-10-01

    This study examined the role of intrarenal ANG II in the renal vascular reactivity changes occurring in the remaining kidney undergoing adaptation following contralateral nephrectomy. Renal blood flow responses to intrarenal injections of ANG II (0.25 to 5 ng) were measured in anesthetized euvolemic male Wistar rats 1, 4, 12, and 24 wk after uninephrectomy (UNX) or sham procedure (SHAM). At week 4, renal vasoconstriction induced by 2 ng ANG II was greater in UNX (69 +/- 5%) than in SHAM rats (50 +/- 3%; P < 0.01). This response was inhibited, by 50 and 66%, and by 20 and 25%, in SHAM and UNX rats, after combined injections of ANG II and losartan, or PD-123319 (P < 0.05), respectively. Characteristics of ANG II receptor binding in isolated preglomerular resistance vessels were similar in the two groups. After prostanoid inhibition with indomethacin, renal vasoconstriction was enhanced by 42 +/- 8% (P < 0.05), only in SHAM rats, whereas after 20-HETE inhibition with HET0016, it was reduced by 53 +/- 16% (P < 0.05), only in UNX rats. These differences vanished after concomitant prostanoid and 20-HETE inhibition in the two groups. After UNX, renal cortical protein expression of cytochrome P-450 2c23 isoform (CYP2c23) and cyclooxygenase-1 (COX-1) was unaltered, but it was decreased for CYP4a and increased for COX-2. In conclusion, renal vascular reactivity to ANG II was significantly increased in the postuninephrectomy adapted kidney, independently of protein expression, but presumably involving interactions between 20-HETE and COX in the renal microvasculature and changes in the paracrine activity of ANG II and 20-HETE.

  9. Regulation and role of connective tissue growth factor in AngII-induced myocardial fibrosis.

    Science.gov (United States)

    Rosin, Nicole L; Falkenham, Alec; Sopel, Mryanda J; Lee, Timothy D G; Légaré, Jean-Francois

    2013-03-01

    Exposure of rodents to angiotensin II (AngII) is a common model of fibrosis. We have previously shown that cellular infiltration of bone marrow-derived progenitor cells (fibrocytes) occurs before deposition of extracellular matrix and is associated with the production of connective tissue growth factor (CTGF). In the present study, we characterized the role of CTGF in promoting fibrocyte accumulation and regulation after AngII exposure. In animals exposed to AngII using osmotic minipumps (2.0 μg/kg per min), myocardial CTGF mRNA peaked at 6 hours (21-fold; P fibrocyte migration (1 day) into the myocardium or ECM deposition (3 days). CTGF protein expression was evident by day 3 of AngII exposure and seemed to be localized to resident cells. Isolated cardiomyocytes and microvascular endothelial cells responded to AngII with increased CTGF production (2.1-fold and 2.8-fold, respectively; P fibrocytes suggested a role in fibrocyte proliferation (twofold; P fibrocytes or TGF-β mRNA up-regulation. In addition, CTGF contributes to fibrocyte proliferation in the myocardium and enhances fibrocyte differentiation into a myofibroblast phenotype responsible for ECM deposition.

  10. High-NaCl intake impairs dynamic autoregulation of renal blood flow in ANG II-infused rats

    DEFF Research Database (Denmark)

    Saeed, Aso; Dibona, Gerald F; Marcussen, Niels

    2010-01-01

    The aim of this study was to investigate dynamic autoregulation of renal blood flow (RBF) in ANG II-infused rats and the influence of high-NaCl intake. Sprague-Dawley rats received ANG II (250 ng·kg(-1)·min(-1) sc) or saline vehicle (sham) for 14 days after which acute renal clearance experiments...

  11. Silencing MR-1 attenuates inflammatory damage in mice heart induced by AngII

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    Dai, Wenjian [Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Key Lab of Antibiotic Biotechnology, Ministry of Health, Beijing 100050 (China); Hunan Environment-Biological Polytechnic College, Hengyang Hunan 421005 (China); Chen, Haiyang [Hunan Environment-Biological Polytechnic College, Hengyang Hunan 421005 (China); Jiang, Jiandong [Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Key Lab of Antibiotic Biotechnology, Ministry of Health, Beijing 100050 (China); Kong, Weijia, E-mail: wjkong894@sohu.com [Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Key Lab of Antibiotic Biotechnology, Ministry of Health, Beijing 100050 (China); Wang, Yiguang, E-mail: wangyh456@yahoo.com.cn [Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Key Lab of Antibiotic Biotechnology, Ministry of Health, Beijing 100050 (China)

    2010-01-15

    Myofibrillogenesis regulator-1(MR-1) can aggravate cardiac hypertrophy induced by angiotensin(Ang) II in mice through activation of NF-{kappa}B signaling pathway, and nuclear transcription factor (NF)-{kappa}B and activator protein-1(AP-1) regulate inflammatory and immune responses by increasing the expression of specific inflammatory genes in various tissues including heart. Whether inhibition of MR-1 expression will attenuate AngII-induced inflammatory injury in mice heart has not been explored. Herein, we monitored the activation of NF-{kappa}B and AP-1, together with expression of pro-inflammatory of interleukin(IL)-6, tumor necrosis factor(TNF)-{alpha}, vascular-cell adhesion molecule (VCAM)-1, platelet endothelial cell adhesion molecule (PECAM), and inflammatory cell infiltration in heart of mice which are induced firstly by AngII (PBS),then received MR-1-siRNA or control-siRNA injecting. We found that the activation of NF-{kappa}B and AP-1 was inhibited significantly, together with the decreased expression of IL-6, TNF-{alpha}, VCAM-1, and PECAM in AngII-induced mice myocardium in MR-1-siRNA injection groups compared with control-siRNA injecting groups. However, the expression level of MR-1 was not an apparent change in PBS-infused groups than in unoperation groups, and MR-1-siRNA do not affect the expression of MR-1 in PBS-infused mice. Our findings suggest that silencing MR-1 protected mice myocardium against inflammatory injury induced by AngII by suppression of pro-inflammatory transcription factors NF-{kappa}B and AP-1 signaling pathway.

  12. Immunosuppression preserves renal autoregulatory function and microvascular P2X1 receptor reactivity in ANG II-hypertensive rats

    OpenAIRE

    2012-01-01

    Autoregulation is critical for protecting the kidney against arterial pressure elevation and is compromised in some forms of hypertension. Evidence indicates that activated lymphocytes contribute importantly to cardiovascular injury in hypertension. We hypothesized that activated lymphocytes contribute to renal vascular dysfunction by impairing autoregulation and P2X1 receptor signaling in ANG II-infused hypertensive rats. Male Sprague-Dawley rats receiving ANG II infusion were treated with a...

  13. The Ang II-induced growth of vascular smooth muscle cells involves a phospholipase D-mediated signaling mechanism.

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    Freeman, E J

    2000-02-15

    Angiotensin (Ang) II acts as a mitogen in vascular smooth muscle cells (VSMC) via the activation of multiple signaling cascades, including phospholipase C, tyrosine kinase, and mitogen-activated protein kinase pathways. However, increasing evidence supports signal-activated phospholipases A(2) and D (PLD) as additional mechanisms. Stimulation of PLD results in phosphatidic acid (PA) formation, and PA has been linked to cell growth. However, the direct involvement of PA or its metabolite diacylglycerol (DAG) in Ang II-induced growth is unclear. PLD activity was measured in cultured rat VSMC prelabeled with [(3)H]oleic acid, while the incorporation of [(3)H]thymidine was used to monitor growth. We have previously reported the Ang II-dependent, AT(1)-coupled stimulation of PLD and growth in VSMC. Here, we show that Ang II (100 nM) and exogenous PLD (0.1-100 units/mL; Streptomyces chromofuscus) stimulated thymidine incorporation (43-208% above control). PA (100 nM-1 microM) also increased thymidine incorporation to 135% of control. Propranolol (100 nM-10 microM), which inhibits PA phosphohydrolase, blocked the growth stimulated by Ang II, PLD, or PA by as much as 95%, an effect not shared by other beta-adrenergic antagonists. Propranolol also increased the production of PA in the presence of Ang II by 320% and reduced DAG and arachidonic acid (AA) accumulation. The DAG lipase inhibitor RHC-80267 (1-10 microM) increased Ang II-induced DAG production, while attenuating thymidine incorporation and release of AA. Thus, it appears that activation of PLD, formation of PA, conversion of PA to DAG, and metabolism of DAG comprise an important signaling cascade in Ang II-induced growth of VSMC.

  14. Elastase-2, an angiotensin II-generating enzyme, contributes to increased Ang II in resistance arteries of mice with myocardial infarction.

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    Becari, Christiane; Silva, Marcondes A B; Durand, Marina T; Prado, Cibele M; Oliveira, Eduardo B; Ribeiro, Mauricio S; Salgado, Helio C; Salgado, Maria Cristina O; Tostes, Rita C

    2017-02-21

    Angiotensin II (Ang II), whose generation largely depends on angiotensin-converting enzyme activity, mediates most of the renin-angiotensin-system effects. Elastase-2 (ELA-2), a chymotrypsin-serine protease elastase family member 2A, alternatively generates Ang II in rat arteries. Myocardial infarction (MI) leads to intense RAS activation, but mechanisms involved on Ang II-generation in resistance arteries are unknown. We hypothesized that ELA-2 contributes to vascular Ang II generation and to cardiac damage in mice submitted to MI. Concentration-effect curves to Ang I and Ang II were performed in mesenteric resistance arteries from male wild type (WT) and ELA-2 knockout (ELA-2KO) mice submitted to left anterior descending coronary artery ligation (myocardial infarction, MI). MI size was similar in WT (29.5 ± 9 %) and ELA-2KO (32 ± 4%) mice. Ejection fraction and fractional shortening after MI similarly decreased in both strains. However, MI decreased stroke volume and cardiac output in WT, but not in ELA-2KO mice. Ang I-induced contractions increased in WT mice submitted to MI (MI-WT) compared to Sham-WT mice. No differences were observed in Ang I reactivity between arteries from Sham-ELA-2KO and ELA-2KO submitted to MI (MI-ELA-2KO). Ang I contractions increased in arteries from MI-WT vs. MI-ELA-2KO mice. Chymostatin attenuated Ang I-induced vascular contractions in WT mice (P ELA-2KO arteries. These results provide the first evidence that ELA-2 contributes to increased Ang II formation in resistance arteries and modulates cardiac function after MI, implicating ELA-2 as a key player in ACE-independent dysregulation of the RAS.

  15. EPC-derived microvesicles protect cardiomyocytes from Ang II-induced hypertrophy and apoptosis.

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    Shenhong Gu

    Full Text Available Cell-released microvesicles (MVs represent a novel way of cell-to-cell communication. Previous evidence indicates that endothelial progenitor cells (EPCs-derived MVs can modulate endothelial cell survival and proliferation. In this study, we evaluated whether EPC-MVs protect cardiomyocytes (CMs against angiotensin II (Ang II-induced hypertrophy and apoptosis. The H9c2 CMs were exposed to Ang II in the presence or absence of EPC-MVs. Cell viability, apoptosis, surface area and β-myosin heavy chain (β-MHC expression were analyzed. Meanwhile, reactive oxygen species (ROS, serine/threonine kinase (Akt, endothelial nitric oxide synthase (eNOS, and their phosphorylated proteins (p-Akt, p-eNOS were measured. Phosphatidylinositol-3-kinase (PI3K and NOS inhibitors were used for pathway verification. The role of MV-carried RNAs in mediating these effects was also explored. Results showed 1 EPC-MVs were able to protect CMs against Ang II-induced changes in cell viability, apoptosis, surface area, β-MHC expression and ROS over-production; 2 The effects were accompanied with the up-regulation of Akt/p-Akt and its downstream eNOS/p-eNOS, and were abolished by PI3K inhibition or partially blocked by NOS inhibition; 3 Depletion of RNAs from EPC-MVs partially or totally eliminated the effects of EPC-MVs. Our data indicate that EPC-MVs protect CMs from hypertrophy and apoptosis through activating the PI3K/Akt/eNOS pathway via the RNAs carried by EPC-MVs.

  16. Increased ANG II sensitivity following recovery from acute kidney injury: role of oxidant stress in skeletal muscle resistance arteries.

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    Phillips, Shane A; Pechman, Kimberly R; Leonard, Ellen C; Friedrich, Jessica L; Bian, Jing-Tan; Beal, Alisa G; Basile, David P

    2010-06-01

    Ischemia-reperfusion (I/R)-induced acute kidney injury (AKI) results in prolonged impairment of peripheral (i.e., nonrenal) vascular function since skeletal muscle resistance arteries derived from rats 5 wk post-I/R injury, show enhanced responses to ANG II stimulation but not other constrictors. Because vascular superoxide increases ANG II sensitivity, we hypothesized that peripheral responsiveness following recovery from AKI was attributable to vascular oxidant stress. Gracilis arteries (GA) isolated from post-I/R rats (approximately 5 wk recovery) showed significantly greater superoxide levels relative to sham-operated controls, as detected by dihydroeithidium, which was further augmented by acute ANG II stimulation in vitro. Hydrogen peroxide measured by dichlorofluorescein was not affected by ANG II. GA derived from postischemic animals manifested significantly greater constrictor responses in vitro to ANG II than GA from sham-operated controls. The addition of the superoxide scavenging reagent Tempol (10(-5) M) normalized the response to values similar to sham-operated controls. Apocynin (10(-6) M) and endothelial denudation nearly abrogated all ANG II-stimulated constrictor activity in GA from post-AKI rats, suggesting an important role for an endothelial-derived source of peripheral oxidative stress. Apocynin treatment in vivo abrogated GA oxidant stress and attenuated ANG II-induced pressor responses post-AKI. Interestingly, gene expression studies in GA vessels indicated a paradoxical reduction in NADPH oxidase subunit and AT(1)-receptor genes and no effect on several antioxidant genes. Taken together, this study demonstrates that AKI alters peripheral vascular responses by increasing oxidant stress, likely in the endothelium, via an undefined mechanism.

  17. Localization of the ANG II type 2 receptor in the microcirculation of skeletal muscle

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    Nora, E. H.; Munzenmaier, D. H.; Hansen-Smith, F. M.; Lombard, J. H.; Greene, A. S.; Cowley, A. W. (Principal Investigator)

    1998-01-01

    Only functional studies have suggested the presence of the ANG II type 2 (AT2) receptor in the microcirculation. To determine the distribution of this receptor in the rat skeletal muscle microcirculation, a polyclonal rabbit anti-rat antiserum was developed and used for immunohistochemistry and Western blot analysis. The antiserum was prepared against a highly specific and antigenic AT2-receptor synthetic peptide and was validated by competition and sensitivity assays. Western blot analysis demonstrated a prominent, single band at approximately 40 kDa in cremaster and soleus muscle. Immunohistochemical analysis revealed a wide distribution of AT2 receptors throughout the skeletal muscle microcirculation in large and small microvessels. Microanatomic studies displayed an endothelial localization of the AT2 receptor, whereas dual labeling with smooth muscle alpha-actin also showed colocalization of the AT2 receptor with vascular smooth muscle cells. Other cells associated with the microvessels also stained positive for AT2 receptors. Briefly, this study confirms previous functional data and localizes the AT2 receptor to the microcirculation. These studies demonstrate that the AT2 receptor is present on a variety of vascular cell types and that it is situated in a fashion that would allow it to directly oppose ANG II type 1 receptor actions.

  18. Ang II enhances noradrenaline release from sympathetic nerve endings thus contributing to the up-regulation of metalloprotease-2 in aortic dissection patients' aorta wall.

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    Zhipeng Hu

    Full Text Available OBJECT: To test the hypothesis that angiotensin II (Ang II could enhance noradrenaline (NA release from sympathetic nerve endings of the aorta thus contributing to the up-regulation of matrix metalloproteinase 2 (MMP-2 during the formation of aortic dissection (AD. METHODS: Ang II, NA, MMP-2, MMP-9 of the aorta sample obtained during operation from aortic dissection patients were detected by High Performance Liquid Chromatography and ELISA and compared with controls. Isotope labelling method was used to test the impact of exogenous Ang II and noradrenaline on the NA release and MMP-2, MMP-9 expression on Sprague Dawley (SD rat aorta rings in vitro. Two kidneys, one clip, models were replicated for further check of that impact in SD rats in vivo. RESULTS: The concentration of Ang II, MMP-2, 9 was increased and NA concentration was decreased in aorta samples from AD patients. Exogenous Ang II enhanced while exogenous NA restrained NA release from aortic sympathetic endings. The Ang II stimulated NA release and the following MMP-2 up-regulation could be weakened by Losartan and chemical sympathectomy. Beta blocker did not influence NA release but down-regulated MMP-2. Long term in vivo experiments confirmed that Ang II could enhance NA release and up-regulate MMP-2. CONCLUSIONS: AD is initiated by MMP-2 overexpression as a result of increased NA release from sympathetic nervous endings in response to Ang II. This indicates an interaction of RAS and SAS during the formation of AD.

  19. Pentosan polysulfate treatment preserves renal autoregulation in ANG II-infused hypertensive rats via normalization of P2X1 receptor activation.

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    Guan, Zhengrong; Fuller, Barry S; Yamamoto, Tatsuo; Cook, Anthony K; Pollock, Jennifer S; Inscho, Edward W

    2010-05-01

    Inflammatory factors are elevated in animal and human subjects with hypertension and renal injury. We hypothesized that inflammation contributes to hypertension-induced renal injury by impairing autoregulation and microvascular reactivity to P2X(1) receptor activation. Studies were conducted in vitro using the blood-perfused juxtamedullary nephron preparation. Rats receiving ANG II (60 ng/min) infusion were treated with the anti-inflammatory agent pentosan polysulfate (PPS) for 14 days. The magnitude and progression of hypertension were similar in ANG II and ANG II+PPS-treated rats (169 ± 5 vs. 172 ± 2 mmHg). Afferent arterioles from control rats exhibited normal autoregulatory behavior with diameter decreasing from 18.4 ± 1.6 to 11.4 ± 1.7 μm when perfusion pressure was increased from 70 to 160 mmHg. In contrast, pressure-mediated vasoconstriction was markedly attenuated in ANG II-treated rats, and diameter remained essentially unchanged over the range of perfusion pressures. However, ANG II-treated rats receiving PPS exhibited normal autoregulatory behavior compared with ANG II alone rats. Arteriolar reactivity to ATP and β,γ-methylene ATP was significantly reduced in ANG II hypertensive rats compared with controls. Interestingly, PPS treatment preserved normal reactivity to P2 and P2X(1) receptor agonists despite the persistent hypertension. The maximal vasoconstriction was 79 ± 3 and 81 ± 2% of the control diameter for ATP and β,γ-methylene ATP, respectively, similar to responses in control rats. PPS treatment significantly reduced α-smooth muscle actin staining in afferent arterioles and plasma transforming growth factor-β1 concentration in ANG II-treated rats. In conclusion, PPS normalizes autoregulation without altering ANG II-induced hypertension, suggesting that inflammatory processes reduce P2X(1) receptor reactivity and thereby impair autoregulatory behavior in ANG II hypertensive rats.

  20. Effects of Ang II receptor blocker irbesartan on adipose tissue function in mice with metabolic disorders.

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    Maeda, Akinobu; Tamura, Kouichi; Wakui, Hiromichi; Ohsawa, Masato; Azushima, Kengo; Uneda, Kazushi; Kobayashi, Ryu; Tsurumi-Ikeya, Yuko; Kanaoka, Tomohiko; Dejima, Toru; Ohki, Koji; Haku, Sona; Yamashita, Akio; Umemura, Satoshi

    2014-01-01

    Recent studies indicate that the functional renin-angiotensin system (RAS) exists in the adipose tissue. The adipose tissue RAS is proposed in the pathophysiology of metabolic disorders. In the present study, we examined therapeutic effects of irbesartan, an angiotensin II (Ang II) type 1 receptor (AT1R)-specific blocker, in genetically obese diabetic KKAy mice, a model of human metabolic disorders without any dietary loading, with our focus on the analysis on possible effect of irbesartan on the adipose tissue. The treatment with irbesartan significantly lowered systolic blood pressure with a concomitant decrease in body weight in KKAy mice. In addition, irbesartan significantly decreased the adipose leptin mRNA expression and tended to decrease IL-6 mRNA expression in the adipose tissue of KKAy mice. Furthermore irbesartan preserved the adipose gene expression of AT1R-associated protein (ATRAP), an endogenous inhibitory molecule of tissue AT1R signaling, with a concomitant tendency of up-regulation of adipose tissue ATRAP/AT1R ratio. Collectively, these results suggest that the irbesartan-induced beneficial suppressive effect on the leptin-IL-6 axis in the adipose tissue in KKAy mice is partly mediated by a trend of up-regulation of the adipose ATRAP/AT1R ratio as one of pleiotropic effects of irbesartan.

  1. Synergistic effect of high glucose and ANG II on proliferation of mouse embryonic stem cells: involvement of PKC and MAPKs as well as AT1 receptor.

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    Kim, Yun Hee; Han, Ho Jae

    2008-05-01

    This study examined the synergistic effect of high glucose levels and ANG II on proliferation and its related signal pathways using mouse embryonic stem (ES) cells. The combined use of a high glucose concentration (25 mM) and ANG II increased the level of [3H]thymidine/BrdU incorporation, and the number of cells compared with either treatment alone. Each treatment with high glucose or ANG II increased the cell population in the S phase compared with control, and the combined treatment of a high glucose concentration and ANG II significantly increased the number of cells in the S phase according to FACS analysis. Moreover, the high glucose-induced increase in [3H]thymidine incorporation was blocked by inhibiting the ANG II type 1 (AT1) receptor. The combined high glucose and ANG II significantly increased the STAT3 phosphorylation compared with high glucose or ANG II alone. ANG II stimulated the influx of Ca2+ in 25 mM glucose compared with 5 mM glucose. High glucose levels increase the level of PKC alpha, epsilon, and zeta translocation from the cytosol to the membrane fraction. In an examination of other signal pathways, the combined treatment significantly increased the level of p44/42, p38 MAPKs phosphorylation compared with either treatment alone. Indeed, the combined treatment increased the mRNA expression level of the protooncogenes and cell cycle regulatory proteins. In conclusion, the combined treatment of a high glucose concentration and ANG II had a synergistic effect in stimulating mouse ES cell proliferation through the Ca2+/PKC, MAPKs, and the AT1 receptor.

  2. Ang II-AT2R increases mesenchymal stem cell migration by signaling through the FAK and RhoA/Cdc42 pathways in vitro.

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    Xu, Xiu-Ping; He, Hong-Li; Hu, Shu-Ling; Han, Ji-Bin; Huang, Li-Li; Xu, Jing-Yuan; Xie, Jian-Feng; Liu, Ai-Ran; Yang, Yi; Qiu, Hai-Bo

    2017-07-12

    Mesenchymal stem cells (MSCs) migrate via the bloodstream to sites of injury and are possibly attracted by inflammatory factors. As a proinflammatory mediator, angiotensin II (Ang II) reportedly enhances the migration of various cell types by signaling via the Ang II receptor in vitro. However, few studies have focused on the effects of Ang II on MSC migration and the underlying mechanisms. Human bone marrow MSCs migration was measured using wound healing and Boyden chamber migration assays after treatments with different concentrations of Ang II, an AT1R antagonist (Losartan), and/or an AT2R antagonist (PD-123319). To exclude the effect of proliferation on MSC migration, we measured MSC proliferation after stimulation with the same concentration of Ang II. Additionally, we employed the focal adhesion kinase (FAK) inhibitor PF-573228, RhoA inhibitor C3 transferase, Rac1 inhibitor NSC23766, or Cdc42 inhibitor ML141 to investigate the role of cell adhesion proteins and the Rho-GTPase protein family (RhoA, Rac1, and Cdc42) in Ang II-mediated MSC migration. Cell adhesion proteins (FAK, Talin, and Vinculin) were detected by western blot analysis. The Rho-GTPase family protein activities were assessed by G-LISA and F-actin levels, which reflect actin cytoskeletal organization, were detected by using immunofluorescence. Human bone marrow MSCs constitutively expressed AT1R and AT2R. Additionally, Ang II increased MSC migration in an AT2R-dependent manner. Notably, Ang II-enhanced migration was not mediated by Ang II-mediated cell proliferation. Interestingly, Ang II-enhanced migration was mediated by FAK activation, which was critical for the formation of focal contacts, as evidenced by increased Talin and Vinculin expression. Moreover, RhoA and Cdc42 were activated by FAK to increase cytoskeletal organization, thus promoting cell contraction. Furthermore, FAK, Talin, and Vinculin activation and F-actin reorganization in response to Ang II were prevented by PD-123319 but

  3. NMNAT3 is involved in the protective effect of SIRT3 in Ang II-induced cardiac hypertrophy.

    Science.gov (United States)

    Yue, Zhongbao; Ma, Yunzi; You, Jia; Li, Zhuoming; Ding, Yanqing; He, Ping; Lu, Xia; Jiang, Jianmin; Chen, Shaorui; Liu, Peiqing

    2016-10-01

    Pathological cardiac hypertrophy is a maladaptive response in a variety of organic heart disease (OHD), which is characterized by mitochondrial dysfunction that results from disturbed energy metabolism. SIRT3, a mitochondria-localized sirtuin, regulates global mitochondrial lysine acetylation and preserves mitochondrial function. However, the mechanisms by which SIRT3 regulates cardiac hypertrophy remains to be further elucidated. In this study, we firstly demonstrated that expression of SIRT3 was decreased in Angiotension II (Ang II)-treated cardiomyocytes and in hearts of Ang II-induced cardiac hypertrophic mice. In addition, SIRT3 overexpression protected myocytes from hypertrophy, whereas SIRT3 silencing exacerbated Ang II-induced cardiomyocyte hypertrophy. In particular, SIRT3-KO mice exhibited significant cardiac hypertrophy. Mechanistically, we identified NMNAT3 (nicotinamide mononucleotide adenylyltransferase 3), the rate-limiting enzyme for mitochondrial NAD biosynthesis, as a new target and binding partner of SIRT3. Specifically, SIRT3 physically interacts with and deacetylates NMNAT3, thereby enhancing the enzyme activity of NMNAT3 and contributing to SIRT3-mediated anti-hypertrophic effects. Moreover, NMNAT3 regulates the activity of SIRT3 via synthesis of mitochondria NAD. Taken together, these findings provide mechanistic insights into the negative regulatory role of SIRT3 in cardiac hypertrophy. Copyright © 2016. Published by Elsevier Inc.

  4. ANG II promotes IGF-IIR expression and cardiomyocyte apoptosis by inhibiting HSF1 via JNK activation and SIRT1 degradation.

    Science.gov (United States)

    Huang, C-Y; Kuo, W-W; Yeh, Y-L; Ho, T-J; Lin, J-Y; Lin, D-Y; Chu, C-H; Tsai, F-J; Tsai, C-H; Huang, C-Y

    2014-08-01

    Hypertension-induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure. Our previous studies found that the activation of insulin-like growth factor receptor II (IGF-IIR) signaling was critical for hypertensive angiotensin II (ANG II)-induced cardiomyocyte apoptosis. However, the detailed mechanism by which ANG II regulates IGF-IIR in heart cells remains elusive. In this study, we found that ANG II activated its downstream kinase JNK to increase IGF-IIR expression through the ANG II receptor angiotensin type 1 receptor. JNK activation subsequently led to sirtuin 1 (SIRT1) degradation via the proteasome, thus preventing SIRT1 from deacetylating heat-shock transcription factor 1 (HSF1). The resulting increase in the acetylation of HSF1 impaired its ability to bind to the IGF-IIR promoter region (nt -748 to -585). HSF1 protected cardiomyocytes by acting as a repressor of IGF-IIR gene expression, and ANG II diminished this HSF1-mediated repression through enhanced acetylation, thus activating the IGF-IIR apoptosis pathway. Taken together, these results suggest that HSF1 represses IGF-IIR gene expression to protect cardiomyocytes. ANG II activates JNK to degrade SIRT1, resulting in HSF1 acetylation, which induces IGF-IIR expression and eventually results in cardiac hypertrophy and apoptosis. HSF1 could be a valuable target for developing treatments for cardiac diseases in hypertensive patients.

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

    Science.gov (United States)

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

    2016-03-01

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

  6. Identification of a putative nuclear localization sequence within ANG II AT(1A) receptor associated with nuclear activation.

    Science.gov (United States)

    Morinelli, Thomas A; Raymond, John R; Baldys, Aleksander; Yang, Qing; Lee, Mi-Hye; Luttrell, Louis; Ullian, Michael E

    2007-04-01

    Angiotensin II (ANG II) type 1 (AT(1)) receptors, similar to other G protein-coupled receptors, undergo desensitization and internalization, and potentially nuclear localization, subsequent to agonist interaction. Evidence suggests that the carboxy-terminal tail may be involved in receptor nuclear localization. In the present study, we examined the carboxy-terminal tail of the receptor for specific regions responsible for the nuclear translocation phenomenon and resultant nuclear activation. Human embryonic kidney cells stably expressing either a wild-type AT(1A) receptor-green fluorescent protein (AT(1A)R/GFP) construct or a site-directed mutation of a putative nuclear localization sequence (NLS) [K307Q]AT(1A)R/GFP (KQ/AT(1A)R/GFP), were examined for differences in receptor nuclear trafficking and nuclear activation. Receptor expression, intracellular signaling, and ANG II-induced internalization of the wild-type/GFP construct and of the KQ/AT(1A)R/GFP mutant was similar. Laser scanning confocal microscopy showed that in cells expressing the AT(1A)R/GFP, trafficking of the receptor to the nuclear area and colocalization with lamin B occurred within 30 min of ANG II (100 nM) stimulation, whereas the KQ/AT(1A)R/GFP mutant failed to demonstrate nuclear localization. Immunoblotting of nuclear lysates with an anti-GFP antibody confirmed these observations. Nuclear localization of the wild-type receptor correlated with increase transcription for both EGR-1 and PTGS-2 genes while the nuclear-deficient KQ/AT(1A)R/GFP mutant demonstrated increases for only the EGR-1 gene. These results suggest that a NLS (KKFKKY; aa307-312) is located within the cytoplasmic tail of the AT(1A) receptor and that nuclear localization of the receptor corresponds with specific activation of transcription for the COX-2 gene PTGS-2.

  7. The Role of the Rho/ROCK Pathway in Ang II and TGF-β1-Induced Atrial Remodeling

    Science.gov (United States)

    Lu, Gui-Hua; Xu, Cheng-Gui; Xu, Zhe; Tang, Kai; Cheng, Yun-Jiu; Gao, Xiu-Ren; Wu, Su-Hua

    2016-01-01

    Objectives To study the role of the Rho/ROCK pathway in Ang II and TGF-β1-induced atrial remodeling. Methods and Results A canine atrial fibrillation (AF) model was established by rapid atrial pacing (RAP) of the left atrium. The roles of TGF-β1, the RhoA/ROCK signaling pathway and connective tissue growth factor (CTGF) in atrial remodeling were studied via both in vitro and in vivo experiments. Each of the dogs that received RAP developed persistent AF within 4 weeks. The mRNA expression levels of TGF-β1 (1.32±0.38), Collagen-I(1.33±0.91), CTGF(5.83±3.71), RhoA(1.23±0.57) and ROCK-1 (1.02±0.27) in the left atrium were significantly increased following 4 weeks of RAP. Angiotensin II (Ang II) induced the proliferation of atrial fibroblasts and up-regulated the expression of both CTGF and ROCK-1 in a dose-dependent manner. Simvastatin and Y27632 reversed Ang II-induced CFs proliferation, as well as ROCK-1(0.89±0.05 and 1.27±0.03, respectively) and CTGF (0.87±0.04 and 0.91±0.02, respectively) expression. The expression mRNA of ROCK-1(1.74±0.13) and CTGF (2.28±0.11) can upregulated by TGF-β1, and down-regulated by Simvastatin (1.22±0.03 vs 2.27±0.11), Y27632 (1.01±0.04 vs 1.64±0.03), Los (1.04±0.11 vs 1.26±0.05), respectively. Losartan and Simvastatin attenuated the effects of TGF-β1, inhibited RhoA activity as opposed to RhoA protein expression. Y27632 had no effect on either the expression or the activity of RhoA. Conclusions The increased expression of profibrotic factors (CTGF, ROCK1 and Smad2/3) played an important role in our RAP-induced AF model. Increased atrial profibrotic factors involve the activation of either the TGF-β1/RhoA/ROCK-1 or the TGF-β1/Smad2/3 signaling pathway. PMID:27611832

  8. Krüppel-like factor (KLF) 5 mediates cyclin D1 expression and cell proliferation via interaction with c-Jun in Ang II-induced VSMCs

    OpenAIRE

    Liu, Yu; Wen, Jin-kun; Dong, Li-Hua; Zheng, Bin; Han, Mei

    2009-01-01

    Aim: To elucidate how krüppel-like factor (KLF5) activates cyclin D1 expression in Ang II-induced vascular smooth muscle cells (VSMC) proliferation. Methods: An adenoviral vector containing the full-length cDNA of KLF5 and a recombinant plasmid expressing c-Jun were constructed. MTT assay and flow cytometric analysis were used to determine the effect of Ang II on cell growth. The luciferase assay and chromatin immunoprecipitation were used to detect the relationship between KLF5 and c-Jun in ...

  9. Metformin Prevents Renal Fibrosis in Mice with Unilateral Ureteral Obstruction and Inhibits Ang II-Induced ECM Production in Renal Fibroblasts

    OpenAIRE

    Yang Shen; Naijun Miao; Jinlan Xu; Xinxin Gan; Dan Xu; Li Zhou; Hong Xue; Wei Zhang; Limin Lu

    2016-01-01

    Renal fibrosis is the final common pathway of chronic kidney disease (CKD), and no effective medication is available clinically for managing its progression. Metformin was initially developed as an anti-diabetic drug and recently gained attention for its potential in the treatment of other diseases. In this study, we investigated its effects on renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO) in vivo and in angiotensin II (Ang II)–treated renal fibroblast NRK-49F cells...

  10. The ACE-2/Ang1-7/Mas cascade enhances bone structure and metabolism following angiotensin-II type 1 receptor blockade.

    Science.gov (United States)

    Abuohashish, Hatem M; Ahmed, Mohammed M; Sabry, Dina; Khattab, Mahmoud M; Al-Rejaie, Salim S

    2017-07-15

    The renin angiotensin system (RAS) regulates numerous systemic functions and is expressed locally in skeletal tissues. Angiotensin1-7 (Ang1-7) is a beneficial member of the RAS, and the therapeutic effects of a large number of angiotensin receptors blockers (ARBs) are mediated by an Ang1-7-dependent cascade. This study examines whether the reported osteo-preservative effects of losartan are mediated through the angiotensin converting enzyme2 (ACE-2)/Ang1-7/Mas pathway in ovariectomized (OVX) rats. Sham and OVX animals received losartan (10mg/kg/d p.o.) for 6 weeks. A specific Mas receptor blocker (A-779) was delivered via mini-osmotic pumps during the losartan treatment period. Serum and urine bone metabolism biomarker levels were measured. Bone trabecular and cortical morphometry were quantified in distal femurs, whereas mineral contents were estimated in ashed bones, serum and urine. Finally, the expression of RAS components, the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) was determined. Losartan significantly improved the elevated bone metabolism marker levels and altered trabecular and cortical structures in OVX animals, and restored normal urinary and skeletal mineral levels. Mas receptor inhibition significantly abolished all osteo-protective effects of losartan and enhanced the deleterious effects of OVX. Losartan enhanced OVX-induced up-regulation of ACE-1, AngII, angiotensin type 1 (AT1) receptor and RANKL expression, and increased ACE-2, Ang1-7, Mas and OPG expression in OVX animals. However, A-779 significantly eradicated the effects of losartan on RAS components and RANKL/OPG expression. Thus, Ang1-7 are involved in the osteo-preservative effects of losartan via Mas receptor, which may add therapeutic value to this well-known antihypertensive agent. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Metformin Prevents Renal Fibrosis in Mice with Unilateral Ureteral Obstruction and Inhibits Ang II-Induced ECM Production in Renal Fibroblasts.

    Science.gov (United States)

    Shen, Yang; Miao, Naijun; Xu, Jinlan; Gan, Xinxin; Xu, Dan; Zhou, Li; Xue, Hong; Zhang, Wei; Lu, Limin

    2016-01-22

    Renal fibrosis is the final common pathway of chronic kidney disease (CKD), and no effective medication is available clinically for managing its progression. Metformin was initially developed as an anti-diabetic drug and recently gained attention for its potential in the treatment of other diseases. In this study, we investigated its effects on renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO) in vivo and in angiotensin II (Ang II)-treated renal fibroblast NRK-49F cells in vitro. Our data showed that UUO induced renal fibrosis and combined with the activation of ERK signaling, the upregulation of fibronectin, collagen I, and transforming growth factor-β (TGF-β). The administration of metformin inhibited the activation of ERK signaling and attenuated the production of extracellular matrix (ECM) proteins and collagen deposition in the obstructed kidneys. In cultured renal fibroblasts, Ang II increased the expression of fibronectin and collagen I and also activated ERK signaling and TGF-β in a time-dependent manner. Pretreatment of the cells with metformin blocked Ang II-induced ERK signaling activation and ECM overproduction. Our results show that metformin prevents renal fibrosis, possibly through the inhibition of ERK signaling, and may be a novel strategy for the treatment of renal fibrosis.

  12. Mechanisms Involving Ang II and MAPK/ERK1/2 Signaling Pathways Underlie Cardiac and Renal Alterations during Chronic Undernutrition

    OpenAIRE

    Silva, Paulo A.; Gustavo Monnerat-Cahli; Amaury Pereira-Acácio; Ricardo Luzardo; Luzia S Sampaio; Marcia A Luna-Leite; Lara, Lucienne S; Marcelo Einicker-Lamas; Rogério Panizzutti; Caroline Madeira; Vieira-Filho, Leucio D.; Carmen de Castro-Chaves; Ribeiro, Valdilene S.; Paixão, Ana D. O.; Emiliano Medei

    2014-01-01

    Background Several studies have correlated protein restriction associated with other nutritional deficiencies with the development of cardiovascular and renal diseases. The driving hypothesis for this study was that Ang II signaling pathways in the heart and kidney are affected by chronic protein, mineral and vitamin restriction. Methodology/Principal Findings Wistar rats aged 90 days were fed from weaning with either a control or a deficient diet that mimics those used in impoverished region...

  13. Angiotensin II type 1 receptor is required for the cardiac fibrosis triggered by mechanical stress independent of Ang II in mice

    Institute of Scientific and Technical Information of China (English)

    YE Yong; YUAN Jie; JIANG Guo-liang; HUANG Jia-yuan; ZHANG Wei-jing; GE Jun-bo; ZOU Yun-zeng; GONG Hui; WU Jian; DING Zhi-wen; SHEN Yi; YIN Pei-pei; WANG Xing-xu; YOU Jie-yun; WANG Shi-jun

    2016-01-01

    AIM:We investigated how AT 1-R stimulated by mechanical stresses induces cardiac fibrosis .METHODS:We produced in vivo cardiac pressure overload model in angiotensinogen knockout ( ATG-/-) mice and in vitro mechanically-stretched cell model in cultured neonatal cardiac cells of ATG-/-mice both lack the participation of Ang II .RESULTS: Pressure overload for 4 weeks in ATG-/-mice induced myocardial hypertrophy accompanied by the significant interstitial fibrosis , however , the TGF-β, a key regulatory factor of fibrosis, was not significantly increased in these ATG-/-mice.Meanwhile, the inhibitor for AT1-R significantly inhibited mechani-cal stress-induced cardiac fibrosis in these ATG-/-models whereas inhibition of TGF-βdid not.CONCLUSION:The results showed that mechanical stress-induced fibrotic responses through AT 1-R required the phosphorylation of Smad 2 but not the involvement of TGF-β.

  14. Metformin Prevents Renal Fibrosis in Mice with Unilateral Ureteral Obstruction and Inhibits Ang II-Induced ECM Production in Renal Fibroblasts

    Directory of Open Access Journals (Sweden)

    Yang Shen

    2016-01-01

    Full Text Available Renal fibrosis is the final common pathway of chronic kidney disease (CKD, and no effective medication is available clinically for managing its progression. Metformin was initially developed as an anti-diabetic drug and recently gained attention for its potential in the treatment of other diseases. In this study, we investigated its effects on renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO in vivo and in angiotensin II (Ang II–treated renal fibroblast NRK-49F cells in vitro. Our data showed that UUO induced renal fibrosis and combined with the activation of ERK signaling, the upregulation of fibronectin, collagen I, and transforming growth factor-β (TGF-β. The administration of metformin inhibited the activation of ERK signaling and attenuated the production of extracellular matrix (ECM proteins and collagen deposition in the obstructed kidneys. In cultured renal fibroblasts, Ang II increased the expression of fibronectin and collagen I and also activated ERK signaling and TGF-β in a time-dependent manner. Pretreatment of the cells with metformin blocked Ang II–induced ERK signaling activation and ECM overproduction. Our results show that metformin prevents renal fibrosis, possibly through the inhibition of ERK signaling, and may be a novel strategy for the treatment of renal fibrosis.

  15. Perinatal Na+ overload programs raised renal proximal Na+ transport and enalapril-sensitive alterations of Ang II signaling pathways during adulthood.

    Directory of Open Access Journals (Sweden)

    Edjair V Cabral

    Full Text Available BACKGROUND: High Na(+ intake is a reality in nowadays and is frequently accompanied by renal and cardiovascular alterations. In this study, renal mechanisms underlying perinatal Na(+ overload-programmed alterations in Na(+ transporters and the renin/angiotensin system (RAS were investigated, together with effects of short-term treatment with enalapril in terms of reprogramming molecular alterations in kidney. METHODOLOGY/PRINCIPAL FINDINGS: Male adult Wistar rats were obtained from dams maintained throughout pregnancy and lactation on a standard diet and drinking water (control or 0.17 M NaCl (saline group. Enalapril (100 mg/l, an angiotensin converting enzyme inhibitor, was administered for three weeks after weaning. Ninety day old offspring from dams that drank saline presented with proximal tubules exhibiting increased (Na(++K(+ATPase expression and activity. Ouabain-insensitive Na(+-ATPase activity remained unchanged but its response to angiotensin II (Ang II was lost. PKC, PKA, renal thiobarbituric acid reactive substances (TBARS, macrophage infiltration and collagen deposition markedly increased, and AT(2 receptor expression decreased while AT(1 expression was unaltered. Early treatment with enalapril reduced expression and activity of (Na(++K(+ATPase, partially recovered the response of Na(+-ATPase to Ang II, and reduced PKC and PKA activities independently of whether offspring were exposed to high perinatal Na(+ or not. In addition, treatment with enalapril per se reduced AT(2 receptor expression, and increased TBARS, macrophage infiltration and collagen deposition. The perinatally Na(+-overloaded offspring presented high numbers of Ang II-positive cortical cells, and significantly lower circulating Ang I, indicating that programming/reprogramming impacted systemic and local RAS. CONCLUSIONS/SIGNIFICANCE: Maternal Na(+ overload programmed alterations in renal Na(+ transporters and in its regulation, as well as severe structural lesions

  16. Xiaoxianggou attenuates atherosclerotic plaque formation in endogenous high Ang II ApoE(-/-) mice via the inhibition of miR-203 on the expression of Ets-2 in endothelial cells.

    Science.gov (United States)

    Nie, Wencheng; Zhang, Xiaoqun; Yan, Hui; Li, Shan; Zhu, Weiguo; Fan, Fangyan; Zhu, Jianhua

    2016-08-01

    Atherosclerosis is a chronic immune-inflammatory disorder and one of the leading causes responsible for cardiovascular morbidity and mortality. Traditional Chinese medicine treatment with multi-targets has shown prospects for the therapeutic effect on atherosclerosis. Thus, this study aims to investigate whether xiaoxianggou has benefit for reducing the atherosclerotic plaque area in endogenous high Ang II ApoE(-/-) mice and investigated the underlying mechanisms. Endogenous high Ang II ApoE(-/-) mice model was generated by using two kidney one clip (2K1C). All mice were treated by intragastric administration with xiaoxianggou two times a week for 16 weeks. En face plaque area was analyzed by oil-red O staining. Serum anti-OxLDL antibodies were measured by ELISA assay. Expression of miR-203 and Ets-2 were evaluated using qRT-RCR and western blotting analysis, respectively. This study revealed that xiaoxianggou treatment dose-dependently reduced the atherosclerotic plaque area and serum autoantibodies against oxLDL, elevated miR-203 expression and reduced Ets-2 expression in endogenous high Ang II ApoE(-/-) mice. In primary arterial ECs, Xiaoxianggou reverses the reduced miR-203 expression and the elevated Ets-2 expression induced by AngII, which was further recovered by miR-203 inhibitor. Additionally, miR-203 regulated the expression of Ets-2 by targeting Ets-2-3' UTR. Moreover, miR-203 inhibitor reversed the reduction of atherosclerotic lesion area induced by Xiaoxianggou. These findings present that xiaoxianggou plays an anti-atherosclerotic role in endogenous high Ang II ApoE(-/-) mice model, which is partly due to its antioxidant actions against atherosclerosis and the inhibition of miR-203 on the expression of Ets-2 in endothelial cells. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  17. Le corps des anges

    OpenAIRE

    Margel,Serge

    2017-01-01

    Ce séminaire fait suite à un cycle de conférences données en 2014 sur la notion de corps de chair dans le premier christianisme. Cette année la recherche a porté sur le corps spécifique des anges dans la patristique grecque et latine. Sur la base d’un corpus de textes délimité, j’ai essayé de montrer deux choses principales : d’un côté, on ne peut pas comprendre la spécificité du corps des anges sans l’inscrire dans le champ de l’angélologie chrétienne, qui assimile l’ange et l’âme, et d’un a...

  18. Morphological and Biomechanical Differences in the Elastase and AngII apoE−/− Rodent Models of Abdominal Aortic Aneurysms

    Directory of Open Access Journals (Sweden)

    Evan H. Phillips

    2015-01-01

    Full Text Available An abdominal aortic aneurysm (AAA is a potentially fatal cardiovascular disease with multifactorial development and progression. Two preclinical models of the disease (elastase perfusion and angiotensin II infusion in apolipoprotein-E-deficient animals have been developed to study the disease during its initiation and progression. To date, most studies have used ex vivo methods to examine disease characteristics such as expanded aortic diameter or analytic methods to look at circulating biomarkers. Herein, we provide evidence from in vivo ultrasound studies of the temporal changes occurring in biomechanical parameters and macromolecules of the aortic wall in each model. We present findings from 28-day studies in elastase-perfused rats and AngII apoE−/− mice. While each model develops AAAs specific to their induction method, they both share characteristics with human aneurysms, such as marked changes in vessel strain and blood flow velocity. Histology and nonlinear microscopy confirmed that both elastin and collagen, both important extracellular matrix molecules, are similarly affected in their levels and spatial distribution. Future studies could make use of the differences between these models in order to investigate mechanisms of disease progression or evaluate potential AAA treatments.

  19. Mechanisms involving Ang II and MAPK/ERK1/2 signaling pathways underlie cardiac and renal alterations during chronic undernutrition.

    Directory of Open Access Journals (Sweden)

    Paulo A Silva

    Full Text Available Several studies have correlated protein restriction associated with other nutritional deficiencies with the development of cardiovascular and renal diseases. The driving hypothesis for this study was that Ang II signaling pathways in the heart and kidney are affected by chronic protein, mineral and vitamin restriction.Wistar rats aged 90 days were fed from weaning with either a control or a deficient diet that mimics those used in impoverished regions worldwide. Such restriction simultaneously increased ouabain-insensitive Na+-ATPase and decreased (Na++K+ATPase activity in the same proportion in cardiomyocytes and proximal tubule cells. Type 1 angiotensin II receptor (AT1R was downregulated by that restriction in both organs, whereas AT2R decreased only in the kidney. The PKC/PKA ratio increased in both tissues and returned to normal values in rats receiving Losartan daily from weaning. Inhibition of the MAPK pathway restored Na+-ATPase activity in both organs. The undernourished rats presented expanded plasma volume, increased heart rate, cardiac hypertrophy, and elevated systolic pressure, which also returned to control levels with Losartan. Such restriction led to electrical cardiac remodeling represented by prolonged ventricular repolarization parameters, induced triggered activity, early after-depolarization and delayed after-depolarization, which were also prevented by Losartan.The mechanisms responsible for these alterations are underpinned by an imbalance in the PKC- and PKA-mediated pathways, with participation of angiotensin receptors and by activation of the MAPK/ERK1/2 pathway. These cellular and molecular alterations culminate in cardiac electric remodeling and in the onset of hypertension in adulthood.

  20. Mouse Sirt3 promotes autophagy in AngII-induced myocardial hypertrophy through the deacetylation of FoxO1

    Science.gov (United States)

    Li, Jingyuan; Chen, Tongshuai; Xiao, Ming; Li, Na; Wang, Shujian; Su, Hongyan; Guo, Xiaobin; Liu, Hui; Yan, Fangying; Yang, Yi; Zhang, Yun; Bu, Peili

    2016-01-01

    Sirt3, a mitochondrial NAD+-dependent histone deacetylase, is the only member proven to promote longevity in mammalian Sirtuin family. The processed short form of Sirt3 has been demonstrated to target many mediators of energy metabolism and mitochondrial stress adaptive program. Autophagy serves as a dynamic recycling mechanism and provides energy or metabolic substrates. Among the mechanisms triggered by cardiac stress, opinions vary as to whether autophagy is a protective or detrimental response. Here, by inducing the Sirt3-knockout mice to myocardial hypertrophy with chronic angiotensin II infusion for four weeks, we determined the role of Sirt3 in myocardial hypertrophy and autophagy. In this study, the Sirt3-knockout mice developed deteriorated cardiac function and impaired autophagy compared to wild-type mice. What's more, the overexpression of Sirt3 by lentivirus transfection attenuated cardiomyocytes hypertrophy by promoting autophagy. We further demonstrated that Sirt3 could bind to FoxO1 and activate its deacetylation. Sequentially, deacetylated FoxO1 translocates to the nucleus where it facilitates downstream E3 ubiquitin ligases such as Muscle RING Finger 1 (MuRF1) and muscle atrophy F-box (MAFbx, Atrogin1). Altogether, these results revealed that Sirt3 activation is essential to improve autophagy flux by reducing the acetylation modification on FoxO1, which in turn alleviates myocardial hypertrophy. PMID:27880725

  1. Enhanced expression of Ang-(1-7 during pregnancy

    Directory of Open Access Journals (Sweden)

    Brosnihan K.B.

    2004-01-01

    Full Text Available Pregnancy is a physiological condition characterized by a progressive increase of the different components of the renin-angiotensin system (RAS. The physiological consequences of the stimulated RAS in normal pregnancy are incompletely understood, and even less understood is the question of how this system may be altered and contribute to the hypertensive disorders of pregnancy. Findings from our group have provided novel insights into how the RAS may contribute to the physiological condition of pregnancy by showing that pregnancy increases the expression of both the vasodilator heptapeptide of the RAS, angiotensin-(1-7 [Ang-(1-7], and of a newly cloned angiotensin converting enzyme (ACE homolog, ACE2, that shows high catalytic efficiency for Ang II metabolism to Ang-(1-7. The discovery of ACE2 adds a new dimension to the complexity of the RAS by providing a new arm that may counter-regulate the activity of the vasoconstrictor component, while amplifying the vasodilator component. The studies reviewed in this article demonstrate that Ang-(1-7 increases in plasma and urine of normal pregnant women. In preeclamptic subjects we showed that plasma Ang-(1-7 was suppressed as compared to the levels found in normal pregnancy. In addition, kidney and urinary levels of Ang-(1-7 were increased in pregnant rats coinciding with the enhanced detection and expression of ACE2. These findings support the concept that in normal pregnancy enhanced ACE2 may counteract the elevation in tissue and circulating Ang II by increasing the rate of conversion to Ang-(1-7. These findings provide a basis for the physiological role of Ang-(1-7 and ACE2 during pregnancy.

  2. Introduction to De’ang Nationality

    Institute of Scientific and Technical Information of China (English)

    1996-01-01

    The De’ang nationality lives on the fabulous lands of southwest China. This ethnic minority has a long history, colorful culture and unique customs. They call themselves "De’ang", meaning "people with noble character on the mountains." This nationality used to be called the Benglong nationality, but in September of 1985, it acquired its present name De’ang.

  3. Angiotensin II type 1 receptor blockade restores angiotensin-(1-7)-induced coronary vasodilation in hypertrophic rat hearts.

    Science.gov (United States)

    Souza, Álvaro P S; Sobrinho, Deny B S; Almeida, Jônathas F Q; Alves, Gisele M M; Macedo, Larissa M; Porto, Juliana E; Vêncio, Eneida F; Colugnati, Diego B; Santos, Robson A S; Ferreira, Anderson J; Mendes, Elizabeth P; Castro, Carlos H

    2013-11-01

    The aim of the present study was to investigate the coronary effects of Ang-(1-7) [angiotensin-(1-7)] in hypertrophic rat hearts. Heart hypertrophy was induced by abdominal aorta CoA (coarctation). Ang-(1-7) and AVE 0991, a non-peptide Mas-receptor agonist, at picomolar concentration, induced a significant vasodilation in hearts from sham-operated rats. These effects were blocked by the Mas receptor antagonist A-779. Pre-treatment with L-NAME (N(G)-nitro-L-arginine methyl ester) or ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinozalin-1-one) [NOS (NO synthase) and soluble guanylate cyclase inhibitors respectively] also abolished the effect of Ang-(1-7) in control hearts. The coronary vasodilation produced by Ang-(1-7) and AVE 0991 was completely blunted in hypertrophic hearts. Chronic oral administration of losartan in CoA rats restored the coronary vasodilation effect of Ang-(1-7). This effect was blocked by A-779 and AT2 receptor (angiotensin II type 2 receptor) antagonist PD123319. Acute pre-incubation with losartan also restored the Ang-(1-7)-induced, but not BK (bradykinin)-induced, coronary vasodilation in hypertrophic hearts. This effect was inhibited by A-779, PD123319 and L-NAME. Chronic treatment with losartan did not change the protein expression of Mas and AT2 receptor and ACE (angiotensin-converting enzyme) and ACE2 in coronary arteries from CoA rats, but induced a slight increase in AT2 receptor in aorta of these animals. Ang-(1-7)-induced relaxation in aortas from sham-operated rats was absent in aortas from CoA rats. In vitro pre-treatment with losartan restored the Ang-(1-7)-induced relaxation in aortic rings of CoA rats, which was blocked by the Mas antagonist A-779 and L-NAME. These data demonstrate that Mas is strongly involved in coronary vasodilation and that AT1 receptor (angiotensin II type 1 receptor) blockade potentiates the vasodilatory effects of Ang-(1-7) in the coronary beds of pressure-overloaded rat hearts through NO-related AT2- and Mas

  4. Histone acetylation is essential for ANG-II-induced IGF-IIR gene expression in H9c2 cardiomyoblast cells and pathologically hypertensive rat heart.

    Science.gov (United States)

    Chu, Chun-Hsien; Lo, Jeng-Fan; Hu, Wei-Syun; Lu, Ru-Band; Chang, Mu-Hsin; Tsai, Fuu-Jen; Tsai, Chang-Hai; Weng, Yueh-Shan; Tzang, Bor-Show; Huang, Chih-Yang

    2012-01-01

    The IGF-II/mannose 6-phosphate receptor (IGF-IIR/Man-6-P) up-regulation correlates with heart disease progression and its signaling cascades directly trigger pathological cardiac hypertrophy, fibrosis, and cardiomyocytes apoptosis. IGF-IIR gene expression/ suppression is able to prevent myocardial remodeling. However, the regulating mechanisms for the IGF-IIR gene remain unclear. This study performed reverse transcriptase PCR (RT-PCR) and methylation-specific PCR (MS-PCR) to detect expression and DNA methylation of CpG islands within the IGF-IIR genomic DNA region. Our finding revealed that the IGF-IIR gene was up-regulated both in H9c2 cells treated with tumor necrosis factor-alpha (TNF-α), lipopolysaccharide (LPS), angiotensin II (ANGII) and inomycin, and age-dependently in spontaneously hypertensive rat (SHR) heart. For the DNA methylation study, although there were four CpG islands within IGF-IIR genomic regions, the DNA methylation distribution showed no change either in cells treated with ANGII or in the SHR heart. Using chemical inhibitors to individually block histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity, we found that histone acetylation was essential for ANGII-induced IGF-IIR gene expression using RT-PCR and luciferase assay. The Chromatin immuno-precipitation assay indicated that acetyl-Histone H3 and acetyl-Histone H4 associated with the IGF-IIR promoter increased in the presence of ANGII, otherwise methyl-CpG binding domain protein 2 (MeCP2) is disassociated with this. Taken together, this study demonstrates that histone acetylation plays a critical role in IGF-IIR up-regulation during pathological cardiac diseases and might provide a targeting gene in transcriptional therapies for the failing heart.

  5. Nonpeptide somatostatin analogs: recent advances in its application and research

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Along with its wide anatomical distribution, somatostatin (SST) acts on multiple targets via a family of 5 receptors to produce a broad spectrum of biological effects. Therefore, a variety of peptide analogs have been produced and are widely used in clinical treatment. However, because of their flaws in the structure of peptide, the clinical efficacy is limited. In this review, we summarize the structure, pharmacological effects and the potential clinical value of non-peptide SST analogs. We focus on the research and development of non-peptide SST analogs since 1998, and discuss the problems and potential prospects for non-peptide SST analogs. We believe that as more non-peptide somatostatin analogs are successfully developed, the extensive clinical application of SSTs will contribute a great deal to medical science.

  6. Downregulation of the ACE2/Ang-(1-7)/Mas axis in transgenic mice overexpressing GH.

    Science.gov (United States)

    Muñoz, Marina C; Burghi, Valeria; Miquet, Johanna G; Giani, Jorge F; Banegas, Ricardo D; Toblli, Jorge E; Fang, Yimin; Wang, Feiya; Bartke, Andrzej; Dominici, Fernando P

    2014-05-01

    The renin-angiotensin system (RAS) plays a crucial role in the regulation of physiological homeostasis and diseases such as hypertension, coronary artery disease, and chronic renal failure. In this cascade, the angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/AT1 receptor axis induces pathological effects, such as vasoconstriction, cell proliferation, and fibrosis, while the ACE2/Ang-(1-7)/Mas receptor axis is protective for end-organ damage. The altered function of the RAS could be a contributing factor to the cardiac and renal alterations induced by GH excess. To further explore this issue, we evaluated the consequences of chronic GH exposure on the in vivo levels of Ang II, Ang-(1-7), ACE, ACE2, and Mas receptor in the heart and the kidney of GH-transgenic mice (bovine GH (bGH) mice). At the age of 7-8 months, female bGH mice displayed increased systolic blood pressure (SBP), a high degree of both cardiac and renal fibrosis, as well as increased levels of markers of tubular and glomerular damage. Angiotensinogen abundance was increased in the liver and the heart of bGH mice, along with a concomitant increase in cardiac Ang II levels. Importantly, the levels of ACE2, Ang-(1-7), and Mas receptor were markedly decreased in both tissues. In addition, Ang-(1-7) administration reduced SBP to control values in GH-transgenic mice, indicating that the ACE2/Ang-(1-7)/Mas axis is involved in GH-mediated hypertension. The data indicate that the altered expression profile of the ACE2/Ang-(1-7)/Mas axis in the heart and the kidney of bGH mice could contribute to the increased incidence of hypertension, cardiovascular, and renal alterations observed in these animals.

  7. ACE2/Ang-(1-7)/Mas axis stimulates vascular repair-relevant functions of CD34+ cells.

    Science.gov (United States)

    Singh, Neha; Joshi, Shrinidh; Guo, Lirong; Baker, Matthew B; Li, Yan; Castellano, Ronald K; Raizada, Mohan K; Jarajapu, Yagna P R

    2015-11-15

    CD34(+) stem/progenitor cells have been identified as a promising cell population for the autologous cell-based therapies in patients with cardiovascular disease. The counter-regulatory axes of renin angiotensin system, angiotensin converting enzyme (ACE)/Ang II/angiotensin type 1 (AT1) receptor and ACE2/Ang-(1-7)/Mas receptor, play an important role in the cardiovascular repair. This study evaluated the expression and vascular repair-relevant functions of these two pathways in human CD34(+) cells. CD34(+) cells were isolated from peripheral blood mononuclear cells (MNCs), obtained from healthy volunteers. Expression of ACE, ACE2, AT1, and angiotensin type 2 and Mas receptors were determined. Effects of Ang II, Ang-(1-7), Norleu(3)-Ang-(1-7), and ACE2 activators, xanthenone (XNT) and diminazene aceturate (DIZE) on proliferation, migration, and adhesion of CD34(+) cells were evaluated. ACE2 and Mas were relatively highly expressed in CD34(+) cells compared with MNCs. Ang-(1-7) or its analog, Norleu(3)-Ang-(1-7), stimulated proliferation of CD34(+) cells that was associated with decrease in phosphatase and tensin homologue deleted on chromosome 10 levels and was inhibited by triciribin, an AKT inhibitor. Migration of CD34(+) cells was enhanced by Ang-(1-7) or Norleu(3)-Ang-(1-7) that was decreased by a Rho-kinase inhibitor, Y-27632. In the presence of Ang II, XNT or DIZE enhanced proliferation and migration that were blocked by DX-600, an ACE2 inhibitor. Treatment of MNCs with Ang II, before the isolation of CD34(+) cells, attenuated the proliferation and migration to stromal derived factor-1α. This attenuation was reversed by apocynin, an NADPH oxidase inhibitor. Adhesion of MNCs or CD34(+) cells to fibronectin was enhanced by Ang II and was unaffected by Ang-(1-7). This study suggests that ACE2/Ang-(1-7)/Mas pathway stimulates functions of CD34(+) cells that are cardiovascular protective, whereas Ang II attenuates these functions by acting on MNCs. These findings

  8. Aris Angelis (1954-2003)

    CERN Multimedia

    2003-01-01

    The value of a person is recognized more by what he leaves behind. Aris Angelis has left a plethora of people: teachers, friends, colleagues, associates, acquaintances, all of whom were shocked and devastated by his untimely and "unjust" departure. Some thought of him as their "mentor" during their crucial and difficult first steps in science... Some others as the ever-giving friend, who put the "common good" in front of himself... Others feel an "unpaid debt" to him, who left so soon and so unexpected... Some feel an enormous loss and a huge vacuum left behind where he was... Others had looked forward to working with him in his new scientific environment... But, ALL of us shall remember Aris with love and joy for what he was and what he has given and left to us. Apostolos D. Panagiotou (Teacher, colleague & friend) Aris was very sensitive to the need for science communication. A CERN guide since 1999, he took part in all special events, such as open days and the Oracle de Delphi, always with the same ...

  9. Ang Demokratikong Sistema at ang mga Modelo ng Pamumuno sa Pilipinas

    Directory of Open Access Journals (Sweden)

    F. P. A. Demeterio

    2010-06-01

    Full Text Available Maraming paraan ang pagsusuri sa problema ng pulitika sa Pilipinas.Para sa mga moralista at ideyalista, halimbawa, maaari itong tingnangamit ang perspektibo ng sistema ng pagpapahalaga (values at moralidad; para sa mga materyalista naman, maaari din itong himayin gamit ang perspektibo ng pagka-di-pantay-pantay ng kayamanan at kapangyarihan(unequal wealth and power ng ating mga mamamayan; o hindi kaya para sa mga eksperto sa sistema at istraktura, maaari din itong dalumatin gamit ang perspektibo ng ating marupok na burukrasya. Susubukan ng papel na ito na pag-aralan ang paksa sa pamamagitan ng pagsusuri sa konsepto ng pamumuno na hinihiling ng ating demokratikong sistema at sa kaparehong konseptong umiiiral naman sa kamalayan ng ating mga kababayan. Gagamitin ng pagsusuring ito, bilang teoretikal na balangkas, ang isang uri ng antropolohikalna teorya at pamamaraan na kilala bilang “kognitibong antropolohiya”(cognitive anthropology.

  10. Non-peptide metabolites from the genus Bacillus.

    Science.gov (United States)

    Hamdache, Ahlem; Lamarti, Ahmed; Aleu, Josefina; Collado, Isidro G

    2011-04-25

    Bacillus species produce a number of non-peptide metabolites that display a broad spectrum of activity and structurally diverse bioactive chemical structures. Biosynthetic, biological, and structural studies of these metabolites isolated from Bacillus species are reviewed. This contribution also includes a detailed study of the activity of the metabolites described, especially their role in biological control mechanisms.

  11. 靶向Ang2的RNAi慢病毒载体的构建及其对恶性黑色素瘤细胞中Ang2基因表达的影响%Construction of Recombinant Lentiviral Vector of siRNA for Ang2 and the Effect of the Expression of Ang2 Gene in Malignant Melanoma Cells

    Institute of Scientific and Technical Information of China (English)

    刘照亮; 王彪; 郭国祥; 单秀英; 王美水; 庄福连; 蔡传书; 张明凤; 张彦定

    2011-01-01

    目的 构建携带促血管生成素2-小干扰RNA(Ang2-siRNA)慢病毒载体,观察其对恶性黑色素瘤细胞中Ang2基因表达的干扰作用.方法 将经XbaⅠ酶切电泳鉴定的带有加强绿色荧光蛋白的转移质粒(pNL-EGFP)载体与pSilencer 1.0-U6启动子-促血管生成素2-小干扰RNA(pSilencer 1.0-U6-Ang2-siRNA)重组质粒连接,产生加强绿色荧光蛋白的转移质粒-U6启动子-促血管生成素2-Ⅰ(pNL-EGFP-U6-Ang2-Ⅰ)、加强绿色荧光蛋白的转移质粒-U6启动子-促血管生成素2-Ⅱ(pNL-EGFP-U6-Ang2-Ⅱ)慢病毒转移质粒,电泳筛选阳性克隆,测序鉴定.用连接成功的慢病毒转移质粒、水疱性口炎病毒G蛋白(pVSVG)包膜质粒和pHelper包装质粒共转染293T细胞,产生pNL-EGFP-U6-Ang2-Ⅰ、pNL-EGFP-U6-Ang2-Ⅱ慢病毒.收集病毒上清,测定病毒滴度.将收集的病毒上清感染恶性黑色素瘤细胞,通过实时荧光定量RT-PCR测定抑制Ang2基因表达的效率.结果 酶切电泳与测序鉴定证实成功构建了Ang2-SiRNA慢病毒载体,293T细胞测定病毒原液滴度为8.0×103/ml.实时荧光定量RT-PCR结果显示:Ang2-siRNA慢病毒载体感染恶性黑色素瘤细胞,抑制了恶性黑色素瘤细胞中Ang2基因的表达(P<0.05).结论 成功构建了Ang2-SiRNA慢病毒载体,体外研究显示Ang2-SiRNA慢病毒载体能抑制恶性黑色素瘤细胞中Ang2 mRNA的表达,为下一步进行裸鼠恶性黑色素瘤移植瘤生长的干预实验奠定基础,为肿瘤的基因治疗提供实验依据.%Objective To construct lentivectors carrying Ang2-small interfering RNA ( siR-NA ), which was used to inhibit Ang2 expression in malignant melanoma cells. Methods Plasmid pNL-EGFP and recombinant plasmid pSilencer 1. 0-U6-Ang2-siRNA were digested with Xbal and li-gated into a target lentiviral transfer plasmid of pNL-EGFP-U6-Ang2- I or pNL-EGFP-U6-Ang2- Ⅱ . Plasmids pNL-EGFP-U6-Ang2- I and pNL-EGFP-U6-Ang2- II were constructed successfully. Lentiviral

  12. Protective role of ACE2-Ang-(1-7)-Mas in myocardial fibrosis by downregulating KCa3.1 channel via ERK1/2 pathway.

    Science.gov (United States)

    Wang, Li-Ping; Fan, Su-Jing; Li, Shu-Min; Wang, Xiao-Jun; Gao, Jun-Ling; Yang, Xiu-Hong

    2016-11-01

    The intermediate-conductance Ca(2+)-activated K(+) (KCa3.1) channel plays a vital role in myocardial fibrosis induced by angiotensin (Ang) II. However, as the antagonists of Ang II, the effect of angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas axis on KCa3.1 channel during myocardial fibrosis remains unknown. This study was designed to explore the function of KCa3.1 channel in the cardioprotective role of ACE2-Ang-(1-7)-Mas. Wild-type (WT) mice, hACE2 transgenic mice (Tg), and ACE2 deficiency mice (ACE2(-/-)) were administrated with Ang II by osmotic mini-pumps. As the activator of ACE2, diminazene aceturate (DIZE) inhibited increase of blood pressure, collagen deposition, and KCa3.1 protein expression in myocardium of WT mice induced by Ang II. In Tg and ACE2(-/-) mice, besides the elevation of blood pressure, Ang II induced transformation of cardiac fibroblast into myofibroblast and resulted in augmentation of hydroxyproline concentration and collagen deposition, as well as KCa3.1 protein expression, but the changes in ACE2(-/-) mice were more obvious than those in Tg mice. Mas antagonist A779 reduced blood pressure, myocardium fibrosis, and myocardium KCa3.1 protein expression by Ang II in Tg mice, but activation of KCa3.1 with SKA-31 in Tg mice promoted the pro-fibrogenic effects of Ang II. Respectively, in ACE2(-/-) mice, TRAM-34, the KCa3.1 blocker, and Ang-(1-7) inhibited increase of blood pressure, collagen deposition, and KCa3.1 protein expression by Ang II. Moreover, DIZE and Ang-(1-7) depressed p-ERK1/2/t-ERK increases by Ang II in WT mice, and after blockage of ERK1/2 pathway with PD98059, the KCa3.1 protein expression was reduced in WT mice. In conclusion, the present study demonstrates that ACE2-Ang-(1-7)-Mas protects the myocardium from hypertension-induced injury, which is related to its inhibiting effect on KCa3.1 channels through ERK1/2 pathway. Our results reveal that KCa3.1 channel is likely to be a critical target on the ACE2-Ang

  13. Role of angiotensin II and vasopressin receptors within the supraoptic nucleus in water and sodium intake induced by the injection of angiotensin II into the medial septal area

    Directory of Open Access Journals (Sweden)

    Antunes V.R.

    1998-01-01

    Full Text Available In this study we investigated the effects of the injection into the supraoptic nucleus (SON of non-peptide AT1- and AT2-angiotensin II (ANG II receptor antagonists, DuP753 and PD123319, as well as of the arginine-vasopressin (AVP receptor antagonist d(CH25-Tyr(Me-AVP, on water and 3% NaCl intake induced by the injection of ANG II into the medial septal area (MSA. The effects on water or 3% NaCl intake were assessed in 30-h water-deprived or in 20-h water-deprived furosemide-treated adult male rats, respectively. The drugs were injected in 0.5 ml over 30-60 s. Controls were injected with a similar volume of 0.15 M NaCl. Antagonists were injected at doses of 20, 80 and 180 nmol. Water and sodium intake was measured over a 2-h period. Previous administration of the AT1 receptor antagonist DuP753 into the SON decreased water (65%, N = 10, P<0.01 and sodium intake (81%, N = 8, P<0.01 induced by the injection of ANG II (10 nmol into the MSA. Neither of these responses was significantly changed by injection of the AT2-receptor antagonist PD123319 into the SON. On the other hand, while there was a decrease in water intake (45%, N = 9, P<0.01, ANG II-induced sodium intake was significantly increased (70%, N = 8, P<0.01 following injection of the V1-type vasopressin antagonist d(CH25-Tyr(Me-AVP into the SON. These results suggest that both AT1 and V1 receptors within the SON may be involved in water and sodium intake induced by the activation of ANG II receptors within the MSA. Furthermore, they do not support the involvement of MSA AT2 receptors in the mediation of these responses.

  14. Quem tem medo da angústia?

    Directory of Open Access Journals (Sweden)

    Vera Lopes Besset

    Full Text Available Este texto insere-se na discussão atual no Grupo de Trabalho “Psicopatologia e Psicanálise”, da Anpepp, sobre o tema da angústia. Nesse sentido, traz a questão da evitação da angústia no contemporâneo, sobretudo a que se observa entre os próprios psicanalistas, às vezes muito ávidos das soluções oferecidas por uma psiquiatria atual ancorada nos novos e eficazes medicamentos.

  15. Angiotensin II, a neuropeptide at the frontier between endocrinology and neuroscience: Is there a link between the angiotensin II type 2 receptor (AT2R and Alzheimer’s disease?

    Directory of Open Access Journals (Sweden)

    Nicole eGallo-Payet

    2011-08-01

    Full Text Available Amyloid-β peptide deposition, abnormal hyperphosphorylation of tau, as well as inflammation and vascular damage, are associated with the development of Alzheimer’s disease. Angiotensin II (Ang II is a peripheral hormone, as well as a neuropeptide, which binds two major receptors, namely the Ang II type-1 receptor (AT1R and the type-2 receptor (AT2R. Activation of the AT2R counteracts most of the AT1R-mediated actions, promoting vasodilation, decreasing the expression of pro-inflammatory cytokines, both in the brain and in the cardiovascular system. There is evidence that treatment with AT1R blockers (ARBs attenuates learning and memory deficits. Studies suggest that the therapeutic effects of ARBs may reflect this unopposed activation of the AT2R in addition to the inhibition of the AT1R. Within the context of Alzheimer’s disease (AD, modulation of AT2R signaling could improve cognitive performance not only through its action on blood flow/brain microcirculation but also through more specific effects on neurons. This review summarizes the current state of knowledge and potential therapeutic relevance of central actions of this enigmatic receptor. In particular, we highlight the possibility that selective AT2R activation by nonpeptide and highly selective agonists, acting on neuronal plasticity, could represent new pharmacological tools that may help improve impaired cognitive performance in Alzheimer’s disease and other neurological cognitive disorders.

  16. Angiotensin II clamp prevents the second step in renal apical NHE3 internalization during acute hypertension

    DEFF Research Database (Denmark)

    Leong, Patrick K K; Yang, Li E; McDonough, Alicia A

    2002-01-01

    . Plasma ANG II concentration of anesthesized Sprague-Dawley rats was clamped by simultaneous infusion of the ANG I-converting enzyme inhibitor captopril (12 microg/min) and ANG II (20 ng. kg(-1). min(-1)). Blood pressure was increased 50 mmHg for 20 min by arterial constriction +/- ANG II clamp or by sham...

  17. Women of De’ang Nationality

    Institute of Scientific and Technical Information of China (English)

    1996-01-01

    Older De’ang women in Yunnan retain some traditional customs, They still live in bamboo houses. They shave off their hair and wrap their heads with black cloth; chew the leaves of the betel tree, and wear rings made of rattan or thin bamboo strips.

  18. Molecular interaction of a potent nonpeptide agonist with the chemokine receptor CCR8

    DEFF Research Database (Denmark)

    Jensen, Pia C; Nygaard, Rie; Thiele, Stefanie;

    2007-01-01

    Most nonpeptide antagonists for CC-chemokine receptors share a common pharmacophore with a centrally located, positively charged amine that interacts with the highly conserved glutamic acid (Glu) located in position 6 of transmembrane helix VII (VII:06). We present a novel CCR8 nonpeptide agonist...

  19. Captopril improves postresuscitation hemodynamics protective against pulmonary embolism by activating the ACE2/Ang-(1-7)/Mas axis.

    Science.gov (United States)

    Xiao, Hong-Li; Li, Chun-Sheng; Zhao, Lian-Xing; Yang, Jun; Tong, Nan; An, Le; Liu, Qi-Tong

    2016-11-01

    Acute pulmonary embolism (APE) has a very high mortality rate, especially at cardiac arrest and even after the return of spontaneous circulation (ROSC). This study investigated the protective effect of the angiotensin-converting enzyme (ACE) inhibitor captopril on postresuscitation hemodynamics, in a porcine model of cardiac arrest established by APE. Twenty-nine Beijing Landrace pigs were infused with an autologous thrombus leading to cardiac arrest and subjected to standard cardiopulmonary resuscitation and thrombolysis. Ten resuscitated pigs were randomly and equally apportioned to receive either captopril (22.22 mg/kg) infusion or the same volume saline, 30 min after ROSC. Hemodynamic changes and ACE-Ang II-angiotensin II type 1 receptor (AT1R) and ACE2/Ang-(1-7)/Mas receptor axis levels were determined. APE was associated with a decline in mean arterial pressure and a dramatic increase in pulmonary artery pressure and mean right ventricular pressure. After ROSC, captopril infusion was associated with significantly lower mean right ventricular pressure and systemic and pulmonary vascular resistance, faster heart rate, and higher Ang-(1-7) levels, ACE2/ACE, and Ang-(1-7)/Ang II, compared with the saline infusion. The ACE2/Ang-(1-7)/Mas pathway correlated negatively with external vascular lung water and pulmonary vascular permeability and positively with the right cardiac index. In conclusion, in a pig model of APE leading to cardiac arrest, captopril infusion was associated with less mean right ventricular pressure overload after resuscitation, compared with saline infusion. The reduction in systemic and pulmonary vascular resistance associated with captopril may be by inhibiting the ACE-Ang II-AT1R axis and activating the ACE2/Ang-(1-7)/Mas axis.

  20. ACE-2/Ang1-7/Mas cascade mediates ACE inhibitor, captopril, protective effects in estrogen-deficient osteoporotic rats.

    Science.gov (United States)

    Abuohashish, Hatem M; Ahmed, Mohammed M; Sabry, Dina; Khattab, Mahmoud M; Al-Rejaie, Salim S

    2017-08-01

    The local role of the renin angiotensin system (RAS) was documented recently beside its conventional systemic functions. Studies showed that the effector angiotensin II (AngII) alters bone health, while inhibition of the angiotensin converting enzyme (ACE-1) preserved these effects. The newly identified Ang1-7 exerts numerous beneficial effects opposing the AngII. Thus, the current study examines the role of Ang1-7 in mediating the osteo-preservative effects of ACEI (captopril) through the G-protein coupled Mas receptor using an ovariectomized (OVX) rat model of osteoporosis. 8 weeks after the surgical procedures, captopril was administered orally (40mgkg(-1) d(-1)), while the specific Mas receptor blocker (A-779) was delivered at infusion rate of 400ngkg(-1)min(-1) for 6 weeks. Bone metabolic markers were measured in serum and urine. Minerals concentrations were quantified in serum, urine and femoral bones by inductive coupled plasma mass spectroscopy (ICP-MS). Trabecular and cortical morphometry was analyzed in the right distal femurs using micro-CT. Finally, the expressions of RAS peptides, enzymes and receptors along with the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) were determined femurs heads. OVX animals markedly showed altered bone metabolism and mineralization along with disturbed bone micro-structure. Captopril significantly restored the metabolic bone bio-markers and corrected Ca(2+) and P values in urine and bones of estrogen deficient rats. Moreover, the trabecular and cortical morphometric features were repaired by captopril in OVX groups. Captopril also improved the expressions of ACE-2, Ang1-7, Mas and OPG, while abolished OVX-induced up-regulation of ACE-1, AngII, Ang type 1 receptor (AT1R) and RANKL. Inhibition of Ang1-7 cascade by A-779 significantly eradicated captopril protective effects on bone metabolism, mineralization and micro-structure. A-779 also restored OVX effects on RANKL expression and ACE-1/AngII/AT1R

  1. Molecular and cellular mechanisms of the inhibitory effects of ACE-2/ANG1-7/Mas axis on lung injury.

    Science.gov (United States)

    Gopallawa, Indiwari; Uhal, Bruce D

    2014-01-01

    An established body of recent literature has demonstrated potent inhibitory effects of the angiotensin converting enzyme-2 (ACE-2)/ANG1-7/ Mas axis on acute lung injury and lung fibrogenesis. One of the mechanisms of this inhibition is the enzymatic action of ACE-2 to degrade its main substrate angiotensin (ANG) II, thereby reducing the injurious and profibrotic activities of this octapeptide. Another, potentially more important mechanism is the production by ACE-2 of the heptapeptide ANG1-7, which inhibits the actions of ANGII through its own receptor Mas, the product of the oncogene of the same name. Very recent efforts to define the molecular and cellular mechanisms of ANG1-7/Mas action have revealed a number of similar, but mechanistically distinct, pathways by which ANG1-7 and Mas act on various lung cell types to inhibit lung injury and fibrosis. In this review we summarize the beneficial actions of the ANG1-7/Mas pathway, specifically on lung cells in non-neoplastic lung injury. We also review the currently known downstream signaling mechanisms of the ANG1-7/Mas pathway in various lung cell types known to be key in acute injury and fibrogenesis.

  2. Protective Role of the ACE2/Ang-(1–9 Axis in Cardiovascular Remodeling

    Directory of Open Access Journals (Sweden)

    María Paz Ocaranza

    2012-01-01

    Full Text Available Despite reduction in cardiovascular (CV events and end-organ damage with the current pharmacologic strategies, CV disease remains the primary cause of death in the world. Pharmacological therapies based on the renin angiotensin system (RAS blockade are used extensively for the treatment of hypertension, heart failure, and CV remodeling but in spite of their success the prevalence of end-organ damage and residual risk remain still high. Novel approaches must be discovered for a more effective treatment of residual CV remodeling and risk. The ACE2/Ang-(1–9 axis is a new and important target to counterbalance the vasoconstrictive/proliferative RAS axis. Ang-(1–9 is hydrolyzed slower than Ang-(1–7 and is able to bind the Ang II type 2 receptor. We review here the current experimental evidence suggesting that activation of the ACE2/Ang-(1–9 axis protects the heart and vessels (and possibly the kidney from adverse cardiovascular remodeling in hypertension as well as in heart failure.

  3. [Non-peptide furin inhibitors based on amidinohydrazones of diarylaldehydes].

    Science.gov (United States)

    Kibirev, V K; Osadchuk, T V; Kozachenko, A P; Vadziuk, O B; Brovarets, V S

    2013-01-01

    A series of novel non-peptidic furin inhibitors containing amidinohydrazone moieties has been synthesized under interaction of dialdehydes, the derivatives of ethylene diethylvanillin ethers, with aminoguanidine bicarbonate. Two aryl cycles were bridged by 1,2-ethylene-, 1,4-buthylene- or 1,4-dimethylenebenzene-group. The compounds have been found to inhibit furin. The antifurin activity was shown to grow with the increase of the length and/or hydrophobicity of the bridge. The most potent compound, containing in the bridge the lypophylic benzene cycle was found to inhibit the activity of furin with Ki = 0.51 microM.

  4. AnGeLi: A Tool for the Analysis of Gene Lists from Fission Yeast

    Directory of Open Access Journals (Sweden)

    Danny A Bitton

    2015-11-01

    Full Text Available Genome-wide assays and screens typically result in large lists of genes or proteins. Enrichments of functional or other biological properties within such lists can provide valuable insights and testable hypotheses. To systematically detect these enrichments can be challenging and time-consuming, because relevant data to compare against query gene lists are spread over many different sources. We have developed AnGeLi (Analysis of Gene Lists, an intuitive, integrated web-tool for comprehensive and customized interrogation of gene lists from the fission yeast, Schizosaccharomyces pombe. AnGeLi searches for significant enrichments among multiple qualitative and quantitative information sources, including gene and phenotype ontologies, genetic and protein interactions, numerous features of genes, transcripts, translation, and proteins such as copy numbers, chromosomal positions, genetic diversity, RNA polymerase II and ribosome occupancy, localization, conservation, half-lives, domains and molecular weight among others, as well as diverse sets of genes that are co-regulated or lead to the same phenotypes when mutated. AnGeLi uses robust statistics which can be tailored to specific needs. It also provides the option to upload user-defined gene sets to compare against the query list. Through an integrated data submission form, AnGeLi encourages the community to contribute additional curated gene lists to further increase the usefulness of this resource and to get the most from the ever increasing large-scale experiments. AnGeLi offers a rigorous yet flexible statistical analysis platform for rich insights into functional enrichments and biological context for query gene lists, thus providing a powerful exploratory tool through which S. pombe researchers can uncover fresh perspectives and unexpected connections from genomic data. AnGeLi is freely available at: www.bahlerlab.info/AnGeLi

  5. Research on the relationship between Ang Ⅱ/Ang-( 1-7 )/Mas and cerebro-cardiac syndrome%AngⅡ/Ang-(1-7)/Mas系统通路与脑心综合征关系的实验研究

    Institute of Scientific and Technical Information of China (English)

    王娜; 夏青; 赵剑; 王玲

    2012-01-01

    then each group was devided into two subgroups: 4 hour and 24 hour(n =8). The cerebral ischemia model was induced by processed thread inside the right middle cerebral artery,the ECG was moniterd simultaneously. The brain slices were stained with TTC to clarify the success of model creation.The contents of Ang II of the myocardial tissues and plasma were detected by chemical luminescence. The contents of Ang-( 1-7) of the myocardial tissues and plasma were detected by ELISA. The extent of myocardial damage was detected by HE. Results The model group showed severe myocardial injury. In losartan group,myocardial injury was reduced. Myocardial in jury in losartan + A779 group was heavier than that in losartan group. HE results of each 24 hour group of myocardial was heavier than that in each 4 hour group. Compared with the blank control group,the content of Ang II in plasma of the model group was increased ( P < 0. 01). Compared with the model group,Ang II of the lostam group was increased (P < 0. 01). Ang II of lostarn + A779 -group was lower than that of lostarn group ( P < 0. 01 ). Compared with the blank control group,the content of Ang-(1-7) in plasma in the model group was decreased(P <0. 01) ; Ang-( 1-7) of lostarn group was higher than that of the model control group (P < 0.01) ; Ang-( 1-7 ) of lastam + A779 group was lower than that of the model group and the lostarn group (P < 0. 01). The content of Ang II and Ang-( 1 -7 ) of each 24 hour group in plasma was increased accordingly with the extension of time respectively ( P < 0. 01 ). The changes of Angll and Ang-( 1-7) of each group in myocardial tissues were consistent with that of plasma. Conclusion Ang-(l-7) gets involved in the development of cerebro-cardial syndrome by Mas receptor,and plays a role in protection of the myocardial injury induced by cerebral infarction.

  6. Evidence for extracellular, but not intracellular, generation of angiotensin II in the rat adrenal zona glomerulosa

    Energy Technology Data Exchange (ETDEWEB)

    Urata, H.; Khosla, M.C.; Bumpus, M.; Husain, A. (Research Institute of the Cleveland Clinic Foundation, OH (USA))

    1988-11-01

    Based on the observation that high levels of renin and angiotensin II (Ang II) are found in the adrenal zona glomerulosa (ZG), it has been postulated that Ang II is formed intracellularly by the renin-converting enzyme cascade in this tissue. To test this hypothesis, the authors examined renin-angiotensin system components in subcellular fractions of the rat adrenal ZG. Renin activity and immunoreactive-Ang II (IR-Ang II) were observed in vesicular fractions but were not colocalized. In addition, angiotensinogen, angiotensin I, and converting enzyme were not observed in the renin or IR-Ang II-containing vesicular fractions. These data do not support the hypothesis that Ang II is formed intracellularly within the renin-containing vesicles of the ZG. Rather, since modulatable renin release from adrenal ZG slices was observed and renin activity was found in dense vesicular fractions (33-39% sucrose), it is likely that Ang II formation in the ZG is extracellular and initiated by the release of vesicular renin. In ZG lysomal fractions {sup 125}I-labeled Ang II was degraded to {sup 125}I-labeled des-(Phe{sup 8})Ang II. Since Ang II antibodies do not recognize des-(Phe{sup 8})Ang II, these finding explain why IR-Ang II in the ZG is due predominantly to Ang II and not to its C-terminal immunoreactive fragments.

  7. Angiotensin metabolism in renal proximal tubules, urine, and serum of sheep: evidence for ACE2-dependent processing of angiotensin II.

    Science.gov (United States)

    Shaltout, Hossam A; Westwood, Brian M; Averill, David B; Ferrario, Carlos M; Figueroa, Jorge P; Diz, Debra I; Rose, James C; Chappell, Mark C

    2007-01-01

    Despite the evidence that angiotensin-converting enzyme (ACE)2 is a component of the renin-angiotensin system (RAS), the influence of ACE2 on angiotensin metabolism within the kidney is not well known, particularly in experimental models other than rats or mice. Therefore, we investigated the metabolism of the angiotensins in isolated proximal tubules, urine, and serum from sheep. Radiolabeled [(125)I]ANG I was hydrolyzed primarily to ANG II and ANG-(1-7) by ACE and neprilysin, respectively, in sheep proximal tubules. The ACE2 product ANG-(1-9) from ANG I was not detected in the absence or presence of ACE and neprilysin inhibition. In contrast, the proximal tubules contained robust ACE2 activity that converted ANG II to ANG-(1-7). Immunoblots utilizing an NH(2) terminal-directed ACE2 antibody revealed a single 120-kDa band in proximal tubule membranes. ANG-(1-7) was not a stable product in the tubule preparation and was rapidly hydrolyzed to ANG-(1-5) and ANG-(1-4) by ACE and neprilysin, respectively. Comparison of activities in the proximal tubules with nonsaturating concentrations of substrate revealed equivalent activities for ACE (ANG I to ANG II: 248 +/- 17 fmol x mg(-1) x min(-1)) and ACE2 [ANG II to ANG-(1-7): 253 +/- 11 fmol x mg(-1) x min(-1)], but lower neprilysin activity [ANG II to ANG-(1-4): 119 +/- 24 fmol x mg(-1) x min(-1); P < 0.05 vs. ACE or ACE2]. Urinary metabolism of ANG I and ANG II was similar to the proximal tubules; soluble ACE2 activity was also detectable in sheep serum. In conclusion, sheep tissues contain abundant ACE2 activity that converts ANG II to ANG-(1-7) but does not participate in the processing of ANG I into ANG-(1-9).

  8. Kierkegaard, a Escola da Angústia e a Psicoterapia

    OpenAIRE

    Ana Maria Lopez Calvo de Feijoo; Myriam Moreira Protasio; Débora Gill; Luiz José Veríssimo

    2015-01-01

    Este artigo busca refletir sobre a relação estabelecida por Soren Kierkegaard, na voz do pseudônimo Vigilius Haufniensis, entre angústia e Psicologia. A Psicologia surge, nesse contexto, como a ciência cuja atmosfera é angústia. Primeiramente, são apresentadas as considerações de Haufniensis sobre a angústia como determinação existencial. Em seguida, exemplificam-se as formas particulares de expressão da angústia por meio de um conto de Grimm, intitulado João sem medo. Observa-se que é da ten...

  9. Angiotensin-(1-7) regulates Angiotensin II-induced VCAM-1 expression on vascular endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Feng [Department of Cardiology, Peking University People' s Hospital, Beijing (China); William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London (United Kingdom); Ren, Jingyi [Department of Cardiology, Peking University People' s Hospital, Beijing (China); Chan, Kenneth [William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London (United Kingdom); Chen, Hong, E-mail: chenhongbj@medmail.com.cn [Department of Cardiology, Peking University People' s Hospital, Beijing (China)

    2013-01-11

    Highlights: Black-Right-Pointing-Pointer We for the first time found that Ang-(1-7) inhibits Ang II-induced VCAM-1 expression. Black-Right-Pointing-Pointer The inhibitory effect of Ang-(1-7) on VCAM-1 is mediated by MAS receptor. Black-Right-Pointing-Pointer The effect of Ang-(1-7) is due to the suppression of NF-kappaB translocation. -- Abstract: Angiotensin II (Ang II) and Angiotensin-(1-7) (Ang-(1-7)) are key effector peptides in the renin-angiotensin system. Increased circulatory Ang II level is associated with the development of hypertension and atherosclerosis, whereas Ang-(1-7) is a counter-regulatory mediator of Ang II which appears to be protective against cardiovascular disease. However, whether Ang-(1-7) regulates the action of Ang II on vascular endothelial cells (EC) remains unclear. We investigated the effects of Ang II and Ang-(1-7) in the context of atherogenesis, specifically endothelial cell VCAM-1 expression that is implicated in early plaque formation. The results show that Ang II increased VCAM-1 mRNA expression and protein displayed on EC surface, while Ang-(1-7) alone exerted no effects. However, Ang-(1-7) significantly suppressed Ang II-induced VCAM-1 expression. Ang-(1-7) also inhibited the Ang II-induced VCAM-1 promoter activity driven by transcription factor NF-KappaB. Furthermore, immunofluorescence assay and ELISA showed that Ang II facilitated the nuclear translocation of NF-kappaB in ECs, and this was attenuated by the presence of Ang-(1-7). The inhibitory effects of Ang-(1-7) on Ang II-induced VCAM-1 promoter activity and NF-kappaB nuclear translocation were all reversed by the competitive antagonist of Ang-(1-7) at the Mas receptor. Our results suggest that Ang-(1-7) mediates its affects on ECs through the Mas receptor, and negatively regulates Ang II-induced VCAM-1 expression by attenuating nuclear translocation of NF-kappaB.

  10. Effects of the nonpeptide V(1) vasopressin receptor antagonist SR49059 in hypertensive patients.

    Science.gov (United States)

    Thibonnier, M; Kilani, A; Rahman, M; DiBlasi, T P; Warner, K; Smith, M C; Leenhardt, A F; Brouard, R

    1999-12-01

    We assessed the clinical and pharmacological profile of the orally active V(1) vascular vasopressin (AVP) receptor nonpeptide antagonist SR49059 (SR) during the osmotic stimulation of AVP release in hypertensive patients. In a double-blind crossover-versus-placebo study, 24 untreated stage I or II essential hypertensive patients (12 whites and 12 blacks) received a single 300 mg oral dose of SR 2 hours before the stimulation of AVP secretion with a 5% hypertonic saline infusion. Hemodynamic, humoral, and hormonal parameters were monitored for up to 28 hours after drug administration. SR did not alter blood pressure or heart rate before the saline infusion and did not reduce the blood pressure increment induced by the hypertonic saline infusion. However, the blood pressure peak at the end of the hypertonic saline infusion was slightly lower in the presence of SR (P=0.04). Heart rate was significantly faster between 4 and 6 hours after SR administration (P=0.02). The rise in plasma sodium and osmolality triggered by the saline infusion was not modified by SR, but AVP release was slightly greater in the presence of SR (P<0.0003). AVP-induced aggregation of blood platelets in vitro was significantly reduced by SR, with a peak effect 2 hours after drug administration that coincided with the SR peak plasma concentration. Plasma renin activity and aldosterone before and after the saline infusion were not modified by SR. Urine volume and osmolality were not altered by SR administration. SR effects were similar in the 2 ethnic groups as well as in salt-sensitive versus salt-resistant patients. In a situation of AVP osmotic release and volume expansion in hypertensive patients, a single oral dose of the V(1) vascular AVP receptor nonpeptide antagonist SR49059, which is able to block AVP-induced platelet aggregation, exerts a transient vasodilation effect that is not associated with a sustained blood pressure reduction. SR49059 is a pure V(1) vascular receptor antagonist that

  11. AVE 0991, a non-peptide Mas-receptor agonist, facilitates penile erection.

    Science.gov (United States)

    da Costa Gonçalves, Andrey C; Fraga-Silva, Rodrigo A; Leite, Romulo; Santos, Robson A S

    2013-03-01

    The renin-angiotensin system plays a crucial role in erectile function. It has been shown that elevated levels of angiotensin II contribute to the development of erectile dysfunction both in humans and in aminals. On the contrary, the heptapeptide angiotensin-(1-7) appears to mediate penile erection by activation of the Mas receptor. Recently, we have shown that the erectile function of Mas gene-deleted mice was substantially reduced, which was associated with a marked increase in fibrous tissue in the corpus cavernosum. We have hypothesized that the synthetic non-peptide Mas agonist, AVE 0991, would potentiate penile erectile function. We showed that intracavernosal injection of AVE 0991 potentiated the erectile response of anaesthetized Wistar rats, measured as the ratio between corpus cavernosum pressure and mean arterial pressure, upon electrical stimulation of the major pelvic ganglion. The facilitatory effect of AVE 0991 on erectile function was dose dependent and completely blunted by the nitric oxide synthesis inhibitor, l-NAME. Importantly, concomitant intracavernosal infusion of the specific Mas receptor blocker, A-779, abolished the effect of AVE 0991. We demonstrated that AVE 0991 potentiates the penile erectile response through Mas in an NO-dependent manner. Importantly, these results suggest that Mas agonists, such as AVE 0991, might have significant therapeutic benefits for the treatment of erectile dysfunction.

  12. Reduced Ang2 expression in aging endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Hohensinner, P.J., E-mail: philipp.hohensinner@meduniwien.ac.at [Department of Internal Medicine II, Medical University of Vienna, Vienna (Austria); Ebenbauer, B. [Department of Internal Medicine II, Medical University of Vienna, Vienna (Austria); Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna (Austria); Kaun, C.; Maurer, G. [Department of Internal Medicine II, Medical University of Vienna, Vienna (Austria); Huber, K. [Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna (Austria); 3rd Medical Department, Wilhelminenhospital, Vienna (Austria); Sigmund Freud University, Medical Faculty, Vienna (Austria); Wojta, J. [Department of Internal Medicine II, Medical University of Vienna, Vienna (Austria); Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna (Austria); Core Facilities, Medical University of Vienna, Vienna (Austria)

    2016-06-03

    Aging endothelial cells are characterized by increased cell size, reduced telomere length and increased expression of proinflammatory cytokines. In addition, we describe here that aging reduces the migratory distance of endothelial cells. Furthermore, we observe an increase of the quiescence protein Ang1 and a decrease of the endothelial activation protein Ang2 upon aging. Supplementing Ang2 to aged endothelial cells restored their migratory capacity. We conclude that aging shifts the balance of the Ang1/Ang2 network favouring a quiescent state. Activation of endothelial cells in aging might be necessary to enhance wound healing capacities. -- Highlights: •Endothelial cells display signs of aging before reaching proliferative senescence. •Aging endothelial cells express more angiopoietin 1 and less angiopoietin 2 than young endothelial cells. •Migratory capacity is reduced in aging endothelial cells.

  13. Interaction between paraventricular nucleus and septal area in the control of physiological responses induced by angiotensin II

    Directory of Open Access Journals (Sweden)

    Camargo L.A.A.

    2002-01-01

    Full Text Available We determined the effects of losartan (40 nmol and PD 123319 (40 nmol (both non-peptides and selective antagonists of the AT1 and AT2 angiotensin receptors, respectively, and [Sar¹, Ala8] angiotensin II (ANG II (40 nmol (a non-selective peptide antagonist of angiotensin receptors injected into the paraventricular nucleus (PVN on the water and salt appetite, diuresis and natriuresis and mean arterial pressure (MAP induced by administration of 10 nmol of ANG II into the medial septal area (MSA of male Holtzman rats weighing 250-300 g. The volume of drug solution injected was 0.5 µl over a period of 10-15 s. The responses were measured over a period of 120 min. ANG II alone injected into the MSA induced an increase in all the above parameters (8.1 ± 1.2, 1.8 ± 0.3, and 17.1 ± 1.0 ml, 217 ± 25 µEq/120 min, and 24 ± 4 mmHg, respectively, N = 10-12 compared with vehicle-treated rats (1.4 ± 0.2, 0.6 ± 0.1, and 9.3 ± 0.5 ml, 47 ± 5 µEq/120 min, and 4.1 ± 0.8 mmHg, respectively, N = 10-14. Pretreatment with losartan and [Sar¹, Ala8] ANG II completely abolished the water and sodium intake, and the pressor increase (0.5 ± 0.2, 1.1 ± 0.2, 0.5 ± 0.2, and 0.8 ± 0.2 ml, and 1.2 ± 3.9, 31 ± 4.6 mmHg, respectively, N = 9-12, whereas losartan blunted the urinary and sodium excretion induced by ANG II (13.9 ± 1.0 ml and 187 ± 10 µEq/120 min, respectively, N = 9. Pretreatment with PD 123319 and [Sar¹, Ala8] ANG II blocked the urinary and sodium excretion (10.7 ± 0.8, 9.8 ± 0.7 ml, and 67 ± 13 and 57 ± 17 µEq/120 min, respectively, N = 9, whereas pretreatment with PD 123319 partially blocked the water and sodium intake, and the MAP induced by ANG II administration (2.3 ± 0.3, 1.1 ± 0.1 ml, and 12 ± 3 mmHg, respectively, N = 9-10. These results suggest the angiotensinergic effect of the MSA on the AT1 and AT2 receptors of the PVN in terms of water and sodium homeostasis and MAP modulation.

  14. Jak2-Independent Activation of Stat3 by Intracellular Angiotensin II in Human Mesangial Cells

    Directory of Open Access Journals (Sweden)

    Rekha Singh

    2011-01-01

    Full Text Available Ang II is shown to mediate the stimulatory effect of high glucose on TGF-b1 and extracellular matrix proteins in glomerular mesangial cells. Also inhibition of Ang II formation in cell media (extracellular and lysates (intracellular blocks high-glucose effects on TGF-b1 and matrix more effectively compared to inhibition of extracellular Ang II alone. To investigate whether intracellular Ang II can stimulate TGF-b1 and matrix independent of extracellular Ang II, cultured human mesangial cells were transfected with Ang II to increase intracellular Ang II levels and its effects on TGF-b1 and matrix proteins were determined. Prior to transfection, cells were treated with candesartan to block extracellular Ang II-induced responses via cell membrane AT1 receptors. Transfection of cells with Ang II resulted in increased levels of intracellular Ang II which was accompanied by increased production of TGF-b1, collagen IV, fibronectin, and cell proliferation as well. On further examination, intracellular Ang II was found to activate Stat3 transcription factor including increased Stat3 protein expression, tyrosine 705 phosphorylation, and DNA-binding activity. Treatment with AG-490, an inhibitor of Jak2, did not block intracellular Ang II-induced Stat3 phosphorylation at tyrosine 705 residue indicating a Jak2-independent mechanism used by intracellular Ang II for Stat3 phosphorylation. In contrast, extracellular Ang II-induced tyrosine 705 phosphorylation of Stat3 was inhibited by AG-490 confirming the presence of a Jak2-dependent pathway. These findings suggest that intracellular Ang II increases TGF-b1 and matrix in human mesangial cells and also activates Stat3 transcription factor without involvement of the extracellular Ang II signaling pathway.

  15. Role of endothelium in angiotensin II formation by the rat aorta and mesenteric arterial bed

    Directory of Open Access Journals (Sweden)

    R. Leite

    1997-05-01

    Full Text Available We investigated the angiotensin II (Ang II-generating system by analyzing the vasoconstrictor effect of Ang II, angiotensin I (Ang I, and tetradecapeptide (TDP renin substrate in the absence and presence of inhibitors of the renin-angiotensin system in isolated rat aortic rings and mesenteric arterial beds with and without functional endothelium. Ang II, Ang I, and TDP elicited a dose-dependent vasoconstrictor effect in both vascular preparations that was completely blocked by the Ang II receptor antagonist saralasin (50 nM. The angiotensin converting enzyme (ACE inhibitor captopril (36 µM completely inhibited the vasoconstrictor effect elicited by Ang I and TDP in aortic rings without affecting that of Ang II. In contrast, captopril (36 µM significantly reduced (80-90% the response to bolus injection of Ang I, without affecting those to Ang II and TDP in mesenteric arteries. Mechanical removal of the endothelium greatly potentiated (70-95% the vasoconstrictor response to Ang II, Ang I, and TDP in aortic rings while these responses were unaffected by the removal of the endothelium of mesenteric arteries with sodium deoxycholate infusion. In addition, endothelium disruption did not change the pattern of response elicited by these peptides in the presence of captopril. These findings indicate that the endothelium may not be essential for Ang II formation in rat mesenteric arteries and aorta, but it may modulate the response to Ang II. Although Ang II formation from Ang I is essentially dependent on ACE in both vessels, our results suggest the existence of an alternative pathway in the mesenteric arterial bed that may play an important role in Ang II generation from TDP in resistance but not in large vessels during ACE inhibition

  16. Angiotensin II activates endothelial constitutive nitric oxide synthase via AT1 receptors.

    Science.gov (United States)

    Saito, S; Hirata, Y; Emori, T; Imai, T; Marumo, F

    1996-09-01

    To determine whether angiotensin (ANG) II, a vasoconstrictor hormone, activates constitutive nitric oxide synthase (cNOS) in endothelial cells (ECs), we investigated the cellular mechanism by which ANG II induces nitric oxide (NO) formation in cultured bovine ECs. ANG II rapidly (within 1 min) and dose-dependently (10(-9)-10(-6) M) increased nitrate/nitrite (NOx) production. This effect of ANG II was abolished by a NOS inhibitor, NG-monomethyl-L-arginine. An ANG II type 1 (AT1) receptor antagonist (DuP 753), but not an ANG II type 2 (AT2) receptor antagonist (PD 123177), dose-dependently inhibited ANG II-induced NOx production. A Ca(2+)-channel blocker (barnidipine) failed to affect ANG II-induced NOx production, whereas an intracellular Ca2+ chelator (BAPTA) and a calmodulin inhibitor (W-7) abolished NOx production induced by ANG II. A protein kinase C (PKC) inhibitor (H-7) and down-regulation of endogenous PKC after pretreatment with phorbol ester decreased NOx production stimulated by ANG II. ANG II transiently stimulated inositol 1,4,5-trisphosphate (IP3) formation, and increased cytosolic free Ca2+ concentrations; these effects were blocked by DuP 753. Our data demonstrate that ANG II stimulates NO release by activation of Ca2+/calmodulin-dependent cNOS via AT1 receptors in bovine ECs.

  17. Entre angústia e desamparo

    Directory of Open Access Journals (Sweden)

    Jacques André

    2001-12-01

    Full Text Available Em sua discussão, o autor diz que a angústia é o motor da análise e de seu progresso: em si mesma é abertura para os enigmas do interior. O desamparo, por sua vez, indica que a vida psíquica continua a ser vivida fora de si, na desesperada abertura para um outro que não responde. Então, na análise, se uma mobiliza, o outro paralisa. O amor (compreendido em sua parte não narcísica é "agarrar-se" aos objetos do mundo exterior, é abertura mantida para o outro e, nesse ponto, homogênea do estado de desamparo do bebê.Between anxiety and helplessness. In this paper the author states that anxiety is the engine of both analysis and its progress: in itself it is an opening to the puzzles of the interior. Helplessness, on the other hand, points out that psychic life is still being lived out of oneself, in a desperate opening to an unresponsive other. So, under the analysis point of view, while one mobilizes, the other paralyses. Love (out of its narcissistic part is "to cling" to objects of the external world, it is an opening to the other and, at that point, homogeneous to the baby's state of helplessness.

  18. Effects of felodipine combined with puerarin on ACE2-Ang (1-7)-Mas axis in renovascular hypertensive rat.

    Science.gov (United States)

    Bai, Song; Huang, Zheng-Gui; Chen, Li; Wang, Jiang-Tao; Ding, Bo-Ping

    2013-06-10

    This study aimed to investigate the effect of combination of felodipine+puerarin on ACE2-Ang (1-7)-Mas axis, and to explore the protective effect of the combination against kidney in renovascular hypertensive rats. Goldblatt rats were randomly divided into 5 groups as follows: 4 groups which were treated with felodipine (Felo), puerarin (Pue), Felo+Pue, and Felo+captopril (Cap), respectively, and a control group of animals that were administrated with distilled water. Contents of Ang II and Ang (1-7) in renal tissues were determined by ELISA kit. The mRNA expression of ACE2/Mas and ACE/AT1 in kidneys was analyzed by RT-PCR. After 8weeks of treatment, compared with Goldblatt group, Felo+Pue reduced SBP, DBP and HR (pword, a combination of Felo+Pue has a more efficient therapeutic effect on DBP and HR, and contributes to a better protection against renal interstitial fibrosis.

  19. ANG-(1–7) DEFICIENCY AND BAROREFLEX IMPAIRMENT PRECEDE THE ANTENATAL BETAMETHASONE EXPOSURE-INDUCED ELEVATION IN BLOOD PRESSURE

    Science.gov (United States)

    Shaltout, Hossam A.; Rose, James C.; Chappell, Mark C.; Diz, Debra I.

    2014-01-01

    Betamethasone is administered to accelerate lung development and improve survival of premature infants, but may be associated with hypertension later in life. In a sheep model of fetal programming resulting from exposure at 80th day of gestation to Betamethasone (Betaexposed), adult sheep at 6–9 months or 1.8 yrs of age have elevated mean arterial pressure (MAP), and attenuated spontaneous baroreflex sensitivity (sBRS) for control of heart rate compared to age-matched controls, associated with imbalances in angiotensin (Ang) II versus Ang-(1–7) tone. At 6 weeks of age, evoked BRS is already low in the Beta-exposed animals. In this study we assessed the potential contribution of the renin-angiotensin system to the impaired sBRS. Female lambs (6 weeks old) with Beta-exposure in utero had similar MAP to control lambs (78±2 vs 77±2 mm Hg, n = 4–5 per group), but lower sBRS (8±1 vs 16±3 ms/mm Hg; p < 0.05) and impaired heart rate variability (HRV). Peripheral AT1 receptor blockade using candesartan lowered MAP in both groups (~10 mm Hg) and improved sBRS and HRV in Beta-exposed lambs to a level similar to control. AT7 receptor blockade by infusion of D-ala Ang-(1–7) (700 ng/kg/min for 45 min) reduced sBRS 46±10 % in Beta-exposed vs in control lambs (p<0.15) and increased MAP in both groups (~6±2 mm Hg). Our data reveal that Beta-exposure impairs sBRS and HRV at a time point preceding the elevation in MAP via mechanisms involving an imbalance in the Ang II/Ang-(1–7) ratio consistent with a progressive loss in Ang-(1–7) function. PMID:22215705

  20. Peptide and non-peptide opioid-induced hyperthermia in rabbits

    Science.gov (United States)

    Kandasamy, S. B.; Williams, B. A.

    1983-01-01

    The intracerebroventricular administration of prototype nonpeptide opioid receptor (mu, kappa, and sigma) agonists, morphine, ketocyclazocine, and N-allyl-normetazocine was found to induce hyperthermia in rabbits. The similar administration of peptide opioids like beta-endorphin (BE), methionine-enkephalin (ME), and its synthetic analogue D-ala2-methionine-enkephalinamide (DAME) was also found to cause hyperthermia. Results indicate that only the liver-like transport system is important to the ventricular inactivation of BE and DAME. Prostaglandins and norepinephrine were determined not to be involved in peptide and nonpeptide opioid-induced hyperthermia. In addition, cAMP was not required since a phosphodiesterase inhibitor, theophylline, did not accentuate the hyperthermia due to peptide and nonpeptide opioids. Naloxone-sensitive receptors were found to be involved in the induction of hyperthermia by morphine, BE, ME, and DAME since naloxone attenuated them. However, the hyperthermic response to ketocyclazocine and N-allyl-normetazocine was not antagonized by naloxone.

  1. Activation of ERK, JNK, Akt, and G-protein coupled signaling by hybrid angiotensin II AT1/bradykinin B2 receptors expressed in HEK-293 cells

    DEFF Research Database (Denmark)

    Yu, Jun; Lubinsky, David; Tsomaia, Natia;

    2007-01-01

    Bradykinin (BK) and angiotensin II (AngII) often have opposite roles in cardiovascular diseases. Our aim here was to construct hybrid receptors which bind AngII but signal as BK. Various sequences of the intracellular face of the AngII type I receptor, AT1R, were replaced with corresponding...

  2. Dissociation between the circulating renin-angiotensin system and angiotensin II receptors in central losartan-induced hypertension

    Directory of Open Access Journals (Sweden)

    A.M. Sugawara

    2002-09-01

    Full Text Available Losartan, an AT1 angiotensin II (ANG II receptor non-peptide antagonist, induces an increase in mean arterial pressure (MAP when injected intracerebroventricularly (icv into rats. The present study investigated possible effector mechanisms of the increase in MAP induced by icv losartan in unanesthetized rats. Male Holtzman rats (280-300 g, N = 6/group with a cannula implanted into the anterior ventral third ventricle received an icv injection of losartan (90 µg/2 µl that induced a typical peak pressor response within 5 min. In one group of animals, this response to icv losartan was completely reduced from 18 ± 1 to 4 ± 2 mmHg by intravenous (iv injection of losartan (2.5-10 mg/kg, and in another group, it was partially reduced from 18 ± 3 to 11 ± 2 mmHg by iv prazosin (0.1-1.0 mg/kg, an alpha1-adrenergic antagonist (P<0.05. Captopril (10 mg/kg, a converting enzyme inhibitor, injected iv in a third group inhibited the pressor response to icv losartan from 24 ± 3 to 7 ± 2 mmHg (P<0.05. Propranolol (10 mg/kg, a ß-adrenoceptor antagonist, injected iv in a fourth group did not alter the pressor response to icv losartan. Plasma renin activity and serum angiotensin-converting enzyme activity were not altered by icv losartan in other animals. The results suggest that the pressor effect of icv losartan depends on angiotensinergic and alpha1-adrenoceptor activation, but not on increased circulating ANG II.

  3. AT2 receptor non-peptide agonist C21 promotes natriuresis in obese Zucker rats.

    Science.gov (United States)

    Ali, Quaisar; Hussain, Tahir

    2012-06-01

    Previously, we demonstrated that angiotensin II type 2 (AT(2)) receptors have a role in natriuresis in obese Zucker rats (OZR). In the present study, we investigated the role of a novel, non-peptide agonist, C21, in natriuresis via AT(2) receptor activation in OZR. Infusion of C21 (1 and 5 μg kg(-1) min(-1)) into rats under anesthesia caused a dose-dependent increase in urine flow (UF) and urinary Na volume (U(Na)V). These effects of C21 were blocked by pre-infusion of the AT(2) receptor antagonist, PD123319, (50 μg kg(-1) min(-1)), suggesting involvement of the AT(2) receptor. Infusion of C21 (5 μg kg(-1) min(-1)) significantly increased the fractional excretion of sodium without changing the glomerular filtration rate or blood pressure, suggesting a tubular effect. Similarly, C21 infusion increased the fractional excretion of lithium, suggesting a proximal tubular effect. Furthermore, we tested the effect of C21 on natriuresis after blocking two main, distal-nephron Na transporters, the epithelial Na channels (ENaC), with amiloride (AM, 3 mg kg(-1) body wt), and the NaCl cotransporters (NCC), with bendroflumethiazide (BFTZ, 7 mg kg(-1) body wt). Infusion of AM + BFTZ caused significant increases in both diuresis and natriuresis, which were further increased by infusion of C21 (5 μg kg(-1) min(-1)). Natriuresis in response to C21 was associated with increases in urinary NO and cGMP levels. The data indicate that the AT(2) receptor agonist, C21, promotes natriuresis via AT(2) receptor activation and that this effect is potentially based in the proximal tubules and linked to the nitric oxide/cyclic guanosine monophosphate pathway. The natriuretic response to C21 may have therapeutic significance by improving kidney function in obesity.

  4. Who Will Be the First College Student of De’ang Nationality?

    Institute of Scientific and Technical Information of China (English)

    1996-01-01

    "DE’ANG" means the "people with noble characters on the mountains". This name with its strong cultural taste is a reminder of the history of the De’ang. Long ago De’ang people preferred to settle on the hillside, probably to escape war or the prevailing plague. The De’ang villages are usually surrounded by big bodhi

  5. Diuretic response to acute hypertension is blunted during angiotensin II clamp

    DEFF Research Database (Denmark)

    Leong, Patrick K K; Zhang, Yibin; Yang, Li E;

    2002-01-01

    ("ANG II clamp"). When blood pressure was acutely increased 50-60 mmHg by arterial constriction without ANG II clamp, urine output and endogenous lithium clearance increased 4.0- and 6.7-fold, respectively. With ANG II clamp, the effects of acute hypertension were reduced 50%: urine output...... and endogenous lithium clearance increased two- and threefold, respectively. We conclude that HOE-140, an inhibitor of the B(2) receptor, potentiates the sensitivity of arterial pressure to ANG II and that clamping systemic ANG II levels during acute hypertension blunts the magnitude of the pressure diuretic...

  6. Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: A mechanism by which angiotensin II antagonizes cGMP signaling

    Science.gov (United States)

    Kim, Dongsoo; Aizawa, Toru; Wei, Heng; Pi, Xinchun; Rybalkin, Sergei D.; Berk, Bradford C.; Yan, Chen

    2014-01-01

    Angiotensin II (Ang II) and nitric oxide (NO)/natriuretic peptide (NP) signaling pathways mutually regulate each other. Imbalance of Ang II and NO/NP has been implicated in the pathophysiology of many vascular diseases. cGMP functions as a key mediator in the interaction between Ang II and NO/NP. Cyclic nucleotide phosphodiesterase 5A (PDE5A) is important in modulating cGMP signaling by hydrolyzing cGMP in vascular smooth muscle cells (VSMC). Therefore, we examined whether Ang II negatively modulates intracellular cGMP signaling in VSMC by regulating PDE5A. Ang II rapidly and transiently increased PDE5A mRNA levels in rat aortic VSMC. Upregulation of PDE5A mRNA was associated with a time-dependent increase of both PDE5 protein expression and activity. Increased PDE5A mRNA level was transcription-dependent and mediated by the Ang II type 1 receptor. Ang II-mediated activation of extracellular signal-regulated kinases 1/2 (ERK1/2) was essential for Ang II-induced PDE5A upregulation. Pretreatment of VSMC with Ang II inhibited C-type NP (CNP) stimulated cGMP signaling, such as cGMP dependent protein kinase (PKG)-mediated phosphorylation of vasodilator-stimulated-phosphoprotein (VASP). Ang II-mediated inhibition of PKG was blocked when PDE5 activity was decreased by selective PDE5 inhibitors, suggesting that upregulation of PDE5A expression is an important mechanism for Ang II to attenuate cGMP signaling. PDE5A may also play a critical role in the growth promoting effects of Ang II because inhibition of PDE5A activity significantly decreased Ang II-stimulated VSMC growth. These observations establish a new mechanism by which Ang II antagonizes cGMP signaling and stimulates VSMC growth. PMID:15623434

  7. Bullying: ato esburacado na angústia

    Directory of Open Access Journals (Sweden)

    Maria de Lourdes Soares Ornellas

    2012-04-01

    Full Text Available A noção de afeto está no campo do (desprazer, resultante de uma experiência afetiva de satisfação ou insatisfação, e que se manifesta nas necessidades do sujeito. Pode-se dizer que o afeto envolve a ambivalência de sentimentos, do mais agradável ao mais insuportável, e desempenha um papel estruturante para que o sujeito reencontre sua estrutura psíquica, exercendo uma ação mediadora e decisiva sobre a constituição do sujeito do desejo, orientando o seu projeto de vida, sua profissão, sua opção sexual, etc. Essa ambivalência de afetos deve ser exercitada na educação familiar e escolar, na fala e na escuta que o afeto (desprazeroso tem relevância e parece ser silenciado. O desprazer pode ser escandido pelos sintomas medo, depressão, irritabilidade, ansiedade, humilhação. Assim posto o bullying é também conhecido como a síndrome da humilhação. O objetivo da humilhação é a tentativa de destruição do sujeito; a perda da identificação revela um fantasma, na medida em que própria vítima se sente culpada por sofrer ou por estar sofrendo um ato esburacado porque uma das peças não é encontrada e, em lugar do encaixe, o que se mostra é um buraco, o que provoca a angústia entre quem perde e aquele que ganha. ABSTRACT: The notion of affect is thus in the field of (dis pleasure, resulting from an affective experience of satisfaction or dissatisfaction, and that manifests itself on the needs of the subject. You could say that the affection involves the ambivalence of feelings, the more enjoyable the more unbearable, and plays a structural role for the subject to rediscover his psychic structure, exerting a mediator and decisive action on the constitution of the subject of desire, directing the its design life, your profession, your sexual orientation, etc.. This ambivalence of feelings should be exercised in family education and school, talking and listening that affect (dis pleasure is relevant and appears to be

  8. LNG-IUS对腺肌症子宫内膜VEGF、Ang-1、Ang-2的影响%The influence of levonorgestrel intrauterine system on endometrial VEGF/Ang-1/Ang-2 of women with adenomyosis

    Institute of Scientific and Technical Information of China (English)

    姚佳娜; 谢梅青

    2013-01-01

    Objective To determine the alteration of endometrial VEGF/Ang-1/Ang-2 expression of women with adenomyosis after using levonogestrel intrauterine system,and elucidate the possible mechanism of breakthrough bleeding in the use of LNG-IUS on angiogenesis and vascular stability.Methods Endometrial biopsies was obtained from 41 women with adenomyosis undergoing treatment with LNG-IUS by using Pipelle suction curette,determine the endometrial VEGF/Ang-1/Ang-2 expression through immunohistochemistry.We also took the endometrial tissue from patients diagnosed as adenomyosis without any treatment as control groups.Results The LNG-IUS group was divided into bleeding group (16 cases) and non-bleeding group (25 cases),according to the bleeding patterns in the last 3 months before biopsy.The staining for VEGF/Ang-2 in bleeding group was significantly higher than that in nonbleeding group (P<0.05).The Ang-1 staining in glandular epithelium and stromal cells between two groups was not significant different (P>0.05).Divided the LNG-IUS group into the less than 1-year group,1-2 year group and more than 2-year group,we had found that the 1-2 year group and the more than 1-year group exhibited significantly lower immunoreactivity for VEGF and Ang-2 in both glandular epithelium and stromal cells (P<0.05),while there were no significant differences in immunoreactivity for the Ang-1 among different groups (P>0.05).Conclusion VEGF and Ang1,Ang-2 may play a role in provoking breakthrough bleeding in the use of LNG-IUS by influencing angiogenesis and vascular stability.%目的 研究子宫腺肌症患者放置左炔诺孕酮宫内缓释系统(LNG-IUS)后子宫内膜血管内皮生长因子(VEGF)、促血管生成素(Ang-1、Ang-2)表达的变化,从血管生成及血管稳定性方面探讨子宫腺肌症患者放置LNG-IUS后不规则出血的发生机制.方法 收集41例放置LNG-IUS腺肌症患者的子宫内膜,应用免疫组化染色(DAKO EnvisionTM System法)检测其子宫内膜VEGF、Ang

  9. Kierkegaard, a Escola da Angústia e a Psicoterapia

    Directory of Open Access Journals (Sweden)

    Ana Maria Lopez Calvo de Feijoo

    Full Text Available Este artigo busca refletir sobre a relação estabelecida por Soren Kierkegaard, na voz do pseudônimo Vigilius Haufniensis, entre angústia e Psicologia. A Psicologia surge, nesse contexto, como a ciência cuja atmosfera é angústia. Primeiramente, são apresentadas as considerações de Haufniensis sobre a angústia como determinação existencial. Em seguida, exemplificam-se as formas particulares de expressão da angústia por meio de um conto de Grimm, intitulado João sem medo. Observa-se que é da tensão entre o universal e o particular que nasce, por um salto qualitativo, a possibilidade de uma existência singular. Ao considerar o tema angústia como centro de investigação, e tendo como intuito pensar uma proposta de psicoterapia, conclui-se que o pensamento da existência, tal como desenvolvido por Haufniensis, proporciona elementos para a elaboração de uma proposta de psicoterapia que não se ocupe nem em julgar nem em teorizar, mas que sustente a existência como espaço onde tudo aparece como possibilidade.

  10. Cellular localization of AT1 receptor mRNA and protein in normal placenta and its reduced expression in intrauterine growth restriction. Angiotensin II stimulates the release of vasorelaxants.

    OpenAIRE

    Li, X.; M Shams; Zhu, J; Khalig, A; Wilkes, M; Whittle, M; Barnes, N; Ahmed, A.

    1998-01-01

    Angiotensin II (ANG II) is a potent vasoconstrictor and growth promoter. Quantitative receptor autoradiography using the nonselective radioligand [125I]ANG II and subtype-selective competing compounds demonstrated the presence of both ANG II receptor (AT)1 and AT2 receptor recognition sites. In addition, a relatively small population of apparently non-AT1/non-AT2 sites was identified that may represent a novel high affinity ANG II recognition site in human placenta. Using placental membrane p...

  11. Decrease in blood pressure and regression of cardiovascular complications by angiotensin II vaccine in mice.

    Directory of Open Access Journals (Sweden)

    Futoshi Nakagami

    Full Text Available Vaccines have been recently developed to treat various diseases such as cancer, rheumatoid arthritis and Alzheimer's disease in addition to infectious diseases. However, before use in the clinical setting, vaccines targeting self-antigens must be demonstrated to be effective and safe, evoking an adequate humoral immune response from B cells while avoiding T cell activation in response to self. Although the vaccine targeting angiotensin II (Ang II is efficient in rodents and humans, little is known regarding the immunological activation and safety of the vaccine. In this study, we evaluated the efficiency and safety of an Ang II peptide vaccine in mice. Immunization with Ang II conjugated to keyhole limpet hemocyanin (KLH successfully induced the production of anti-Ang II antibody, which blocked Ang II signaling in human aortic smooth muscle cells. However, Ang II itself did not activate T cells, as assessed by the proliferation and lymphokine production of T cells in immunized mice, whereas KLH activated T cells. In an Ang II-infused model, the non-immunized mice showed high blood pressure (BP, whereas the immunized mice (Ang II-KLH showed a significant decrease in systolic BP, accompanied by significant reductions in cardiac hypertrophy and fibrosis. Importantly, anti-Ang II antibody titer was not elevated even after the administration of large amounts of Ang II, indicating that Ang II itself boosted antibody production, most likely due to less activation of T cells. In addition, no accumulation of inflammatory cells was observed in immunized mice, because endogenous Ang II would not activate T cells after immunization with Ang II-KLH. Taken together, these data indicate that vaccines targeting Ang II might be effective to decrease high BP and prevent cardiovascular complications without severe side effects.

  12. Thermoluminescence authentication of T`ang and Han Dynasty pottery

    Energy Technology Data Exchange (ETDEWEB)

    Price, D.M. [Wollongong Univ., NSW (Australia). School of Geosciences

    1997-12-31

    More than 80 pieces of T`ang Dynasty and 40 Han Dynasty style ceramic wares have been analysed to determine the amount of thermoluminescence (TL) accumulated since the initial firing of the object and the level of the radiation flux which has created the TL. This paper presents a summary of the thermoluminescence analysis results. Approximately 60% of Han ceramics and 45% of the T`ang pottery authenticated have been shown to belong to periods other than that stylistically suggested. Items which have been found not to be of the anticipated antiquity generally fall into distinct age groups. Of the T`ang wares the most commonly copied item is found to be the horse and for the Han pieces, human figures and ewers/pots/vases represent the most frequently reproduced wares.

  13. Suppression of Gonadotropins and Estradiol in Premenopausal Women by Oral Administration of the Nonpeptide Gonadotropin-Releasing Hormone Antagonist Elagolix

    OpenAIRE

    Struthers, R. Scott; Nicholls, Andrew J.; Grundy, John; Chen, Takung; Jimenez, Roland; Yen, Samuel S. C.; Bozigian, Haig P.

    2008-01-01

    Context: Parenteral administration of peptide GnRH analogs is widely employed for treatment of endometriosis and fibroids and in assisted-reproductive therapy protocols. Elagolix is a novel, orally available nonpeptide GnRH antagonist.

  14. Angiotensin II in Refractory Septic Shock.

    Science.gov (United States)

    Antonucci, Elio; Gleeson, Patrick J; Annoni, Filippo; Agosta, Sara; Orlando, Sergio; Taccone, Fabio Silvio; Velissaris, Dimitrios; Scolletta, Sabino

    2017-05-01

    Refractory septic shock is defined as persistently low mean arterial blood pressure despite volume resuscitation and titrated vasopressors/inotropes in patients with a proven or suspected infection and concomitant organ dysfunction. Its management typically requires high doses of catecholamines, which can induce significant adverse effects such as ischemia and arrhythmias. Angiotensin II (Ang II), a key product of the renin-angiotensin-aldosterone system, is a vasopressor agent that could be used in conjunction with other vasopressors to stabilize critically ill patients during refractory septic shock, and reduce catecholamine requirements. However, very few clinical data are available to support Ang II administration in this setting. Here, we review the current literature on this topic to better understand the role of Ang II administration during refractory septic shock, differentiating experimental from clinical studies. We also consider the potential role of exogenous Ang II administration in specific organ dysfunction and possible pitfalls with Ang II in sepsis. Various issues remain unresolved and future studies should investigate important topics such as: the optimal dose and timing of Ang II administration, a comparison between Ang II and the other vasopressors (epinephrine; vasopressin), and Ang II effects on microcirculation.

  15. Estrogen regulation of the brain renin-angiotensin system in protection against angiotensin II-induced sensitization of hypertension.

    Science.gov (United States)

    Xue, Baojian; Zhang, Zhongming; Beltz, Terry G; Guo, Fang; Hay, Meredith; Johnson, Alan Kim

    2014-07-15

    This study investigated sex differences in the sensitization of angiotensin (ANG) II-induced hypertension and the role of central estrogen and ANG-(1-7) in this process. Male and female rats were implanted for telemetered blood pressure (BP) recording. A subcutaneous subpressor dose of ANG II was given alone or concurrently with intracerebroventricular estrogen, ANG-(1-7), an ANG-(1-7) receptor antagonist A-779 or vehicle for 1 wk (induction). After a 1-wk rest (delay), a pressor dose of ANG II was given for 2 wk (expression). In males and ovariectomized females, subpressor ANG II had no sustained effect on BP during induction, but produced an enhanced hypertensive response to the subsequent pressor dose of ANG II during expression. Central administration of estrogen or ANG-(1-7) during induction blocked ANG II-induced sensitization. In intact females, subpressor ANG II treatment produced a decrease in BP during induction and delay, and subsequent pressor ANG II treatment given during expression produced only a slight but significant increase in BP. However, central blockade of ANG-(1-7) by intracerebroventricular infusion of A-779 during induction restored the decreased BP observed in females during induction and enhanced the pressor response to the ANG II treatment during expression. RT-PCR analyses indicated that estrogen given during induction upregulated mRNA expression of the renin-angiotensin system (RAS) antihypertensive components, whereas both central estrogen and ANG-(1-7) downregulated mRNA expression of RAS hypertensive components in the lamina terminalis. The results indicate that females are protected from ANG II-induced sensitization through central estrogen and its regulation of brain RAS.

  16. Crocin prevents acute angiotensin II-induced hypertension in anesthetized rats

    Directory of Open Access Journals (Sweden)

    Mohammad Naser Shafei

    2017-06-01

    Full Text Available Objective: Angiotensin II (Ang II, the main product of renin-angiotensin system (RAS has a well-known role in cardiovascular regulation. Over-production of Ang II is one of the important underlying mechanisms of hypertension. In this study, the effect of crocin on cardiovascular responses in rats with acute hypertension induced by Ang II was evaluated. Materials and methods: Rats were divided into six groups (n = 6: 1 Control: rats that received saline, 2 Ang II: rats that received Ang II (300 ng/kg infused in two min, 3 Losartan (Los + Ang II : rats that received Los (10 mg/kg, i.v before Ang II, and 4-6 Crocin (Cro + Ang II groups: rats that received three doses of crocin (50, 100 and 200 mg/kg, slow i.v 10 min before Ang II. Femoral artery and vein were cannulated for recording of cardiovascular parameters and injection of drugs, respectively. Systolic blood pressure (SBP, mean arterial blood pressure (MAP and heart rate (HR were continuously recorded by power lab system. After injection of reagents and extracts, maximum changes (∆ of MAP, SBP and HR were recorded and compared with control group. Results: Ang II (300 ng/kg increased maximal changes in MAP, SBP and HR compared to control group (p

  17. Nonpeptidic Tetrafluorophenoxymethyl Ketone Cruzain Inhibitors as Promising New Leads for Chagas Disease Chemotherapy†

    Science.gov (United States)

    Brak, Katrien; Kerr, Iain D.; Barrett, Kimberly T.; Fuchi, Nobuhiro; Debnath, Moumita; Engel, Juan C.; McKerrow, James H.; Doyle, Patricia S.; Brinen, Linda S.; Ellman, Jonathan A.

    2010-01-01

    A century after discovering that the Trypanosoma cruzi parasite is the etiological agent of Chagas disease, treatment is still plagued by limited efficacy, toxicity, and the emergence of drug resistance. The development of inhibitors of the major T. cruzi cysteine protease, cruzain, has been demonstrated to be a promising drug discovery avenue for this neglected disease. Here we establish that a nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitor substantially ameliorates symptoms of acute Chagas disease in a mouse model with no apparent toxicity. A high-resolution crystal structure confirmed the mode of inhibition and revealed key binding interactions of this novel inhibitor class. Subsequent structure-guided optimization then resulted in inhibitor analogs with improvements in potency despite minimal or no additions in molecular weight. Evaluation of the analogs in cell culture showed enhanced activity. These results suggest that nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors have the potential to fulfill the urgent need for improved Chagas disease chemotherapy. PMID:20088534

  18. Angiotensin II Induces C-Reactive Protein Expression via AT1-ROS-MAPK-NF-κB Signal Pathway in Hepatocytes

    Directory of Open Access Journals (Sweden)

    Jingjing Zhao

    2013-09-01

    Full Text Available Background: C-reactive protein (CRP participates in development of inflammatory diseases. Hepatocytes are a major contributor of circulating CRP. Although angiotensin II (Ang II is known to evoke inflammatory response, it remains unknown whether Ang II induces CRP expression in hepatocytes. The present study observed effect of Ang II on CRP expression and the related signal pathway in hepatocytes. Methods: mRNA and protein expressions in human hepatocytes were determined with RT-PCR and Western blot respectively. Reactive oxygen species (ROS was measured using a fluorescence probe. CRP in liver and serum of rats was determined by immunohistochemistry and ELISA respectively. Results: Ang II induced mRNA and protein expression of CRP in hepatocytes and increased CRP production in liver and CRP level in serum. Losartan reduced Ang II- induced CRP expression in hepatocytes. Losartan and thenoyltrifluoroacetone decreased Ang II-stimulated ROS production. N-acetylcysteine antagonized Ang II-induced CRP expression. Losartan and N-acetylcysteine inhibited Ang II-activated ERK1/2. Unlike ERK1/2, only losartan inhibited Ang II-activated JNK. Furthermore, pyrrolidine dithiocarbamate abolished Ang II-induced CRP expression. Conclusion: Ang II has ability to induce CRP expression in hepatocytes in vitro and in vivo through AT1 receptor followed by ROS, MAPK and NF-κB signal pathway.

  19. Molecular interaction of a potent nonpeptide agonist with the chemokine receptor CCR8.

    Science.gov (United States)

    Jensen, Pia C; Nygaard, Rie; Thiele, Stefanie; Elder, Amy; Zhu, Guoming; Kolbeck, Roland; Ghosh, Shomir; Schwartz, Thue W; Rosenkilde, Mette M

    2007-08-01

    Most nonpeptide antagonists for CC-chemokine receptors share a common pharmacophore with a centrally located, positively charged amine that interacts with the highly conserved glutamic acid (Glu) located in position 6 of transmembrane helix VII (VII:06). We present a novel CCR8 nonpeptide agonist, 8-[3-(2-methoxyphenoxy)benzyl]-1-phenethyl-1,3,8-triaza-spiro[4.5]decan-4-one (LMD-009), that also contains a centrally located, positively charged amine. LMD-009 selectively stimulated CCR8 among the 20 identified human chemokine receptors. It mediated chemotaxis, inositol phosphate accumulation, and calcium release with high potencies (EC50 from 11 to 87 nM) and with efficacies similar to that of the endogenous agonist CCL1, and it competed for 125I-CCL1 binding with an affinity of 66 nM. A series of 29 mutations targeting 25 amino acids broadly distributed in the minor and major ligand-binding pockets of CCR8 uncovered that the binding of LMD-009 and of four analogs [2-(1-(3-(2-methoxyphenoxy)benzyl)-4-hydroxypiperidin-4-yl)benzoic acid (LMD-584), N-ethyl-2-4-methoxybenzenesulfonamide (LMD-902), N-(1-(3-(2-methoxyphenoxy)benzyl)piperidin-4-yl)-2-phenyl-4-(pyrrolidin-1yl)butanamide (LMD-268), and N-(1-(3-(2-methoxyphenoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydro-2-oxoquinoline-4-carboxamide (LMD-174)] included several key-residues for nonpeptide antagonists targeting CCR1, -2, and -5. It is noteworthy that a decrease in potency of nearly 1000-fold was observed for all five compounds for the Ala substitution of the anchor-point GluVII:06 (Glu(286)) and a gain-of-function of 19-fold was observed for LMD-009 (but not the four other analogs) for the Ala substitution of PheVI:16 (Phe(254)). These structural hallmarks were particularly important in the generation of a model of the molecular mechanism of action for LMD-009. In conclusion, we present the first molecular mapping of the interaction of a nonpeptide agonist with a chemokine receptor and show that the binding

  20. Chymase-dependent generation of angiotensin II from angiotensin-(1-12 in human atrial tissue.

    Directory of Open Access Journals (Sweden)

    Sarfaraz Ahmad

    Full Text Available Since angiotensin-(1-12 [Ang-(1-12] is a non-renin dependent alternate precursor for the generation of cardiac Ang peptides in rat tissue, we investigated the metabolism of Ang-(1-12 by plasma membranes (PM isolated from human atrial appendage tissue from nine patients undergoing cardiac surgery for primary control of atrial fibrillation (MAZE surgical procedure. PM was incubated with highly purified ¹²⁵I-Ang-(1-12 at 37°C for 1 h with or without renin-angiotensin system (RAS inhibitors [lisinopril for angiotensin converting enzyme (ACE, SCH39370 for neprilysin (NEP, MLN-4760 for ACE2 and chymostatin for chymase; 50 µM each]. ¹²⁵I-Ang peptide fractions were identified by HPLC coupled to an inline γ-detector. In the absence of all RAS inhibitor, ¹²⁵I-Ang-(1-12 was converted into Ang I (2±2%, Ang II (69±21%, Ang-(1-7 (5±2%, and Ang-(1-4 (2±1%. In the absence of all RAS inhibitor, only 22±10% of ¹²⁵I-Ang-(1-12 was unmetabolized, whereas, in the presence of the all RAS inhibitors, 98±7% of ¹²⁵I-Ang-(1-12 remained intact. The relative contribution of selective inhibition of ACE and chymase enzyme showed that ¹²⁵I-Ang-(1-12 was primarily converted into Ang II (65±18% by chymase while its hydrolysis into Ang II by ACE was significantly lower or undetectable. The activity of individual enzyme was calculated based on the amount of Ang II formation. These results showed very high chymase-mediated Ang II formation (28±3.1 fmol × min⁻¹ × mg⁻¹, n = 9 from ¹²⁵I-Ang-(1-12 and very low or undetectable Ang II formation by ACE (1.1±0.2 fmol×min⁻¹ × mg⁻¹. Paralleling these findings, these tissues showed significant content of chymase protein that by immunocytochemistry were primarily localized in atrial cardiac myocytes. In conclusion, we demonstrate for the first time in human cardiac tissue a dominant role of cardiac chymase in the formation of Ang II from Ang-(1-12.

  1. An extensive library of 2500-10500 Ang synthetic spectra

    CERN Document Server

    Munari, U; Castelli, F; Zwitter, T

    2005-01-01

    We present a complete library of synthetic spectra based on Kurucz's codes that covers the 2500-10500 Ang wavelength range at resolving powers 20000, 11500, 8500, 2000 and uniform dispersions of 1 and 10 Ang/pix. The library maps the whole HR diagram, exploring 67800 combinations of the atmospheric parameters spanning the ranges: 3500 <= T_eff <= 47500 K, 0.0 <= log g <= 5.0, -2.5 <= [M/H] <= +0.5, [a/Fe] =0.0,+0.4, csi =1,2,4 km/sec, 0 <= V_rot <= 500 km/sec. The spectra are available both as absolute fluxes as well as continuum normalized. Foreseen applications of the library are briefly discussed, including automatic classification of data from spectroscopic surveys (like RAVE, SLOAN, GAIA) and calibration of differential photometric indices. Data distribution and access to the library via dedicated web page are outlined.

  2. A angústia de viver na cidade

    Directory of Open Access Journals (Sweden)

    Ana Claudia Aymoré Martins

    2015-04-01

    Full Text Available No romance Angústia, de Graciliano Ramos, a gradual dissolução psíquica de Luís da Silva tem uma relação intrínseca com as condições da vida urbana na modernidade, sendo a cidade referida ou semantizada ora como Babel, o caos urbano original, ora como Babilônia, a urbs corrompida pelo vício. Além disso, a recorrência de metáforas como a dos ratos (significando a degradação da vida, a corrupção da sexualidade ou o caráter predatório do materialismo burguês e a ênfase no estado de angústia revelam as interlocuções com conceitos filosóficos/psicológicos da Angst, tais como expressos em Freud, Kierkegaard e Heidegger.

  3. Angiotensin-(1–7) abrogates angiotensin II-induced proliferation, migration and inflammation in VSMCs through inactivation of ROS-mediated PI3K/Akt and MAPK/ERK signaling pathways

    Science.gov (United States)

    Zhang, Feng; Ren, Xingsheng; Zhao, Mingxia; Zhou, Bing; Han, Ying

    2016-01-01

    The proliferation, migration and inflammation of vascular smooth muscle cells (VSMCs) contribute to the pathogenesis and progression of several cardiovascular diseases such as atherosclerosis and hypertension. Angiotensin (Ang)-(1–7) and Ang II are identified to be involved in regulating cardiovascular activity. The present study is designed to determine the interaction between Ang-(1–7) and Ang II on VSMCs proliferation, migration and inflammation as well as their underlying mechanisms. We found that Ang-(1–7) significantly suppressed the positive effects of Ang II on VSMCs proliferation, migration and inflammation, as well as on induction of the phosphorylation of Akt and ERK1/2 and increase of superoxide anion level and NAD(P)H oxidase activity in VSMCs, whereas Ang-(1–7) alone had no significant effects. This inhibitory effects of Ang-(1–7) were abolished by Mas receptor antagonist A-779. In addition, Ang II type 1 (AT1) receptor antagonist losartan, but not A-779, abolished Ang II induced VSMCs proliferation, migration and inflammation responses. Furthermore, superoxide anion scavenger N-acetyl-L-cysteine (NAC) or NAD(P)H oxidase inhibitor apocynin inhibited Ang II-induced activation of Akt and ERK1/2 signaling. These results indicate that Ang-(1–7) antagonizes the Ang II-induced VSMC proliferation, migration and inflammation through activation of Mas receptor and then suppression of ROS-dependent PI3K/Akt and MAPK/ERK signaling pathways. PMID:27687768

  4. Angiogenin levels and ANG genotypes: dysregulation in amyotrophic lateral sclerosis.

    Directory of Open Access Journals (Sweden)

    Russell Lewis McLaughlin

    Full Text Available OBJECTIVE: To determine whether 5 single nucleotide polymorphisms (SNPs associate with ALS in 3 different populations. We also assessed the contribution of genotype to angiogenin levels in plasma and CSF. METHODS: Allelic association statistics were calculated for polymorphisms in the ANG gene in 859 patients and 1047 controls from Sweden, Ireland and Poland. Plasma, serum and CSF angiogenin levels were quantified and stratified according to genotypes across the ANG gene. The contribution of SNP genotypes to variance in circulating angiogenin levels was estimated in patients and controls. RESULTS: All SNPs showed association with ALS in the Irish group. The SNP rs17114699 replicated in the Swedish cohort. No SNP associated in the Polish cohort. Age- and sex-corrected circulating angiogenin levels were significantly lower in patients than in controls (p<0.001. An allele dose-dependent regulation of angiogenin levels was observed in controls. This regulation was attenuated in the ALS cohort. A significant positive correlation between CSF plasma angiogenin levels was present in controls and abolished in ALS. CONCLUSIONS: ANG variants associate with ALS in the Irish and Swedish populations, but not in the Polish. There is evidence of dysregulation of angiogenin expression in plasma and CSF in sporadic ALS. Angiogenin expression is likely to be important in the pathogenesis of ALS.

  5. Early interference with p44/42 mitogen-activated protein kinase signaling in hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension.

    Science.gov (United States)

    Yu, Yang; Xue, Bao-Jian; Zhang, Zhi-Hua; Wei, Shun-Guang; Beltz, Terry G; Guo, Fang; Johnson, Alan Kim; Felder, Robert B

    2013-04-01

    Blood-borne angiotensin II (ANG II) can upregulate p44/42 mitogen-activated protein kinase (MAPK) signaling and ANG II type-1 receptors in the hypothalamic paraventricular nucleus (PVN), a critical cardiovascular and autonomic center. We tested the hypothesis that brain p44/42 MAPK signaling contributes to the development of ANG II-induced hypertension. The ANG II infusion (120 ng/kg per min, subcutaneously) induced increases in phosphorylated p44/42 MAPK and ANG II type-1 receptors in the PVN after 1 week, before the onset of hypertension, that were sustained as hypertension developed during a 2- or 3-week infusion protocol. Bilateral PVN microinjections of small interfering RNAs for p44/42 MAPK, at the onset of the ANG II infusion or 1 week later, prevented the early increase in p44/42 MAPK activity. The early treatment normalized ANG II type-1 receptor expression in the PVN and attenuated the hypertensive response to the 2-week infusion of ANG II. The later small interfering RNA microinjections had a transient effect on ANG II type-1 receptor expression in PVN and no effect on the hypertensive response to the 3-week infusion of ANG II. The early treatment also normalized the pressure response to ganglionic blockade. The ANG II infusion induced increases in mRNA for proinflammatory cytokines that were not affected by either small interfering RNA treatment. These results suggest that the full expression of ANG II-induced hypertension depends on p44/42 MAPK-mediated effects. A potential role for p44/42 MAPK in modulating the ANG II-induced central inflammatory response might also be considered. MAPK signaling in PVN may be a novel target for early intervention in the progression of ANG II-dependent hypertension.

  6. Mechanism of angiotensin II-induced arachidonic acid metabolite release in aortic smooth muscle cells: involvement of phospholipase D.

    Science.gov (United States)

    Shinoda, J; Kozawa, O; Suzuki, A; Watanabe-Tomita, Y; Oiso, Y; Uematsu, T

    1997-02-01

    In a previous study, we have shown that angiotensin II (Ang II) activates phosphatidylcholine-hydrolyzing phospholipase D due to Ang II-induced Ca2+ influx from extracellular space in subcultured rat aortic smooth muscle cells. In the present study, we have investigated the role of phospholipase D in Ang II-induced arachidonic acid (AA) metabolite release and prostacyclin synthesis in subcultured rat aortic smooth muscle cells. Ang II significantly stimulated AA metabolite release in a concentration-dependent manner in the range between 1 nmol/I and 0.1 mumol/I. D.L.-Propranolol hydrochloride (propranolol), an inhibitor of phosphatidic acid phosphohydrolase, significantly inhibited the Ang II-induced release of AA metabolites. The Ang II-induced AA metabolite release was reduced by chelating extracellular Ca2+ with EGTA. Genistein, an inhibitor of protein tyrosine kinases, significantly suppressed the Ang II-induced AA metabolite release. 1,6-Bis-(cyclohexyloximinocarbonylamino)-hexane (RHC-80267), a potent and selective inhibitor of diacylglycerol lipase, significantly inhibited the Ang II-induced AA metabolite release. Both propranolol and RHC-80267 inhibited the Ang II-induced synthesis of 6-keto-prostaglandin F1 alpha, a stable metabolite of prostacyclin. The synthesis was suppressed by genistein. These results strongly suggest that the AA metabolite release induced by Ang II is mediated, at least in part, through phosphatidylcholine hydrolysis by phospholipase D activation in aortic smooth muscle cells.

  7. Angiotensin-II mediates ACE2 Internalization and Degradation through an Angiotensin-II type I receptor-dependent mechanism

    OpenAIRE

    Deshotels, Matthew R.; Xia, Huijing; Lazartigues, Eric; Filipeanu, Catalin M.

    2014-01-01

    Angiotensin Converting Enzyme type 2 (ACE2) is a pivotal component of the renin-angiotensin system, promoting the conversion of Angiotensin (Ang)-II to Ang-(1-7). We previously reported that decreased ACE2 expression and activity contribute to the development of Ang-II-mediated hypertension in mice. The present study aimed to investigate the mechanisms involved in ACE2 down-regulation during neurogenic hypertension. In ACE2-transfected Neuro-2A cells, Ang-II treatment resulted in a significan...

  8. Mas receptor mediates cardioprotection of angiotensin-(1-7) against Angiotensin II-induced cardiomyocyte autophagy and cardiac remodelling through inhibition of oxidative stress.

    Science.gov (United States)

    Lin, Li; Liu, Xuebo; Xu, Jianfeng; Weng, Liqing; Ren, Jun; Ge, Junbo; Zou, Yunzeng

    2016-01-01

    Angiotensin II (Ang II) plays an important role in the onset and development of cardiac remodelling associated with changes of autophagy. Angiotensin1-7 [Ang-(1-7)] is a newly established bioactive peptide of renin-angiotensin system, which has been shown to counteract the deleterious effects of Ang II. However, the precise impact of Ang-(1-7) on Ang II-induced cardiomyocyte autophagy remained essentially elusive. The aim of the present study was to examine if Ang-(1-7) inhibits Ang II-induced autophagy and the underlying mechanism involved. Cultured neonatal rat cardiomyocytes were exposed to Ang II for 48 hrs while mice were infused with Ang II for 4 weeks to induce models of cardiac hypertrophy in vitro and in vivo. LC3b-II and p62, markers of autophagy, expression were significantly elevated in cardiomyocytes, suggesting the presence of autophagy accompanying cardiac hypertrophy in response to Ang II treatment. Besides, Ang II induced oxidative stress, manifesting as an increase in malondialdehyde production and a decrease in superoxide dismutase activity. Ang-(1-7) significantly retarded hypertrophy, autophagy and oxidative stress in the heart. Furthermore, a role of Mas receptor in Ang-(1-7)-mediated action was assessed using A779 peptide, a selective Mas receptor antagonist. The beneficial responses of Ang-(1-7) on cardiac remodelling, autophagy and oxidative stress were mitigated by A779. Taken together, these result indicated that Mas receptor mediates cardioprotection of angiotensin-(1-7) against Ang II-induced cardiomyocyte autophagy and cardiac remodelling through inhibition of oxidative stress. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  9. Angiotensin II impairs endothelial progenitor cell number and function in vitro and in vivo: implications for vascular regeneration.

    Science.gov (United States)

    Endtmann, Cathleen; Ebrahimian, Talin; Czech, Thomas; Arfa, Omar; Laufs, Ulrich; Fritz, Mathias; Wassmann, Kerstin; Werner, Nikos; Petoumenos, Vasileios; Nickenig, Georg; Wassmann, Sven

    2011-09-01

    Endothelial progenitor cells (EPCs) contribute to endothelial regeneration. Angiotensin II (Ang II) through Ang II type 1 receptor (AT(1)-R) activation plays an important role in vascular damage. The effect of Ang II on EPCs and the involved molecular mechanisms are incompletely understood. Stimulation with Ang II decreased the number of cultured human early outgrowth EPCs, which express both AT(1)-R and Ang II type 2 receptor, mediated through AT(1)-R activation and induction of oxidative stress. Ang II redox-dependently induced EPC apoptosis through increased apoptosis signal-regulating kinase 1, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase phosphorylation; decreased Bcl-2 and increased Bax expression; and activation of caspase 3 but had no effect on the low cell proliferation. In addition, Ang II impaired colony-forming and migratory capacities of early outgrowth EPCs. Ang II infusion diminished numbers and functional capacities of EPCs in wild-type (WT) but not AT(1)a-R knockout mice (AT(1)a(-/-)). Reendothelialization after focal carotid endothelial injury was decreased during Ang II infusion. Salvage of reendothelialization by intravenous application of spleen-derived progenitor cells into Ang II-treated WT mice was pronounced with AT(1)a(-/-) cells compared with WT cells, and transfusion of Ang II-pretreated WT cells into WT mice without Ang II infusion was associated with less reendothelialization. Transplantation of AT(1)a(-/-) bone marrow reduced atherosclerosis development in cholesterol-fed apolipoprotein E-deficient mice compared with transplantation of apolipoprotein E-deficient or WT bone marrow. Randomized treatment of patients with stable coronary artery disease with the AT(1)-R blocker telmisartan significantly increased the number of circulating CD34/KDR-positive EPCs. Ang II through AT(1)-R activation, oxidative stress, and redox-sensitive apoptosis signal-regulating kinase 1-dependent proapoptotic pathways impairs EPCs in

  10. Mechanisms of angiotensin II stimulation of NCC are time-dependent in mDCT15 cells.

    Science.gov (United States)

    Ko, Benjamin; Mistry, Abinash; Hanson, Lauren; Mallick, Rickta; Hoover, Robert S

    2015-04-01

    Angiotensin II (ANG II) increases thiazide-sensitive sodium-chloride cotransporter (NCC) activity both acutely and chronically. ANG II has been implicated as a switch that turns WNK4 from an inhibitor of NCC into an activator of NCC, and ANG II's effect on NCC appears to require WNK4. Chronically, ANG II stimulation of NCC results in an increase in total and phosphorylated NCC, but the role of NCC phosphorylation in acute ANG II actions is unclear. Here, using a mammalian cell model with robust native NCC activity, we corroborate the role that ANG II plays in WNK4 regulation and clarify the role of Ste20-related proline alanine-rich kinase (SPAK)-induced NCC phosphorylation in ANG II action. ANG II was noted to have a biphasic effect on NCC, with a peak increase in NCC activity in the physiologic range of 10(-11) M ANG II. This effect was apparent as early as 15 min and remained sustained through 120 min. These changes correlated with significant increases in NCC surface protein expression. Knockdown of WNK4 expression sharply attenuated the effect of ANG II. SPAK knockdown did not affect ANG II action at early time points (15 and 30 min), but it did attenuate the response at 60 min. Correspondingly, NCC phosphorylation did not increase at 15 or 30 min, but increased significantly at 60 min. We therefore conclude that within minutes of an increase in ANG II, NCC is rapidly trafficked to the cell surface in a phosphorylation-independent but WNK4-dependent manner. Then, after 60 min, ANG II induces SPAK-dependent phosphorylation of NCC.

  11. Angiotensin I conversion to angiotensin II stimulates cortical collecting duct sodium transport.

    Science.gov (United States)

    Komlosi, Peter; Fuson, Amanda L; Fintha, Attila; Peti-Peterdi, János; Rosivall, Laszlo; Warnock, David G; Bell, Phillip Darwin

    2003-08-01

    Angiotensin (Ang) II directly stimulates epithelial sodium channel activity in the rabbit cortical collecting duct. Because Ang I and converting enzyme analogues might be present in the distal nephron, this raises the possibility of intraluminal generation of Ang II. Conversion of Ang I to Ang II was monitored by Ang II-dependent changes in intracellular sodium concentration as a reflection of sodium transport across the apical membrane. This involved imaging-based fluorescence microscopy with sodium-binding benzofuran isophthalate in isolated, perfused, cortical collecting-duct segments from rabbit kidney. Principal and intercalated cells were differentiated by rhodamine-conjugated peanut lectin. Control principal cell intracellular sodium concentration, during perfusion with 25 mmol/L NaCl and zero sodium in the bath plus monensin (10(-5) mol/L) averaged 5.8+/-0.14 mmol/L (n=156). The increase in intracellular sodium concentration, when luminal NaCl was increased from 25 to 150 mmol/L, was elevated by 3.5-fold in the presence of intraluminal Ang I (10(-6) mol/L). Also, the effects of Ang I on sodium transport were not significantly different from the effects of Ang II (10(-9) mol/L). Ang I was used in micromolar concentrations to ensure that there was sufficient substrate available for conversion to Ang II. Inhibition of the angiotensin-converting enzyme with captopril reduced the stimulatory effect of Ang I. These results suggest that intraluminal conversion of Ang I to Ang II can occur in the cortical collecting duct, resulting in enhanced apical sodium entry.

  12. Angiotensin II contributes to renal fibrosis independently of Notch pathway activation.

    Directory of Open Access Journals (Sweden)

    Carolina Lavoz

    Full Text Available Recent studies have described that the Notch signaling pathway is activated in a wide range of renal diseases. Angiotensin II (AngII plays a key role in the progression of kidney diseases. AngII contributes to renal fibrosis by upregulation of profibrotic factors, induction of epithelial mesenchymal transition and accumulation of extracellular matrix proteins. In cultured human tubular epithelial cells the Notch activation by transforming growth factor-β1 (TGF-β1 has been involved in epithelial mesenchymal transition. AngII mimics many profibrotic actions of TGF-β1. For these reasons, our aim was to investigate whether AngII could regulate the Notch/Jagged system in the kidney, and its potential role in AngII-induced responses. In cultured human tubular epithelial cells, TGF-β1, but not AngII, increased the Notch pathway-related gene expression, Jagged-1 synthesis, and caused nuclear translocation of the activated Notch. In podocytes and renal fibroblasts, AngII did not modulate the Notch pathway. In tubular epithelial cells, pharmacological Notch inhibition did not modify AngII-induced changes in epithelial mesenchymal markers, profibrotic factors and extracellular matrix proteins. Systemic infusion of AngII into rats for 2 weeks caused tubulointerstitial fibrosis, but did not upregulate renal expression of activated Notch-1 or Jagged-1, as observed in spontaneously hypertensive rats. Moreover, the Notch/Jagged system was not modulated by AngII type I receptor blockade in the model of unilateral ureteral obstruction in mice. These data clearly indicate that AngII does not regulate the Notch/Jagged signaling system in the kidney, in vivo and in vitro. Our findings showing that the Notch pathway is not involved in AngII-induced fibrosis could provide important information to understand the complex role of Notch system in the regulation of renal regeneration vs damage progression.

  13. Angiotensin II contributes to renal fibrosis independently of Notch pathway activation.

    Science.gov (United States)

    Lavoz, Carolina; Rodrigues-Diez, Raquel; Benito-Martin, Alberto; Rayego-Mateos, Sandra; Rodrigues-Diez, Raúl R; Alique, Matilde; Ortiz, Alberto; Mezzano, Sergio; Egido, Jesús; Ruiz-Ortega, Marta

    2012-01-01

    Recent studies have described that the Notch signaling pathway is activated in a wide range of renal diseases. Angiotensin II (AngII) plays a key role in the progression of kidney diseases. AngII contributes to renal fibrosis by upregulation of profibrotic factors, induction of epithelial mesenchymal transition and accumulation of extracellular matrix proteins. In cultured human tubular epithelial cells the Notch activation by transforming growth factor-β1 (TGF-β1) has been involved in epithelial mesenchymal transition. AngII mimics many profibrotic actions of TGF-β1. For these reasons, our aim was to investigate whether AngII could regulate the Notch/Jagged system in the kidney, and its potential role in AngII-induced responses. In cultured human tubular epithelial cells, TGF-β1, but not AngII, increased the Notch pathway-related gene expression, Jagged-1 synthesis, and caused nuclear translocation of the activated Notch. In podocytes and renal fibroblasts, AngII did not modulate the Notch pathway. In tubular epithelial cells, pharmacological Notch inhibition did not modify AngII-induced changes in epithelial mesenchymal markers, profibrotic factors and extracellular matrix proteins. Systemic infusion of AngII into rats for 2 weeks caused tubulointerstitial fibrosis, but did not upregulate renal expression of activated Notch-1 or Jagged-1, as observed in spontaneously hypertensive rats. Moreover, the Notch/Jagged system was not modulated by AngII type I receptor blockade in the model of unilateral ureteral obstruction in mice. These data clearly indicate that AngII does not regulate the Notch/Jagged signaling system in the kidney, in vivo and in vitro. Our findings showing that the Notch pathway is not involved in AngII-induced fibrosis could provide important information to understand the complex role of Notch system in the regulation of renal regeneration vs damage progression.

  14. Angiotensin II receptor alterations during pregnancy in rabbits

    Energy Technology Data Exchange (ETDEWEB)

    Brown, G.P.; Venuto, R.C.

    1986-07-01

    Despite activation of the renin-angiotensin system during pregnancy, renal and peripheral vascular blood flows increase, and the systemic blood pressure and the pressor response to exogenous angiotensin II (Ang II) fall. Gestational alterations in Ang II receptors could contribute to these changes. Ang II binding parameters were determining utilizing SVI-Ang II in vascular (glomeruli and mesenteric arteries) and nonvascular (adrenal glomerulosa) tissues from 24- to 28-day pregnant rabbits. Comparisons were made utilizing tissues from nonpregnant rabbits. Binding site concentrations (N) and dissociation constants (K/sub d/) were obtained by Scatchard analyses of binding inhibition data. Meclofenamate (M) inhibits prostaglandin synthesis, reduces plasma renin activity, and enhances the pressor response to infused Ang II in pregnant rabbits. Administration of M to pregnant rabbits increased N in glomerular and in mesenteric artery membranes. These data demonstrate that Ang II receptors in glomeruli and mesenteric arteries are down regulated during gestation in rabbits. Elevated endogenous Ang II during pregnancy in rabbits may contribute to the down regulation of vascular Ang II receptors.

  15. Angiotensin II modulates the intrarenal effects of atrial natriuretic peptide.

    Science.gov (United States)

    Siragy, H M; Lamb, N E; Rose, C E; Peach, M J; Carey, R M

    1988-09-01

    The mechanism by which atrial natriuretic peptide (ANP) increases renal water and solute excretion is not fully understood. We studied the renal effects of ANP and angiotensin II (ANG II) separately and together in uninephrectomized conscious dogs (n = 7) in sodium metabolic balance (80 meq/day). Exogenous ANG II and ANP were without measurable systemic effects as demonstrated by absence of changes in blood pressure, plasma aldosterone concentration, and plasma renin activity. The quantity of ANG II that had significant renal effects that were without measurable systemic effects was 0.2 pmol.kg-1.min-1. Three infusion rates of ANP had significant renal effects (1, 10, and 20 pmol.kg-1.min-1). These quantities of ANP caused significant diuresis, natriuresis, kaliuresis, and increased glomerular filtration rate without significant changes in renal plasma flow. ANG II alone caused significant antidiuresis, antinatriuresis, and decreased glomerular filtration rate and renal plasma flow. When ANG II and ANP were given together, no change in urinary flow rate, urinary sodium or potassium excretion, or renal plasma flow was observed, whereas glomerular filtration rate increased. Filtration fraction increased significantly with ANG II and ANP separately and together. Intrarenal ANP prevents the ANG II-induced decrement in urinary sodium excretion and urine flow rate. ANP may play an important role in escape from the sodium-retaining action of intrarenal ANG II.

  16. Construction of Ang2-siRNA chitosan magnetic nanoparticles and the effect on Ang2 gene expression in human malignant melanoma cells

    Science.gov (United States)

    LIU, ZHAO-LIANG; YOU, CAI-LIAN; WANG, BIAO; LIN, JIAN-HONG; HU, XUE-FENG; SHAN, XIU-YING; WANG, MEI-SHUI; ZHENG, HOU-BING; ZHANG, YAN-DING

    2016-01-01

    The aim of the present study was to construct angiopoietin-2 (Ang2)-small interfering (si)RNA chitosan magnetic nanoparticles and to observe the interference effects of the nanoparticles on the expression of the Ang2 gene in human malignant melanoma cells. Ang2-siRNA chitosan magnetic nanoparticles were constructed and transfected into human malignant melanoma cells in vitro. Red fluorescent protein expression was observed, and the transfection efficiency was analyzed. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to assess the inhibition efficiency of Ang2 gene expression. Ang2-siRNA chitosan magnetic nanoparticles were successfully constructed, and at a mass ratio of plasmid to magnetic chitosan nanoparticles of 1:100, the transfection efficiency into human malignant melanoma cells was the highest of the ratios assessed, reaching 61.17%. RT-qPCR analysis showed that the magnetic chitosan nanoparticles effectively inhibited Ang2 gene expression in cells, and the inhibition efficiency reached 59.56% (P<0.05). Ang2-siRNA chitosan magnetic nanoparticles were successfully constructed. The in vitro studies showed that the nanoparticles inhibited Ang2 gene expression in human malignant melanoma tumor cells, which laid the foundation and provided experimental evidence for additional future in vivo studies of intervention targeting malignant melanoma tumor growth in nude mice. PMID:27313729

  17. A structural feature of the non-peptide ligand interactions with mice mu-opioid receptors.

    Science.gov (United States)

    Noori, Hamid R; Mucksch, Christian; Urbassek, Herbert M

    2014-01-01

    By binding to and activating the G-protein coupled μ-, κ- and δ-opioid receptors in the central nervous system, opiates are known to induce analgesic and sedative effects. In particular, non-peptide opioid ligands are often used in clinical applications to induce these therapeutically beneficial effects, due to their superior pharmacokinetics and bioavailability in comparison to endogenous neuropeptides. However, since opioid alkaloids are highly addictive substances, it is necessary to understand the exact mechanisms of their actions, specifically the ligand-binding properties of the target receptors, in order to safely apply opiates for therapeutic purposes. Using an in silico molecular docking approach (AutoDock Vina) combined with two-step cluster analysis, we have computationally obtained the docking scores and the ligand-binding pockets of twelve representative non-peptide nonendogenous agonists and antagonists at the crystallographically identified μ-opioid receptor. Our study predicts the existence of two main binding sites that are congruently present in all opioid receptor types. Interestingly, in terms of the agonist or antagonist properties of the substances on the receptors, the clustering analysis suggests a relationship with the position of the ligand-binding pockets, particularly its depth within the receptor structure. Furthermore, the binding affinity of the substances is directly correlated to the proximity of the binding pockets to the extracellular space. In conclusion, the results provide further insights into the structural features of the functional pharmacology of opioid receptors, suggesting the importance of the binding position of non-peptide agonists and antagonists- specifically the distance and the level of exposure to the extracellular space- to their dissociation kinetics and subsequent potency.

  18. A peptide vaccine targeting angiotensin II attenuates the cardiac dysfunction induced by myocardial infarction

    Science.gov (United States)

    Watanabe, Ryo; Suzuki, Jun-ichi; Wakayama, Kouji; Maejima, Yasuhiro; Shimamura, Munehisa; Koriyama, Hiroshi; Nakagami, Hironori; Kumagai, Hidetoshi; Ikeda, Yuichi; Akazawa, Hiroshi; Morishita, Ryuichi; Komuro, Issei; Isobe, Mitsuaki

    2017-01-01

    A peptide vaccine targeting angiotensin II (Ang II) was recently developed as a novel treatment for hypertension to resolve the problem of noncompliance with pharmacotherapy. Ang II plays a crucial role in the pathogenesis of cardiac remodeling after myocardial infarction (MI), which causes heart failure. In the present study, we examined whether the Ang II vaccine is effective in preventing heart failure. The injection of the Ang II vaccine in a rat model of MI attenuated cardiac dysfunction in association with an elevation in the serum anti-Ang II antibody titer. Furthermore, any detrimental effects of the Ang II vaccine were not observed in the rats that underwent sham operations. Treatment with immunized serum from Ang II vaccine-injected rats significantly suppressed post-MI cardiac dysfunction in MI rats and Ang II-induced remodeling-associated signaling in cardiac fibroblasts. Thus, our present study demonstrates that the Ang II vaccine may provide a promising novel therapeutic strategy for preventing heart failure. PMID:28266578

  19. Angiotensin II attenuates the natriuresis of water immersion in humans

    DEFF Research Database (Denmark)

    Schou, Morten; Gabrielsen, Anders; Bruun, Niels Eske;

    2002-01-01

    (-1) (WI + ANG II-low), and 3) a seated time control (Con). In another almost identical protocol, 7-10 healthy young males were investigated to delineate the tubular site(s) of action of ANG II by the lithium clearance method (C(Li)) and were on an additional fourth study day subjected to infusion...

  20. Hemopexin activity is associated with angiotensin II responsiveness in humans

    NARCIS (Netherlands)

    Krikken, Jan A.; Lely, Anna T.; Borghuis, Theo; Faas, Marijke M.; van Goor, Harry; Navis, Gerjan; Bakker, Stephanus; Bakker, Willem

    2013-01-01

    Background: Hemopexin, an acute phase protein, can downregulate the angiotensin (ang) II type 1 receptor (AT1-R) in vitro. Whether hemopexin is involved in the responsiveness to ang II in vivo is unknown. Therefore, we tested whether variations in endogenous hemopexin activity are associated with th

  1. Alternative pathways for angiotensin II generation in the cardiovascular system

    Directory of Open Access Journals (Sweden)

    C. Becari

    2011-09-01

    Full Text Available The classical renin-angiotensin system (RAS consists of enzymes and peptides that regulate blood pressure and electrolyte and fluid homeostasis. Angiotensin II (Ang II is one of the most important and extensively studied components of the RAS. The beneficial effects of angiotensin converting enzyme (ACE inhibitors in the treatment of hypertension and heart failure, among other diseases, are well known. However, it has been reported that patients chronically treated with effective doses of these inhibitors do not show suppression of Ang II formation, suggesting the involvement of pathways alternative to ACE in the generation of Ang II. Moreover, the finding that the concentration of Ang II is preserved in the kidney, heart and lungs of mice with an ACE deletion indicates the important role of alternative pathways under basal conditions to maintain the levels of Ang II. Our group has characterized the serine protease elastase-2 as an alternative pathway for Ang II generation from Ang I in rats. A role for elastase-2 in the cardiovascular system was suggested by studies performed in heart and conductance and resistance vessels of normotensive and spontaneously hypertensive rats. This mini-review will highlight the pharmacological aspects of the RAS, emphasizing the role of elastase-2, an alternative pathway for Ang II generation.

  2. Aldosterone breakthrough caused by chronic blockage of angiotensin II type 1 receptors in human adrenocortical cells: possible involvement of bone morphogenetic protein-6 actions.

    Science.gov (United States)

    Otani, Hiroyuki; Otsuka, Fumio; Inagaki, Kenichi; Suzuki, Jiro; Miyoshi, Tomoko; Kano, Yoshihiro; Goto, Junko; Ogura, Toshio; Makino, Hirofumi

    2008-06-01

    Circulating aldosterone concentrations occasionally increase after initial suppression with angiotensin II (Ang II) converting enzyme inhibitors or Ang II type 1 receptor blockers (ARBs), a phenomenon referred to as aldosterone breakthrough. However, the underlying mechanism causing the aldosterone breakthrough remains unknown. Here we investigated whether aldosterone breakthrough occurs in human adrenocortical H295R cells in vitro. We recently reported that bone morphogenetic protein (BMP)-6, which is expressed in adrenocortical cells, enhances Ang II- but not potassium-induced aldosterone production in human adrenocortical cells. Accordingly, we examined the roles of BMP-6 in aldosterone breakthrough induced by long-term treatment with ARB. Ang II stimulated aldosterone production by adrenocortical cells. This Ang II stimulation was blocked by an ARB, candesartan. Interestingly, the candesartan effects on Ang II-induced aldosterone synthesis and CYP11B2 expression were attenuated in a course of candesartan treatment for 15 d. The impairment of candesartan effects on Ang II-induced aldosterone production was also observed in Ang II- or candesartan-pretreated cells. Levels of Ang II type 1 receptor mRNA were not changed by chronic candesartan treatment. However, BMP-6 enhancement of Ang II-induced ERK1/2 signaling was resistant to candesartan. The BMP-6-induced Smad1, -5, and -8 phosphorylation, and BRE-Luc activity was augmented in the presence of Ang II and candesartan in the chronic phase. Chronic Ang II exposure decreased cellular expression levels of BMP-6 and its receptors activin receptor-like kinase-2 and activin type II receptor mRNAs. Cotreatment with candesartan reversed the inhibitory effects of Ang II on the expression levels of these mRNAs. The breakthrough phenomenon was attenuated by neutralization of endogenous BMP-6 and activin receptor-like kinase-2. Collectively, these data suggest that changes in BMP-6 availability and response may be involved

  3. Insight into the interactive residues between two domains of human somatic Angiotensin-converting enzyme and Angiotensin II by MM-PBSA calculation and steered molecular dynamics simulation.

    Science.gov (United States)

    Guan, Shan-shan; Han, Wei-wei; Zhang, Hao; Wang, Song; Shan, Ya-ming

    2016-01-01

    Angiotensin-converting enzyme (ACE), a membrane-bound zinc metallopeptidase, catalyzes the formation of Angiotensin-II (AngII) and the deactivation of bradykinin in the renin-angiotensin-aldosterone and kallikrein-kinin systems. As a hydrolysis product of ACE, AngII is regarded as an inhibitor and displays stronger competitive inhibition in the C-domain than the N-domain of ACE. However, the AngII binding differences between the two domains and the mechanisms behind AngII dissociation from the C-domain are rarely explored. In this work, molecular docking, Molecular Mechanics/Poisson-Boltzmann Surface Area calculation, and steered molecular dynamics (SMD) are applied to explore the structures and interactions in the binding or unbinding of AngII with the two domains of human somatic ACE. Calculated free energy values suggest that the C-domain-AngII complex is more stable than the N-domain-AngII complex, consistent with available experimental data. SMD simulation results imply that electrostatic interaction is dominant in the dissociation of AngII from the C-domain. Moreover, Gln106, Asp121, Glu123, and Tyr213 may be the key residues in the unbinding pathway of AngII. The simulation results in our work provide insights into the interactions between the two domains of ACE and its natural peptide inhibitor AngII at a molecular level. Moreover, the results provide theoretical clues for the design of new inhibitors.

  4. Vasopressin and sympathetic system mediate the cardiovascular effects of the angiotensin II in the bed nucleus of the stria terminalis in rat.

    Science.gov (United States)

    Nasimi, Ali; Kafami, Marzieh

    2016-07-01

    The bed nucleus of the stria terminalis (BST) is involved in cardiovascular regulation. The angiotensin II (Ang II) receptor (AT1), and angiotensinogen were found in the BST. In our previous study we found that microinjection of Ang II into the BST produced a pressor response. This study was performed to find the mechanisms mediating this response in anesthetized rats. Ang II was microinjected into the BST and the cardiovascular responses were re-tested after systemic injection of a blocker of autonomic or vasopressin V1 receptor. The ganglionic nicotinic receptor blocker, hexamethonium dichloride, attenuated the pressor response to Ang II, indicating that the cardiovascular sympathetic system is involved in the pressor effect of Ang II. A selective vasopressin V1 receptor antagonist greatly attenuated the pressor effect of Ang II, indicating that the Ang II increases the arterial pressure via stimulation of vasopressin release as well. In conclusion, in the BST, Ang II as a neurotransmitter increases blood pressure by exciting cardiovascular sympathetic system and directly or indirectly causing vasopressin to release into bloodstream by VPN. This is an interesting new finding that not only circulating Ang II but also brain Ang II makes vasopressin release. Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  5. Exergy of LNG regasification - possible utilization method. Case study of LNG - ANG coupling

    Science.gov (United States)

    Roszak, E. A.; Chorowski, M.

    2014-01-01

    This article gives an overview on new exergy recovery methods for LNG. The concept is based on coupling the LNG regasification unit with the filling process of Adsorbed Natural Gas (ANG) tanks. The latent heat of the LNG vaporization is directly used for precooling the ANG adsorption bed. This reduces the back pressure from filling ANG tanks due to strong adsorption temperature dependency. This improves the economic attractiveness of ANG storage (no need for compressors, longer lifetime cycle of adsorbent). This case study presents the concept of LNG - ANG coupling. Presented results are based on experimental adsorption data. A brief exergy analysis of the process shows an advantage of this method over others. This LNG-ANG method is worth consideration as a cost optimizing solution, especially for periodically working regasification stations.

  6. Angiotensin II increases nerve-evoked contractions in mouse tail artery by a T-type Ca(2+) channel-dependent mechanism.

    Science.gov (United States)

    Reardon, Trent F; Callaghan, Brid P; Brock, James A

    2015-08-15

    Angiotensin II (Ang II) increases sympathetic nerve-evoked contractions of arterial vessels. Here the mechanisms underlying this effect were investigated in mouse tail artery. Isometrically mounted segments of mouse distal tail artery were used to investigate the effects of endothelium denudation, blocking Ca(2+) channels and inhibiting superoxide signalling on Ang II-induced facilitation of nerve-evoked contractions. In addition, in situ amperometry was used to assess effects of Ang II on noradrenaline release. Ang II (0.1-1nM) increased nerve-evoked contractions but did not change noradrenaline release. Losartan (Ang II type 1 receptor antagonist), but not PD 123319 (Ang II type 2 receptor antagonist), blocked the facilitatory effect of Ang II on nerve-evoked contractions. Ang II increased vascular muscle reactivity to phenylephrine and UK-14304 (α1- and α2-adrenoceptor agonists, respectively). Endothelial denudation increased nerve-evoked contractions and reduced the facilitatory effect of Ang II on these responses. Efonidipine (L- and T-type Ca(2+) channel blocker) and NNC 55-0396 (T-type Ca(2+) channel blocker) also attenuated this effect of Ang II, while nifedipine (L-type Ca(2+) channel blocker) did not. Blockers of superoxide generation/signalling did not change the facilitatory effect of Ang II on nerve-evoked contractions. The findings indicate that Ang II increases the contribution of T-type Ca(2+) channels to neural activation of the vascular muscle. In addition, Ang II appears to reduce the inhibitory influence of the endothelium on nerve-evoked contractions.

  7. Angiotensin II Removes Kidney Resistance Conferred by Ischemic Preconditioning

    Directory of Open Access Journals (Sweden)

    Hee-Seong Jang

    2014-01-01

    Full Text Available Ischemic preconditioning (IPC by ischemia/reperfusion (I/R renders resistance to the kidney. Strong IPC triggers kidney fibrosis, which is involved in angiotensin II (AngII and its type 1 receptor (AT1R signaling. Here, we investigated the role of AngII/AT1R signal pathway in the resistance of IPC kidneys to subsequent I/R injury. IPC of kidneys was generated by 30 minutes of bilateral renal ischemia and 8 days of reperfusion. Sham-operation was performed to generate control (non-IPC mice. To examine the roles of AngII and AT1R in IPC kidneys to subsequent I/R, IPC kidneys were subjected to either 30 minutes of bilateral kidney ischemia or sham-operation following treatment with AngII, losartan (AT1R blocker, or AngII plus losartan. IPC kidneys showed fibrotic changes, decreased AngII, and increased AT1R expression. I/R dramatically increased plasma creatinine concentrations in non-IPC mice, but not in IPC mice. AngII treatment in IPC mice resulted in enhanced morphological damage, oxidative stress, and inflammatory responses, with functional impairment, whereas losartan treatment reversed these effects. However, AngII treatment in non-IPC mice did not change I/R-induced injury. AngII abolished the resistance of IPC kidneys to subsequent I/R via the enhancement of oxidative stress and inflammatory responses, suggesting that the AngII/AT1R signaling pathway is associated with outcome in injury-experienced kidney.

  8. Construction of Ang2-siRNA chitosan magnetic nanoparticles and the effect on Ang2 gene expression in human malignant melanoma cells.

    Science.gov (United States)

    Liu, Zhao-Liang; You, Cai-Lian; Wang, Biao; Lin, Jian-Hong; Hu, Xue-Feng; Shan, Xiu-Ying; Wang, Mei-Shui; Zheng, Hou-Bing; Zhang, Yan-Ding

    2016-06-01

    The aim of the present study was to construct angiopoietin-2 (Ang2)-small interfering (si)RNA chitosan magnetic nanoparticles and to observe the interference effects of the nanoparticles on the expression of the Ang2 gene in human malignant melanoma cells. Ang2-siRNA chitosan magnetic nanoparticles were constructed and transfected into human malignant melanoma cells in vitro. Red fluorescent protein expression was observed, and the transfection efficiency was analyzed. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to assess the inhibition efficiency of Ang2 gene expression. Ang2-siRNA chitosan magnetic nanoparticles were successfully constructed, and at a mass ratio of plasmid to magnetic chitosan nanoparticles of 1:100, the transfection efficiency into human malignant melanoma cells was the highest of the ratios assessed, reaching 61.17%. RT-qPCR analysis showed that the magnetic chitosan nanoparticles effectively inhibited Ang2 gene expression in cells, and the inhibition efficiency reached 59.56% (Pconstructed. The in vitro studies showed that the nanoparticles inhibited Ang2 gene expression in human malignant melanoma tumor cells, which laid the foundation and provided experimental evidence for additional future in vivo studies of intervention targeting malignant melanoma tumor growth in nude mice.

  9. Captopril avoids hypertension, the increase in plasma angiotensin II but increases angiotensin 1-7 and angiotensin II-induced perfusion pressure in isolated kidney in SHR.

    Science.gov (United States)

    Castro-Moreno, P; Pardo, J P; Hernández-Muñoz, R; López-Guerrero, J J; Del Valle-Mondragón, L; Pastelín-Hernández, G; Ibarra-Barajas, M; Villalobos-Molina, R

    2012-10-01

    We investigated captopril effects, an ACE inhibitor, on hypertension development, on Ang II and Ang-(1-7) plasma concentrations, on Ang II-induced contraction in isolated kidneys, and on kidney AT1R from spontaneously hypertensive (SHR) rats. Five weeks-old SHR and Wistar Kyoto (WKY) rats were treated with captopril at 30 mg/kg/day, in drinking water for 2 or 14 weeks. Systolic blood pressure (SBP) was measured, and isolated kidneys were tested for perfusion pressure and AT1R expression; while Ang II and Ang-(1-7) concentrations were determined in plasma. Captopril did not modify SBP in WKY rats and avoided its increase as SHR aged. Plasma Ang-II concentration was ∼4-5 folds higher in SHR rats, and captopril reduced it (Pcaptopril increased Ang-(1-7) by ∼2 fold in all rat groups. Captopril increased Ang II-induced pressor response in kidneys of WKY and SHR rats, phenomenon not observed in kidneys stimulated with phenylephrine, a α₁-adrenoceptor agonist. Captopril did not modify AT1R in kidney cortex and medulla among rat strains and ages. Data indicate that captopril increased Ang II-induced kidney perfusion pressure but not AT₁R density in kidney of WKY and SHR rats, due to blockade of angiotensin II synthesis; however, ACE inhibitors may have other actions like activating signaling processes that could contribute to their diverse effects. © 2012 Blackwell Publishing Ltd.

  10. Angiotensin II dependent cardiac remodeling in the eel Anguilla anguilla involves the NOS/NO system

    DEFF Research Database (Denmark)

    Filice, Mariacristina; Amelio, Daniela; Garofalo, Filippo

    2017-01-01

    Angiotensin II (AngII), the principal effector of the Renin-Angiotensin System (RAS), plays an important role in controlling mammalian cardiac morpho-functional remodelling. In the eel Anguilla anguilla, one month administration of AngII improves cardiac performance and influences the expression...

  11. Comparison of the antagonistic effects of different angiotensin II receptor blockers in human coronary arteries

    DEFF Research Database (Denmark)

    Pantev, Emil; Stenman, Emelie; Wackenfors, Angelica;

    2002-01-01

    BACKGROUND: Angiotensin II (Ang II) is a potent vasoconstrictor and a deleterious factor in cardiovascular pathophysiology. Ang II receptor blockers (ARBs) have recently been introduced into clinical practice for treatment of hypertension and congestive heart failure. AIMS: This study was underta...

  12. Angiotensin II upregulates the expression of placental growth factor in human vascular endothelial cells and smooth muscle cells

    Directory of Open Access Journals (Sweden)

    Guo Yingqiang

    2010-05-01

    Full Text Available Abstract Background Atherosclerosis is now recognized as a chronic inflammatory disease. Angiotensin II (Ang II is a critical factor in inflammatory responses, which promotes the pathogenesis of atherosclerosis. Placental growth factor (PlGF is a member of the vascular endothelial growth factor (VEGF family cytokines and is associated with inflammatory progress of atherosclerosis. However, the potential link between PlGF and Ang II has not been investigated. In the current study, whether Ang II could regulate PlGF expression, and the effect of PlGF on cell proliferation, was investigated in human vascular endothelial cells (VECs and smooth muscle cells (VSMCs. Results In growth-arrested human VECs and VSMCs, Ang II induced PlGF mRNA expression after 4 hour treatment, and peaked at 24 hours. 10-6 mol/L Ang II increased PlGF protein production after 8 hour treatment, and peaked at 24 hours. Stimulation with Ang II also induced mRNA expression of VEGF receptor-1 and -2(VEGFR-1 and -2 in these cells. The Ang II type I receptor (AT1R antagonist blocked Ang II-induced PlGF gene expression and protein production. Several intracellular signals elicited by Ang II were involved in PlGF synthesis, including activation of protein kinase C, extracellular signal-regulated kinase 1/2 (ERK1/2 and PI3-kinase. A neutralizing antibody against PlGF partially inhibited the Ang II-induced proliferation of VECs and VSMCs. However, this antibody showed little effect on the basal proliferation in these cells, whereas blocking antibody of VEGF could suppress both basal and Ang II-induced proliferation in VECs and VSMCs. Conclusion Our results showed for the first time that Ang II could induce the gene expression and protein production of PlGF in VECs and VSMCs, which might play an important role in the pathogenesis of vascular inflammation and atherosclerosis.

  13. GluVII:06--a highly conserved and selective anchor point for non-peptide ligands in chemokine receptors

    DEFF Research Database (Denmark)

    Rosenkilde, Mette M; Schwartz, Thue W

    2006-01-01

    to be crucially important for the binding and action of a number of non-peptide ligands in for example the CCR1, CCR2 and CCR5 receptors. It is proposed that in chemokine receptors in general GluVII:06 serves as a selective anchor point for the centrally located, positively charged nitrogen of the small molecule...

  14. Synergistic effect of angiotensin II on vascular endothelial growth factor-A-mediated differentiation of bone marrow-derived mesenchymal stem cells into endothelial cells

    OpenAIRE

    Ikhapoh, Izuagie Attairu; Pelham, Christopher J; Agrawal, Devendra K.

    2015-01-01

    Introduction Increased levels of angiotensin II (Ang II) and activity of Ang II receptor type 1 (AT1R) elicit detrimental effects in cardiovascular disease. However, the role of Ang II receptor type 2 (AT2R) remains poorly defined. Mesenchymal stem cells (MSCs) replenish and repair endothelial cells in the cardiovascular system. Herein, we investigated a novel role of angiotensin signaling in enhancing vascular endothelial growth factor (VEGF)-A-mediated differentiation of MSCs into endotheli...

  15. Long-Term Reduction of High Blood Pressure by Angiotensin II DNA Vaccine in Spontaneously Hypertensive Rats.

    Science.gov (United States)

    Koriyama, Hiroshi; Nakagami, Hironori; Nakagami, Futoshi; Osako, Mariana Kiomy; Kyutoku, Mariko; Shimamura, Munehisa; Kurinami, Hitomi; Katsuya, Tomohiro; Rakugi, Hiromi; Morishita, Ryuichi

    2015-07-01

    Recent research on vaccination has extended its scope from infectious diseases to chronic diseases, including Alzheimer disease, dyslipidemia, and hypertension. The aim of this study was to design DNA vaccines for high blood pressure and eventually develop human vaccine therapy to treat hypertension. Plasmid vector encoding hepatitis B core-angiotensin II (Ang II) fusion protein was injected into spontaneously hypertensive rats using needleless injection system. Anti-Ang II antibody was successfully produced in hepatitis B core-Ang II group, and antibody response against Ang II was sustained for at least 6 months. Systolic blood pressure was consistently lower in hepatitis B core-Ang II group after immunization, whereas blood pressure reduction was continued for at least 6 months. Perivascular fibrosis in heart tissue was also significantly decreased in hepatitis B core-Ang II group. Survival rate was significantly improved in hepatitis B core-Ang II group. This study demonstrated that Ang II DNA vaccine to spontaneously hypertensive rats significantly lowered high blood pressure for at least 6 months. In addition, Ang II DNA vaccines induced an adequate humoral immune response while avoiding the activation of self-reactive T cells, assessed by ELISPOT assay. Future development of DNA vaccine to treat hypertension may provide a new therapeutic option to treat hypertension.

  16. Angiotensin II in the paraventricular nucleus stimulates sympathetic outflow to the cardiovascular system and make vasopressin release in rat.

    Science.gov (United States)

    Khanmoradi, Mehrangiz; Nasimi, Ali

    2016-10-06

    The hypothalamic paraventricular nucleus (PVN) plays essential roles in neuroendocrine and autonomic functions, including cardiovascular regulation. It was shown that microinjection of angiotensin II (AngII) into the PVN produced a pressor response. In this study, we explored the probable mechanisms of this pressor response. AngII was microinjected into the PVN and cardiovascular responses were recorded. Then, the responses were re-tested after systemic injection of a ganglionic blocker, Hexamethonium, or a vasopressin V1 receptor blocker. Hexamethonium pretreatment (i.v.) greatly and significantly attenuated the pressor response to AngII, with no significant effect on heart rate, indicating that the sympathetic system is involved in the cardiovascular effect of AngII in the PVN. Systemic pretreatment (i.v.) with V1 antagonist greatly and significantly attenuated the pressor response to AngII, with no significant effect on heart rate, indicating that vasopressin release is involved in the cardiovascular effect of AngII in the PVN. Overall, we found that AngII microinjected into the PVN produced a pressor response mediated by the sympathetic system and vasopressin release, indicating that other than circulating AngII, endogenous AngII of the PVN increases the vasopressin release from the PVN. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. Endogenous angiotensin II in the paraventricular nucleus regulates arterial pressure during hypotension in rat, a single-unit study.

    Science.gov (United States)

    Khanmoradi, Mehrangiz; Nasimi, Ali

    2017-01-01

    The hypothalamic paraventricular nucleus (PVN) controls cardiovascular regulation through vasopressin and sympathetic system. The PVN contains angiotensin II (AngII) and AngII receptors. We have already shown that microinjection of AngII into PVN produced a pressor response concomitant with an increase in firing rate of some PVN neurons. This study was performed to find if PVN AngII plays a regulatory function during hypotension. Hypovolemic-hypotension was induced and the possible role of the PVN AngII in returning arterial pressure toward normal was assessed by monitoring cardiovascular response and single-unit activity of the PVN neurons. Hemorrhage augmented the pressor, tachycardic and single-unit responses to AngII. After-hemorrhage injection of PD123319, an AT2 antagonist, into PVN resulted in a significant decrease in firing rate of some neurons, indicating that AngII was released into the PVN due to hemorrhage. Using single-unit recording, we found that PVN receives electrical signals from baroreceptors and from circulating AngII through circumventricular organs. In addition, by producing hemorrhagic-hypotension and bilateral blockade of AT2 receptors of the PVN, we found that AngII regulates arterial pressure toward normal during hypotension. So for the first time, it was verified that brain renin-angiotensin system is also a major regulatory system of the cardiovascular system. Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  18. Angiotensin II induces kidney inflammatory injury and fibrosis through binding to myeloid differentiation protein-2 (MD2)

    Science.gov (United States)

    Xu, Zheng; Li, Weixin; Han, Jibo; Zou, Chunpeng; Huang, Weijian; Yu, Weihui; Shan, Xiaoou; Lum, Hazel; Li, Xiaokun; Liang, Guang

    2017-01-01

    Growing evidence indicates that angiotensin II (Ang II), a potent biologically active product of RAS, is a key regulator of renal inflammation and fibrosis. In this study, we tested the hypothesis that Ang II induces renal inflammatory injury and fibrosis through interaction with myeloid differentiation protein-2 (MD2), the accessory protein of toll-like receptor 4 (TLR4) of the immune system. Results indicated that in MD2−/− mice, the Ang II-induced renal fibrosis, inflammation and kidney dysfunction were significantly reduced compared to control Ang II-infused wild-type mice. Similarly, in the presence of small molecule MD2 specific inhibitor L6H21 or siRNA-MD2, the Ang II-induced increases of pro-fibrotic and pro-inflammatory molecules were prevented in tubular NRK-52E cells. MD2 blockade also inhibited activation of NF-κB and ERK. Moreover, MD2 blockade prevented the Ang II-stimulated formation of the MD2/TLR4/MyD88 signaling complex, as well as the increased surface binding of Ang II in NRK-52E cells. In addition, Ang II directly bound recombinant MD2 protein, rather than TLR4 protein. We conclude that MD2 is a significant contributor in the Ang II-induced kidney inflammatory injury in chronic renal diseases. Furthermore, MD2 inhibition could be a new and important therapeutic strategy for preventing progression of chronic renal diseases.

  19. High fat diet confers vascular hyper-contractility against angiotensin II through upregulation of MLCK and CPI-17

    Science.gov (United States)

    2017-01-01

    Obesity is a critical risk factor for the hypertension. Although angiotensin II (Ang II) in obese individuals is known to be upregulated in obesity-induced hypertension, direct evidence that explains the underlying mechanism for increased vascular tone and consequent increase in blood pressure (BP) is largely unknown. The purpose of this study is to investigate the novel mechanism underlying Ang II-induced hyper-contractility and hypertension in obese rats. Eight-week old male Sprague-Dawley rats were fed with 60% fat diet or normal diet for 4 months. Body weight, plasma lipid profile, plasma Ang II level, BP, Ang II-induced vascular contraction, and expression of regulatory proteins modulating vascular contraction with/without Ang II stimulation were measured. As a result, high fat diet (HFD) accelerated age-dependent body weight gaining along with increased plasma Ang II concentration. It also increased BP and Ang II-induced aortic contraction. Basal expression of p-CPI-17 and myosin light chain (MLC) kinase was increased by HFD along with increased phosphorylation of MLC. Ang II-induced phosphorylation of CPI-17 and MLC were also higher in HFD group than control group. In conclusion HFD-induced hypertension is through at least in part by increased vascular contractility via increased expression and activation of contractile proteins and subsequent MLC phosphorylation induced by increased Ang II. PMID:28066146

  20. Control of sodium excretion by angiotensin II: intrarenal mechanisms and blood pressure regulation.

    Science.gov (United States)

    Hall, J E

    1986-06-01

    Angiotensin II (ANG II) is one of the body's most powerful regulators of Na excretion, operating through extrarenal mechanisms, such as stimulation of aldosterone secretion, as well as intrarenal mechanisms. Considerable evidence suggests that the intrarenal actions of ANG II are quantitatively more important than changes in aldosterone secretion in the normal day-to-day regulation of Na balance and arterial pressure. ANG II at physiological concentrations increases proximal tubular reabsorption, but further studies are needed to determine whether ANG II also has an important effect on more distal tubular segments. ANG II also markedly constricts efferent arterioles, tending to increase Na reabsorption by altering peritubular capillary physical forces and also helping to prevent excessive decreases in glomerular filtration rate. ANG II may also decrease Na excretion and increase urine concentrating ability by reducing renal medullary blood flow. Regulation of Na excretion by ANG II is closely linked with arterial pressure control and volume homeostasis through the renal pressure natriuresis mechanism. Under many physiological conditions, such as changes in Na intake, ANG II greatly multiplies the effectiveness of the pressure natriuresis mechanism to prevent fluctuations in body fluid volume and arterial pressure. In circumstances associated with circulatory depression, such as decreased cardiac function, reductions in blood pressure and increased ANG II formation cause Na retention until arterial pressure is restored to normal. However, in pathophysiological conditions in which ANG II is inappropriately elevated, increased arterial pressure (hypertension) is required for the kidney to "escape" the potent antinatriuretic actions of ANG II and to return Na excretion to normal via the pressure natriuresis mechanism.

  1. Angiotensin(1-7) attenuated Angiotensin II-induced hepatocyte EMT by inhibiting NOX-derived H2O2-activated NLRP3 inflammasome/IL-1β/Smad circuit.

    Science.gov (United States)

    Zhang, Li-Li; Huang, Shan; Ma, Xiao-Xin; Zhang, Wen-Yong; Wang, Dan; Jin, Si-Yi; Zhang, Yan-Ping; Li, Yang; Li, Xu

    2016-08-01

    Epithelial-mesenchymal transition (EMT) is correlated with NAPDH oxidase (NOX)-derived reactive oxygen species (ROS). The ROS-induced NOD-like receptor pyrin domain containing-3 (NLRP3) inflammasome is a novel mechanism of EMT. Angiotensin II (AngII) induces EMT by regulating intracellular ROS. Nevertheless, it has not been reported whether AngII could induce hepatocyte EMT. Angiotensin-(1-7) [Ang-(1-7)] can inhibit the effects of AngII via a counter-regulatory mechanism. However, whether Ang-(1-7) attenuated the effects of AngII on hepatocyte EMT remains unclear. The aim of this study was to determine whether Ang-(1-7) attenuated AngII-induced hepatocyte EMT by inhibiting the NOX-derived ROS-mediated NLRP3 inflammasome/IL-1ß/Smad circuit. In vivo, two animal models were established. In the first model, rats were infused AngII. In the second model, Ang-(1-7) was constantly infused into double bile duct ligated (BDL) rats. In vitro, hepatocytes were pretreated with antioxidant, NLRP3 siRNA, NOX4 siRNA, or Ang-(1-7) before exposure to AngII. In vitro, AngII induced hepatocyte EMT, which was inhibited by N-acetylcysteine (NAC), diphenylene iodonium (DPI), and NOX4 siRNA. NLRP3 inflammasome, which was activated by hydrogen peroxide (H2O2), mediated AngII-induced hepatocyte EMT. Ang-(1-7) suppressed AngII-induced EMT by inhibiting the NOX-derived H2O2-activated NLRP3 inflammasome/IL-1ß/Smad circuit. In vivo, infusion of AngII induced activation of H2O2-correlated NLRP3 inflammasome in rat livers and accumulation of α-collagen I (Col1A1) in hepatocytes. Infusion of Ang-(1-7) alleviated BDL-induced liver fibrosis and inhibited the expression of Col1A1 and the activation of NLRP3 inflammasome in hepatocytes. Ang-(1-7) attenuated AngII-induced hepatocyte EMT by inhibiting the NOX-derived H2O2-activated NLRP3 inflammasome/IL-1ß/Smad circuit. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Calpain-2 compensation promotes angiotensin II-induced ascending and abdominal aortic aneurysms in calpain-1 deficient mice.

    Directory of Open Access Journals (Sweden)

    Venkateswaran Subramanian

    Full Text Available Recently, we demonstrated that angiotensin II (AngII-infusion profoundly increased both aortic protein and activity of calpains, calcium-activated cysteine proteases, in mice. In addition, pharmacological inhibition of calpain attenuated AngII-induced abdominal aortic aneurysm (AA in mice. Recent studies have shown that AngII infusion into mice leads to aneurysmal formation localized to the ascending aorta. However, the precise functional contribution of calpain isoforms (-1 or -2 in AngII-induced abdominal AA formation is not known. Similarly, a functional role of calpain in AngII-induced ascending AA remains to be defined. Using BDA-410, an inhibitor of calpains, and calpain-1 genetic deficient mice, we examined the relative contribution of calpain isoforms in AngII-induced ascending and abdominal AA development.To investigate the relative contribution of calpain-1 and -2 in development of AngII-induced AAs, male LDLr -/- mice that were either calpain-1 +/+ or -/- were fed a saturated fat-enriched diet and infused with AngII (1,000 ng/kg/min for 4 weeks. Calpain-1 deficiency had no significant effect on body weight or blood pressure during AngII infusion. Moreover, calpain-1 deficiency showed no discernible effects on AngII-induced ascending and abdominal AAs. Interestingly, AngII infusion induced increased expression of calpain-2 protein, thus compensating for total calpain activity in aortas of calpain-1 deficient mice. Oral administration of BDA-410, a calpain inhibitor, along with AngII-infusion significantly attenuated AngII-induced ascending and abdominal AA formation in both calpain-1 +/+ and -/- mice as compared to vehicle administered mice. Furthermore, BDA-410 administration attenuated AngII-induced aortic medial hypertrophy and macrophage accumulation. Western blot and immunostaining analyses revealed BDA-410 administration attenuated AngII-induced C-terminal fragmentation of filamin A, an actin binding cytoskeletal protein in aorta

  3. The angiotensin-(1-7)/Mas axis reduces myonuclear apoptosis during recovery from angiotensin II-induced skeletal muscle atrophy in mice.

    Science.gov (United States)

    Meneses, Carla; Morales, María Gabriela; Abrigo, Johanna; Simon, Felipe; Brandan, Enrique; Cabello-Verrugio, Claudio

    2015-09-01

    Angiotensin-(1-7) [Ang (1-7)] is a peptide belonging to the non-classical renin-angiotensin system (RAS). Ang (1-7), through its receptor Mas, has an opposite action to angiotensin II (Ang II), the typical peptide of the classical RAS axis. Ang II produces skeletal muscle atrophy, a pathological condition characterised by the loss of strength and muscle mass. A feature of muscle atrophy is the decrease of the myofibrillar proteins produced by the activation of the ubiquitin-proteasome pathway (UPP), evidenced by the increase in the expression of two muscle-specific ubiquitin ligases: atrogin-1 and MuRF-1. In addition, it has been described that Ang II also induces myonuclear apoptosis during muscle atrophy. We assessed the effects of Ang (1-7) and Mas participation on myonuclear apoptosis during skeletal muscle atrophy induced by Ang II. Our results show that Ang (1-7), through Mas, prevents the effects induced by Ang II in the diaphragm muscles and decreases several events associated with apoptosis in the diaphragm (increased apoptotic nuclei, increased expression of caspase-8 and caspase-9, increased caspase-3 activity and increased Bax/Bcl-2 ratio). Concomitantly, Ang (1-7) also attenuates the decrease in fibre diameter and muscle strength, and prevents the increase in atrogin-1 and MuRF-1 during the muscle wasting induced by Ang II. Interestingly, these effects of Ang (1-7) are dependent on the Mas receptor. Thus, we demonstrated for the first time that Ang (1-7) prevents myonuclear apoptosis during the recovery of skeletal muscle atrophy induced by Ang II.

  4. Structure-based design of nonpeptidic HIV protease inhibitors: the sulfonamide-substituted cyclooctylpyramones.

    Science.gov (United States)

    Skulnick, H I; Johnson, P D; Aristoff, P A; Morris, J K; Lovasz, K D; Howe, W J; Watenpaugh, K D; Janakiraman, M N; Anderson, D J; Reischer, R J; Schwartz, T M; Banitt, L S; Tomich, P K; Lynn, J C; Horng, M M; Chong, K T; Hinshaw, R R; Dolak, L A; Seest, E P; Schwende, F J; Rush, B D; Howard, G M; Toth, L N; Wilkinson, K R; Romines, K R

    1997-03-28

    Recently, cyclooctylpyranone derivatives with m-carboxamide substituents (e.g. 2c) were identified as potent, nonpeptidic HIV protease inhibitors, but these compounds lacked significant antiviral activity in cell culture. Substitution of a sulfonamide group at the meta position, however, produces compounds with excellent HIV protease binding affinity and antiviral activity. Guided by an iterative structure-based drug design process, we have prepared and evaluated a number of these derivatives, which are readily available via a seven-step synthesis. A few of the most potent compounds were further evaluated for such characteristics as pharmacokinetics and toxicity in rats and dogs. From this work, the p-cyanophenyl sulfonamide derivative 35k emerged as a promising inhibitor, was selected for further development, and entered phase I clinical trials.

  5. A Novel Non-Peptidic Agonist of the Ghrelin Receptor with Orexigenic Activity In vivo

    Science.gov (United States)

    Pastor-Cavada, Elena; Pardo, Leticia M.; Kandil, Dalia; Torres-Fuentes, Cristina; Clarke, Sarah L.; Shaban, Hamdy; McGlacken, Gerard P.; Schellekens, Harriet

    2016-11-01

    Loss of appetite in the medically ill and ageing populations is a major health problem and a significant symptom in cachexia syndromes, which is the loss of muscle and fat mass. Ghrelin is a gut-derived hormone which can stimulate appetite. Herein we describe a novel, simple, non-peptidic, 2-pyridone which acts as a selective agonist for the ghrelin receptor (GHS-R1a). The small 2-pyridone demonstrated clear agonistic activity in both transfected human cells and mouse hypothalamic cells with endogenous GHS-R1a receptor expression. In vivo tests with the hit compound showed significant increased food intake following peripheral administration, which highlights the potent orexigenic effect of this novel GHS-R1a receptor ligand.

  6. EPOXYEICOSATRIENOIC ACID ANALOG ATTENUATES ANGIOTENSIN II HYPERTENSION AND KIDNEY INJURY

    Directory of Open Access Journals (Sweden)

    Md. Abdul Hye Khan

    2014-09-01

    Full Text Available Epoxyeicosatrienoic acids (EETs contribute to blood pressure regulation leading to the concept that EETs can be therapeutically targeted for hypertension and the associated end-organ damage. In the present study, we investigated anti-hypertensive and kidney protective actions of an EET analog, EET-B in angiotensin II (ANG II-induced hypertension. EET-B was administered in drinking water for 14 days (10mg/kg/d and resulted in a decreased blood pressure elevation in ANG II hypertension. At the end of the two-week period, blood pressure was 30 mmHg lower in EET analog-treated ANG II hypertensive rats. The vasodilation of mesenteric resistance arteries to acetylcholine was impaired in ANG II hypertension; however, it was improved with EET-B treatment. Further, EET-B protected the kidney in ANG II hypertension as evidenced by a marked 90% decrease in albuminuria and 54% decrease in nephrinuria. Kidney histology demonstrated a decrease in renal tubular cast formation in EET analog-treated hypertensive rats. In ANG II hypertension, EET-B treatment markedly lowered renal inflammation. Urinary monocyte chemoattractant protein-1 excretion was decreased by 55% and kidney macrophage infiltration was reduced by 52% with EET-B treatment. Overall, our results demonstrate that EET-B has anti-hypertensive properties, improves vascular function, and decreases renal inflammation and injury in ANG II hypertension.

  7. Epoxyeicosatrienoic acid analog attenuates angiotensin II hypertension and kidney injury.

    Science.gov (United States)

    Khan, Abdul Hye; Falck, John R; Manthati, Vijaya L; Campbell, William B; Imig, John D

    2014-01-01

    Epoxyeicosatrienoic acids (EETs) contribute to blood pressure regulation leading to the concept that EETs can be therapeutically targeted for hypertension and the associated end organ damage. In the present study, we investigated anti-hypertensive and kidney protective actions of an EET analog, EET-B in angiotensin II (ANG II)-induced hypertension. EET-B was administered in drinking water for 14 days (10 mg/kg/d) and resulted in a decreased blood pressure elevation in ANG II hypertension. At the end of the two-week period, blood pressure was 30 mmHg lower in EET analog-treated ANG II hypertensive rats. The vasodilation of mesenteric resistance arteries to acetylcholine was impaired in ANG II hypertension; however, it was improved with EET-B treatment. Further, EET-B protected the kidney in ANG II hypertension as evidenced by a marked 90% decrease in albuminuria and 54% decrease in nephrinuria. Kidney histology demonstrated a decrease in renal tubular cast formation in EET analog-treated hypertensive rats. In ANG II hypertension, EET-B treatment markedly lowered renal inflammation. Urinary monocyte chemoattractant protein-1 excretion was decreased by 55% and kidney macrophage infiltration was reduced by 52% with EET-B treatment. Overall, our results demonstrate that EET-B has anti-hypertensive properties, improves vascular function, and decreases renal inflammation and injury in ANG II hypertension.

  8. Analysis of responses to angiotensin II in the mouse

    Directory of Open Access Journals (Sweden)

    Trinity J Bivalacqua

    2001-03-01

    Full Text Available Responses to angiotensin II (Ang II were investigated in anaesthetised CD1 mice. Injections of Ang II caused dose-related increases in systemic arterial pressure that were antagonised by candesartan. Responses to Ang II were not altered by PD 123319. At the lowest dose studied (20 µg/kg i.v., the inhibitory effects of candesartan were competitive, whereas at the highest dose (100 µg/kg i.v., the dose-response curve for Ang II was shifted to the right in a non-parallel manner. The inhibitory effects of candesartan were selective and were similar in animals pretreated with enalaprilat to reduce endogenous Ang II production. Pressor responses to Ang II were not altered by propranolol, phentolamine or atropine, but were enhanced by hexamethonium. Increases in total peripheral resistance were inhibited by the AT1-receptor antagonist (ARB but were not altered by AT2-receptor, alpha- or beta-receptor antagonists. These results suggest that pressor responses to Ang II are mediated by AT 1-receptors, are buffered by the baroreceptors, are not modulated by effects on AT2receptors, and that activation of the sympathetic nervous system plays little role in mediating rapid haemodynamic responses to the peptide in anaesthetised mice.

  9. Novel EGFR inhibitors attenuate cardiac hypertrophy induced by angiotensin II.

    Science.gov (United States)

    Peng, Kesong; Tian, Xinqiao; Qian, Yuanyuan; Skibba, Melissa; Zou, Chunpeng; Liu, Zhiguo; Wang, Jingying; Xu, Zheng; Li, Xiaokun; Liang, Guang

    2016-03-01

    Cardiac hypertrophy is an important risk factor for heart failure. Epidermal growth factor receptor (EGFR) has been found to play a role in the pathogenesis of various cardiovascular diseases. The aim of this current study was to examine the role of EGFR in angiotensin II (Ang II)-induced cardiac hypertrophy and identify the underlying molecular mechanisms. In this study, we observed that both Ang II and EGF could increase the phospohorylation of EGFR and protein kinase B (AKT)/extracellular signal-regulated kinase (ERK), and then induce cell hypertrophy in H9c2 cells. Both pharmacological inhibitors and genetic silencing significantly reduced Ang II-induced EGFR signalling pathway activation, hypertrophic marker overexpression, and cell hypertrophy. In addition, our results showed that Ang II-induced EGFR activation is mediated by c-Src phosphorylation. In vivo, Ang II treatment significantly led to cardiac remodelling including cardiac hypertrophy, disorganization and fibrosis, accompanied by the activation of EGFR signalling pathway in the heart tissues, while all these molecular and pathological alterations were attenuated by the oral administration with EGFR inhibitors. In conclusion, the c-Src-dependent EGFR activation may play an important role in Ang II-induced cardiac hypertrophy, and inhibition of EGFR by specific molecules may be an effective strategy for the treatment of Ang II-associated cardiac diseases. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  10. Sulforaphane Prevents Angiotensin II-Induced Testicular Cell Death via Activation of NRF2

    Science.gov (United States)

    Wang, Yonggang; Xin, Ying; Tan, Yi

    2017-01-01

    Although angiotensin II (Ang II) was reported to facilitate sperm motility and intratesticular sperm transport, recent findings shed light on the efficacy of Ang II in stimulating inflammatory events in testicular peritubular cells, effect of which may play a role in male infertility. It is still unknown whether Ang II can induce testicular apoptotic cell death, which may be a more direct action of Ang II in male infertility. Therefore, the present study aims to determine whether Ang II can induce testicular apoptotic cell death and whether this action can be prevented by sulforaphane (SFN) via activating nuclear factor (erythroid-derived 2)-like 2 (NRF2), the governor of antioxidant-redox signalling. Eight-week-old male C57BL/6J wild type (WT) and Nrf2 gene knockout mice were treated with Ang II, in the presence or absence of SFN. In WT mice, SFN activated testicular NRF2 expression and function, along with a marked attenuation in Ang II-induced testicular oxidative stress, inflammation, endoplasmic reticulum stress, and apoptotic cell death. Deletion of the Nrf2 gene led to a complete abolishment of these efficacies of SFN. The present study indicated that Ang II may result in testicular apoptotic cell death, which can be prevented by SFN via the activation of NRF2. PMID:28191275

  11. Sulforaphane Prevents Angiotensin II-Induced Testicular Cell Death via Activation of NRF2

    Directory of Open Access Journals (Sweden)

    Yonggang Wang

    2017-01-01

    Full Text Available Although angiotensin II (Ang II was reported to facilitate sperm motility and intratesticular sperm transport, recent findings shed light on the efficacy of Ang II in stimulating inflammatory events in testicular peritubular cells, effect of which may play a role in male infertility. It is still unknown whether Ang II can induce testicular apoptotic cell death, which may be a more direct action of Ang II in male infertility. Therefore, the present study aims to determine whether Ang II can induce testicular apoptotic cell death and whether this action can be prevented by sulforaphane (SFN via activating nuclear factor (erythroid-derived 2-like 2 (NRF2, the governor of antioxidant-redox signalling. Eight-week-old male C57BL/6J wild type (WT and Nrf2 gene knockout mice were treated with Ang II, in the presence or absence of SFN. In WT mice, SFN activated testicular NRF2 expression and function, along with a marked attenuation in Ang II-induced testicular oxidative stress, inflammation, endoplasmic reticulum stress, and apoptotic cell death. Deletion of the Nrf2 gene led to a complete abolishment of these efficacies of SFN. The present study indicated that Ang II may result in testicular apoptotic cell death, which can be prevented by SFN via the activation of NRF2.

  12. Angiotensin II stimulates superoxide production by nitric oxide synthase in thick ascending limbs.

    Science.gov (United States)

    Gonzalez-Vicente, Agustin; Saikumar, Jagannath H; Massey, Katherine J; Hong, Nancy J; Dominici, Fernando P; Carretero, Oscar A; Garvin, Jeffrey L

    2016-02-01

    Angiotensin II (Ang II) causes nitric oxide synthase (NOS) to become a source of superoxide (O2 (-)) via a protein kinase C (PKC)-dependent process in endothelial cells. Ang II stimulates both NO and O2 (-) production in thick ascending limbs. We hypothesized that Ang II causes O2 (-) production by NOS in thick ascending limbs via a PKC-dependent mechanism. NO production was measured in isolated rat thick ascending limbs using DAF-FM, whereas O2 (-) was measured in thick ascending limb suspensions using the lucigenin assay. Consistent stimulation of NO was observed with 1 nmol/L Ang II (P thick ascending limbs via a PKC- and NADPH oxidase-dependent process; and (2) the effect of Ang II is not due to limited substrate.

  13. Identification and characterization of a novel angiotensin binding site in cultured vascular smooth muscle cells that is specific for the hexapeptide (3-8) fragment of angiotensin II, angiotensin IV.

    Science.gov (United States)

    Hall, K L; Hanesworth, J M; Ball, A E; Felgenhauer, G P; Hosick, H L; Harding, J W

    1993-03-19

    This study demonstrates the existence of a previously unrecognized class of angiotensin binding sites on vascular smooth muscle that exhibit high affinity and specificity for the hexapeptide (3-8) fragment of angiotensin II (AngIV). Binding of [125I]AngIV is saturable, reversible and describes a pharmacologic profile that is distinct and separate from the classic AT1 or AT2 angiotensin receptors. Saturation binding studies utilizing cultured vascular smooth muscle cells obtained from bovine aorta (BVSM) revealed that [125I]AngIV bound to a single high affinity site with an associated Hill coefficient of 0.99 +/- 0.003, exhibiting a KD = 1.85 +/- 0.45 nM and a corresponding Bmax = 960 +/- 100 fmol mg-1 protein. Competition binding curves in BVSM demonstrated the following rank order effectiveness: AngIV > AngII(3-7) > AngIII > Sar1,Ile8 AngII > AngII > AngII(1-7) > AngII(4-8), DuP 753, PD123177. The presence of the non-hydrolyzable GTP analog GTP gamma S, had no effect on [125I]AngIV binding affinity in BVSM. The presence of this novel angiotensin binding site on smooth muscle in high concentration suggests the possibility that this system may play an important, yet unrecognized role in vascular control.

  14. Angiotensin II inhibits ADH-stimulated cAMP: role on O2- and transport-related oxygen consumption in the loop of Henle.

    Science.gov (United States)

    Silva, G B; Juncos, L I; Baigorria, S T; Garcia, N H

    2013-01-01

    Dehydration and acute reductions of blood pressure increases ADH and Ang II levels. These hormones increase transport along the distal nephron. In the thick ascending limb (TAL) ADH increases transport via cAMP, while Ang II acts via superoxide (O2-). However, the mechanism of interaction of these hormones in this segment remains unclear. The aim of this study was to explore ADH/Ang II interactions on TAL transport. For this, we measured the effects of ADH/Ang II, added sequentially to TAL suspensions from Wistar rats, on oxygen consumption (QO2) -as a transport index-, cAMP and O2-. Basal QO2 was 112+-5 nmol O2/min/mg protein. Addition of ADH (1nM) increased QO2 by 227 percent. In the presence of ADH, Ang II (1nM) elicited a QO2 transient response. During an initial 3.1+-0.7 minutes after adding Ang II, QO2 decreased 58 percent (p less than 0.03 initial vs. ADH) and then rose by 188 percent (p less than 0.03 late vs initial Ang II). We found that Losartan blocked the initial effects of Ang II and the latter blocked ADH and forskolin-stimulated cAMP. The NOS inhibitor L-NAME or the AT2 receptor antagonist PD123319 showed no effect on transported related oxygen consumption. Then, we assessed the late period after adding Ang II. The O2- scavenger tempol blocked the late Ang II effects on QO2, while Ang II increased O2- production during this period. We conclude that 1) Ang II has a transient effect on ADH-stimulated transport; 2) this effect is mediated by AT1 receptors; 3) the initial period is mediated by decreased cAMP and 4) the late period is mediated by O2-.

  15. Angiotensin II-Induced Endothelial Dysfunction is Temporally Linked with Increases in Intereukin-6 and Vascular Macrophage Accumulation

    Directory of Open Access Journals (Sweden)

    Sean P Didion

    2014-10-01

    Full Text Available Angiotensin II (Ang II is associated with vascular hypertrophy, endothelial dysfunction and activation of a number of inflammatory molecules, however the linear events involved in the development of hypertension and endothelial dysfunction produced in response to Ang II are not well defined. The goal of this study was to examine the dose- and temporal-dependent development of endothelial dysfunction in response to Ang II. Blood pressure and responses of carotid arteries were examined in control (C57Bl/6 mice and in mice infused with 50, 100, 200, 400, or 1000 ng/kg/min Ang II for either 14 or 28 Days. Infusion of Ang II was associated with graded and marked increases in systolic blood pressure and plasma Ang II concentrations. While low doses of Ang II (ie, 50 and 100 ng/kg/min had little to no effect on blood pressure or endothelial function, high doses of Ang II (e.g., 1000 ng/kg/min were associated with large increases in arterial pressure and marked impairment of endothelial function. In contrast, intermediate doses of Ang II (200 and 400 ng/kg/min while initially having no effect on systolic blood pressure were associated with significant increases in pressure over time. Despite increasing blood pressure, 200 ng/kg/min had no effect on endothelial function, whereas 400 ng/kg/min produced modest impairment on Day 14 and marked impairment of endothelial function on Day 28. The degree of endothelial dysfunction produced by 400 and 1000 ng/kg/min Ang II was reflective of parallel increases in plasma IL-6 levels and vascular macrophage content, suggesting that increases in arterial blood pressure precede the development of endothelial dysfunction. These findings are important as they demonstrate that along with increases in arterial pressure that increases in IL-6 and vascular macrophage accumulation correlate with the impairment of endothelial function produced by Ang II.

  16. Ang Kasaysayan at Panitikan sa Pagbuo ng Bayan: Rebyu ng Nobelang The Feet of Juan Bacnang ni F. Sionil Jose

    Directory of Open Access Journals (Sweden)

    Moreal Nagarit Camba

    2013-06-01

    Full Text Available Mababasa sa The Feet of Juan Bacnang (2011, ang pinakabagong nobela ni F. (Francisco Sionil Jose o Frankie sa kanyang mga kaibigan, ang mahigpit na ugnayan ng manunulat at ng kanyang bayan. Siya ang nagsisilbing zeitgeist ng maraming panahon; ang espiritu at boses ng nakaraan at kasalukuyan, isang manunulat na kumakatha ng mga akdang sumasalamin sa mayamang karanasan at kasaysayan ng kultura at lahing pinag-usbungan. Kung saan ang kanyang nobelang Juan Bacnang, katulad ng iba pa niyang naunang mga nobela, bagamat likhang-isip, ay repleksyon ng buhay, pasakit, at aspirasyon ng manunulat at lipunang lumikha rito; mga tunguhing hindi nalalayo sa layunin ng mga ninuno nitong anyong panitikan, ang mga epiko at kuwentong bayan. Ibig sabihin, ang akda bilang Weltanschauung na ayon kay Terry Eagleton ay “partikular na paraan ng pagtingin sa mundo; na may kaugnayan sa gahum na nagtatakda kung paano tingnan ang mundo na maituturing na ‘pag-iisip ng lipunan’ o ideyolohiya ng panahon”1 (sinipi ni Geok-Lin Lim A Modern National Epic 74. Dagdag pa rito, ang kanyang (mga nobela, partikular ang Juan Bacnang, ay nagsisilbing “siwang sa mga kurtinang-papel” sa kasaysayan;2 mga tala ng karanasan at pang-araw-araw na buhay, na madalas hindi naisusulat ng mga tradisyunal na historyador. Ito (ang mga tala, ayon kay Pierre Macherey, ang mga puwang o pinipi na boses na naisantabi ng maraming akdang pangkasaysayan (sinipi ni Eagleton Marxism and Literary Criticism 34-35.

  17. An interaction of renin-angiotensin and kallikrein-kinin systems contributes to vascular hypertrophy in angiotensin II-induced hypertension: in vivo and in vitro studies.

    Directory of Open Access Journals (Sweden)

    Graziela S Ceravolo

    Full Text Available The kallikrein-kinin and renin-angiotensin systems interact at multiple levels. In the present study, we tested the hypothesis that the B1 kinin receptor (B1R contributes to vascular hypertrophy in angiotensin II (ANG II-induced hypertension, through a mechanism involving reactive oxygen species (ROS generation and extracellular signal-regulated kinase (ERK1/2 activation. Male Wistar rats were infused with vehicle (control rats, 400 ng/Kg/min ANG II (ANG II rats or 400 ng/Kg/min ANG II plus B1 receptor antagonist, 350 ng/Kg/min des-Arg(9-Leu(8-bradykinin (ANGII+DAL rats, via osmotic mini-pumps (14 days or received ANG II plus losartan (10 mg/Kg, 14 days, gavage - ANG II+LOS rats. After 14 days, ANG II rats exhibited increased systolic arterial pressure [(mmHg 184 ± 5.9 vs 115 ± 2.3], aortic hypertrophy; increased ROS generation [2-hydroxyethidium/dihydroethidium (EOH/DHE: 21.8 ± 2.7 vs 6.0 ± 1.8] and ERK1/2 phosphorylation (% of control: 218.3 ± 29.4 vs 100 ± 0.25]. B1R expression was increased in aortas from ANG II and ANG II+DAL rats than in aortas from the ANG II+LOS and control groups. B1R antagonism reduced aorta hypertrophy, prevented ROS generation (EOH/DHE: 9.17 ± 3.1 and ERK1/2 phosphorylation (137 ± 20.7% in ANG II rats. Cultured aortic vascular smooth muscle cells (VSMC stimulated with low concentrations (0.1 nM of ANG II plus B1R agonist exhibited increased ROS generation, ERK1/2 phosphorylation, proliferating-cell nuclear antigen expression and [H3]leucine incorporation. At this concentration, neither ANG II nor the B1R agonist produced any effects when tested individually. The ANG II/B1R agonist synergism was inhibited by losartan (AT1 blocker, 10 µM, B1R antagonist (10 µM and Tiron (superoxide anion scavenger, 10 mM. These data suggest that B1R activation contributes to ANG II-induced aortic hypertrophy. This is associated with activation of redox-regulated ERK1/2 pathway that controls aortic smooth muscle cells growth

  18. Renal Inhibition of Heme Oxygenase-1 Increases Blood Pressure in Angiotensin II-Dependent Hypertension

    Directory of Open Access Journals (Sweden)

    Eva Csongradi

    2012-01-01

    Full Text Available The goal of this study was to test the hypothesis that renal medullary heme oxygenase (HO acts as a buffer against Ang-II dependent hypertension. To test this hypothesis, renal medullary HO activity was blocked using QC-13, an imidazole-dioxolane HO-1 inhibitor, or SnMP, a classical porphyrin based HO inhibitor. HO inhibitors were infused via IRMI catheters throughout the study starting 3 days prior to implantation of an osmotic minipump which delivered Ang II or saline vehicle. MAP was increased by Ang II infusion and further increased by IRMI infusion of QC-13 or SnMP. MAP averaged 113±3, 120±7, 141±2, 153±2, and 154±3 mmHg in vehicle, vehicle + IRMI QC-13, Ang II, Ang II + IRMI QC-13, and Ang II + IRMI SnMP treated mice, respectively (n=6. Inhibition of renal medullary HO activity with QC-13 in Ang II infused mice was also associated with a significant increase in superoxide production as well as significant decreases in antioxidant enzymes catalase and MnSOD. These results demonstrate that renal inhibition of HO exacerbates Ang II dependent hypertension through a mechanism which is associated with increases in superoxide production and decreases in antioxidant enzymes.

  19. Reduced plasma noradrenaline during angiotensin II-induced acute hypertension in man

    DEFF Research Database (Denmark)

    Henriksen, J H; Kastrup, J; Christensen, N J

    1985-01-01

    .005) and similarly to the decrease obtained with ANG II infusion. 4. The results indicate that a decrease in sympathoadrenal activity occurs during ANG II-induced acute hypertension in man. This may be elicited by the arterial baroreflex, which seems to dominate any direct sympathoadrenergic facilitating effect...

  20. The ACE2/Ang-(1-7)/Mas axis can inhibit hepatic insulin resistance.

    Science.gov (United States)

    Cao, Xi; Yang, Fang-Yuan; Xin, Zhong; Xie, Rong-Rong; Yang, Jin-Kui

    2014-08-05

    Blocking the renin-angiotensin system (RAS) can reduce the risk of diabetes. Meanwhile, the angiotensin (Ang)-converting enzyme-2 (ACE2)/Ang-(1-7)/Mas axis has recently been proposed to function as a negative regulator of the RAS. In previous studies, we first demonstrated that ACE2 knockout (ACE2(-/)(y)) mice exhibit impaired glucose tolerance or diabetes. However the precise roles of ACE2 on glucose metabolism are unknown. Here we show that the ACE2/Ang-(1-7)/Mas axis can ameliorate insulin resistance in the liver. Activation of the ACE2/Ang-(1-7)/Mas axis increases glucose uptake and decreases glycogen synthesis in the liver accompanied by increased expression of glucose transporters, insulin receptor substrates and decreased expression of enzymes for glycogen synthesis. ACE2 knockout mice displayed elevated levels of oxidative stress and exposure to Ang-(1-7) reduced the stress in hepatic cells. As a consequence of anti-oxidative stress, activation of the ACE2/Ang-(1-7)/Mas axis led to improved hepatic insulin resistance through the Akt/PI3K/IRS-1/JNK insulin signaling pathway. This is the first time documented that the ACE2/Ang-(1-7)/Mas axis can ameliorate insulin resistance in the liver. As insulin resistance in the liver is considered to be the primary cause of the development of type 2 diabetes, this axis may serve as a new diabetes target. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  1. Ets-1 targeted by microrna-221 regulates angiotensin II-induced renal fibroblast activation and fibrosis.

    Science.gov (United States)

    Di, Jia; Jiang, Lei; Zhou, Yang; Cao, Hongdi; Fang, Li; Wen, Ping; Li, Xiurong; Dai, Chunsun; Yang, Junwei

    2014-01-01

    Fibroblast activation is one of the most important mechanisms for Angiotensin II (Ang II) in promoting renal fibrosis. Transcription factor Ets-1 is recognized to play a key role in kidney diseases. However, the role and mechanisms of Ets-1 in Ang-II induced fibroblast activation and kidney fibrosis are not fully understood. Mice were treated with Ang II via osmotic mini-pumps or Ang II expression plasmid (pAng II). Cultured normal rat kidney interstitial fibroblast (NRK-49F) cells were incubated with Ang II. Role of Ets-1 in renal fibrosis and fibroblast activation were assessed by Western blot, Immunohistochemical staining'MTT, Boyden chamber and Immunofluorescence staining. Effects of miR-221 on Ets-1 and fibroblast activation were investigated by MTT, Boyden chamber, Western blot and Q-PCR. We found that Ets-1 was up-regulated in fibrotic kidneys. Similarly, Ang II could activate NRK-49F cells as demonstrated by up-regulated α-SMA and fibronectin(FN) expression and enhanced cell proliferation and migration. Ang II also induced Ets-1 expression in NRK-49F cells in a dose and time dependent manner. Knock-down of Ets-1 by RNA interference attenuated Ang II-induced activation of NRK-49F cells. Ets-1 was previously reported as a target of microRNA-221 (miR-221). In Ang II-induced fibrotic kidney, miR-221 was down-regulated. Similar results were observed in Ang II treated NRK-49F cells. Ectopic expression of miR-221 mimic attenuated the up-regulation of Ets-1 by Ang II in NRK-49F cells, which further prevented the activation of NRK-49F cells. However, the inhibitor of miR-221 aggravated Ang II induced Ets-1 expression and NRK-49F cells activation. Our study suggests that miR-221/Ets-1 axis takes an important role in mediating AngII induced interstitial fibroblast activation and renal fibrosis. © 2014 S. Karger AG, Basel.

  2. Role of Jagged1-Hey1 Signal in Angiotensin II-induced Impairment of Myocardial Angiogenesis

    Science.gov (United States)

    Guan, Ai-Li; He, Tao; Shao, Yi-Bing; Chi, Yi-Fan; Dai, Hong-Yan; Wang, Yan; Xu, Li; Yang, Xuan; Ding, Hua-Min; Cai, Shang-Lang

    2017-01-01

    Background: Angiotensin II (Ang II) is a major contributor to the development of heart failure. However, the molecular and cellular mechanisms that underlie this process remain elusive. Inadequate angiogenesis in the myocardium leads to a transition from cardiac hypertrophy to dysfunction, and our previous study showed that Ang II significantly impaired the angiogenesis response. The current study was designed to examine the role of Jagged1-Notch signaling in the effect of Ang II during impaired angiogenesis and cardiac hypertrophy. Methods: Ang II was subcutaneously infused into 8-week-old male C57BL/6 mice at a dose of 200 ng·kg−1·min−1 for 2 weeks using Alzet micro-osmotic pumps. N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine tert-butyl ester (DAPT), a γ-secretase inhibitor, was injected subcutaneously during Ang II infusion at a dose of 10.0 mg·kg−1·d−1. Forty mice were divided into four groups (n = 10 per group): control group; Ang II group, treated with Ang II; DAPT group, treated with DAPT; and Ang II + DAPT group, treated with both Ang II and DAPT. At the end of experiments, myocardial (left ventricle [LV]) tissue from each experimental group was evaluated using immunohistochemistry, Western blotting, and real-time polymerase chain reaction. Data were analyzed using one-way analysis of variance test followed by the least significant difference method or independent samples t-test. Results: Ang II treatment significantly induced cardiac hypertrophy and impaired the angiogenesis response compared to controls, as shown by hematoxylin and eosin (HE) staining and immunohistochemistry for CD31, a vascular marker (P < 0.05 for both). Meanwhile, Jagged1 protein was significantly increased, but gene expression for both Jag1 and Hey1 was decreased in the LV following Ang II treatment, compared to that in controls (relative ratio for Jag1 gene: 0.45 ± 0.13 vs. 0.84 ± 0.15; relative ratio for Hey1 gene: 0.51 ± 0.08 vs. 0.91 ± 0.09; P < 0

  3. Selective nonpeptidic fluorescent ligands for oxytocin receptor: design, synthesis, and application to time-resolved FRET binding assay.

    Science.gov (United States)

    Karpenko, Iuliia A; Margathe, Jean-François; Rodriguez, Thiéric; Pflimlin, Elsa; Dupuis, Elodie; Hibert, Marcel; Durroux, Thierry; Bonnet, Dominique

    2015-03-12

    The design and the synthesis of the first high-affinity fluorescent ligands for oxytocin receptor (OTR) are described. These compounds enabled the development of a TR-FRET based assay for OTR, readily amenable to high throughput screening. The validation of the assay was achieved by competition experiments with both peptide and nonpeptide OTR ligands as competitors. These probes represent the first selective fluorescent ligands for the oxytocin G protein-coupled receptor.

  4. Angiotensin II induced venoconstriction in normotensive and hypertensive rats: study of action mechanisms, localization and expression of AT1 and AT2 receptors.

    OpenAIRE

    Rodrigo Azevedo Loiola

    2007-01-01

    Neste estudo, avaliamos e caracterizamos o efeito de Ang II em leito venular mesentérico (LVM) e anéis de veia porta (AVP) de wistar e SHR. A reatividade vascular para Ang II foi estudada na presença e ausência de diferentes antagonistas para elucidar os mecanismos envolvidos na venoconstrição induzida por Ang II. Nossos resultados sugerem que a Ang II induz venoconstrição através da ativação de receptores AT1 e AT2 em Wistar e receptor AT1 em SHR. Essa venoconstrição parece ser contrabalanc...

  5. Cytotoxic effect of a non-peptidic small molecular inhibitor of the p53-HDM2 interaction on tumor cells

    Institute of Scientific and Technical Information of China (English)

    Wen-Dong Li; Mi-Juan Wang; Fang Ding; Da-Li Yin; Zhi-Hua Liu

    2005-01-01

    AIM: To investigate if non-peptidic small molecular inhibitors of the p53-HDM2 interaction could restore p53 function and kill tumor cells.METHODS: A series of non-peptidic small HDM2 inhibitors were designed by computer-aided model and synthesized by chemical method. Syl-155 was one of these inhibitors. Cytotoxic effect of syl-155 on three tumor cell lines with various states of p53, HT1080 (wild-type p53), KYSE510 (mutant p53), MG63 (p53 deficiency) was evaluated by MTT assay, Western blot and flow cytometry.RESULTS: Syl-155 stimulated the accumulation of p53 and p21 protein in HT1080 cells expressing wild-type p53, but not in KYSE510 and MG63 cells. Consequently, syl-155 induced cell cycle arrest and apoptosis in HT1080 cells.CONCLUSION: Non-peptidic small molecular inhibitors of the p53-HDM2 interaction show promise in treatment of tumors expressing wild-type p53.

  6. Chemotaxis of human and rat leukocytes by the delta-selective non-peptidic opioid SNC 80.

    Science.gov (United States)

    Ordaz-Sánchez, Iván; Weber, Richard J; Rice, Kenner C; Zhang, Xiaoyan; Rodríguez-Padilla, C; Tamez-Guerra, R; Méndez-Vázquez, José L; Gómez-Flores, R

    2003-01-01

    Opioids like morphine, represent a major source of relief for most chronic moderate to severe nonmalignant pain. However, opioid abuse may lead to infections such as hepatitis and AIDS because opioids have been associated with suppressing various parameters of immune function including antimicrobial resistance, antibody production, monocyte-mediated phagocytosis, and both neutrophil and monocyte chemotaxis. We have previously reported immunopotentiating properties of non-peptidic opioid receptor selective agonists and antagonists. In this study, we evaluated the effects of the nonpeptidic delta-opioid receptor agonist (+)-4-((alpha R)-alpha-((2S, 5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N, N-diethyl-benzamide (SNC 80) on chemotaxis of rat thymic and human peripheral blood mononuclear cells by using a modified Wilkinson chamber. Cell recruitment is an essential process in acute and chronic inflammatory responses. We observed that SNC 80 at concentrations of 10(-10), 10(-9), 10(-8), 10(-7), and 10(-6) M, significantly (p SNC 80 on chemotaxis of rat and human leukocytes were antagonized by naloxone, indicating that the modulation of chemotaxis by SNC 80 is via a classic opioid receptor. The development and use of non-peptidic opioids like SNC 80 could have an immediate impact not only as potent analgesics, but in immunoregulation.

  7. Angiotensin II stimulates hyperplasia but not hypertrophy in immature ovine cardiomyocytes.

    Science.gov (United States)

    Sundgren, N C; Giraud, G D; Stork, P J S; Maylie, J G; Thornburg, K L

    2003-05-01

    Rat and sheep cardiac myocytes become binucleate as they complete the 'terminal differentiation' process soon after birth and are not able to divide thereafter. Angiotensin II (Ang II) is known to stimulate hypertrophic changes in rodent cardiomyocytes under both in vivo and in vitro conditions via the AT1 receptor and intracellular extracellular regulated kinase (ERK) signalling cascade. We sought to develop culture methods for immature sheep cardiomyocytes in order to test the hypothesis that Ang II is a hypertrophic agent in the immature myocardium of the sheep. We isolated fetal sheep cardiomyocytes and cultured them for 96 h, added Ang II and phenylephrine (PE) for 48 h, and measured footprint area and proliferation (5-bromo-2'-deoxyuridine (BrdU) uptake) separately in mono- vs. binucleate myocytes. We found that neither Ang II nor PE changed the footprint area of mononucleated cells. PE stimulated an increase in footprint area of binucleate cells but Ang II did not. Ang II increased myocyte BrdU uptake compared to serum free conditions, but PE did not affect BrdU uptake. The MAP kinase kinase (MEK) inhibitor UO126 prevented BrdU uptake in Ang II-stimulated cells and prevented cell hypertrophy in PE-stimulated cells. This paper establishes culture methods for immature sheep cardiomyocytes and reports that: (1) Ang II is not a hypertrophic agent; (2) Ang II stimulates hyperplastic growth among mononucleate myocytes; (3) PE is a hypertrophic agent in binucleate myocytes; and (4) the ERK cascade is required for the proliferation effect of Ang II and the hypertrophic effect of PE.

  8. Effects of valsartan on angiotensin II-induced migration of human coronary artery smooth muscle cells.

    Science.gov (United States)

    Kohno, M; Ohmori, K; Nozaki, S; Mizushige, K; Yasunari, K; Kano, H; Minami, M; Yoshikawa, J

    2000-11-01

    The migration as well as proliferation of coronary artery medial smooth muscle cells (SMC) into the intima is proposed to be an important process of intimal thickening in coronary atherosclerosis. In the current study, we examined the effects of the angiotensin type 1 receptor antagonist valsartan on angiotensin II (Ang II)-induced migration of cultured human coronary artery SMC using Boyden's chamber methods. Ang II significantly stimulated human coronary artery SMC migration in a concentration-dependent manner between 10(-6) and 10(-8) mol/l when cells of passage 4 to 6 were used. However, the migration response to Ang II was moderately decreased in cells of passage 10 to 12, and was markedly decreased in cells of passage 15 to 17, compared to that of passage 4 to 6. Ang II-induced migration was blocked by the Ang II type 1 (AT1) receptor antagonist valsartan in a concentration-dependent manner. By contrast, the Ang II type 2 (AT2) receptor antagonist PD 123319 did not affect Ang II-induced migration. Ang II modestly increased the cell number of human coronary artery SMC after a 24-h incubation. This increase in cell numbers was also clearly blocked by valsartan, but not by PD 123319. These results indicate that Ang II stimulates migration as well as proliferation via AT1 receptors in human coronary artery SMC when cells of passage 4 to 6 are used. Valsartan may prevent the progression of coronary atherosclerosis through an inhibition of Ang II-induced migration and proliferation in these cells, although in vivo evidence is lacking.

  9. A density dependent delayed predator-prey model with Beddington-DeAngelis type function response incorporating a prey refuge

    Science.gov (United States)

    Tripathi, Jai Prakash; Abbas, Syed; Thakur, Manoj

    2015-05-01

    This paper describes a predator-prey model incorporating a prey refuge. The feeding rate of consumers (predators) per consumer (i.e. functional response) is considered to be of Beddington-DeAngelis type. The Beddington-DeAngelis functional response is similar to the Holling-type II functional response but contains an extra term describing mutual interference by predators. We investigate the role of prey refuge and degree of mutual interference among predators in the dynamics of system. The dynamics of the system is discussed mainly from the point of view of permanence and stability. We obtain conditions that affect the persistence of the system. Local and global asymptotic stability of various equilibrium solutions is explored to understand the dynamics of the model system. The global asymptotic stability of positive interior equilibrium solution is established using suitable Lyapunov functional. The dynamical behaviour of the delayed system is further analyzed through incorporating discrete type gestation delay of predator. It is found that Hopf bifurcation occurs when the delay parameter τ crosses some critical value. The analytical results found in the paper are illustrated with the help of numerical examples.

  10. Advance in Research of Angiotensin II and Its Receptor and Malignant Tumor

    Directory of Open Access Journals (Sweden)

    Lulu SUN

    2016-09-01

    Full Text Available Angiotensin AngII, a linear small peptide,which is composed of eight amino acids, is the main effectors of renin-angiotensin systen (Renin-angiotensin system, RAS. AngII, a main biopolypeptide of the RAS, has important pathophysiologic in effects participating in cardiac hypertrophy, vascular cell proproliferation, inflammation and tissue remodeling through G-protein-coupled receptors. In recent years, Ang II can promote tumor cell proliferation, tumor vessel formation and inhibit the differentiation of the tumor cells. This suggests that inhibit the production of AngII or block its effect is expected to become a new measure for the treatment of malignant tumors. This article reviews the advances in research on the relationship between AngII and its receptor and malignant tumor in recent years.

  11. Interaction of angiotensin II with the C-terminal 300-320 fragment of the rat angiotensin II receptor AT1a monitored by NMR.

    Science.gov (United States)

    D'Amelio, Nicola; Gaggelli, Elena; Gaggelli, Nicola; Lozzi, Luisa; Neri, Paolo; Valensin, Daniela; Valensin, Gianni

    2003-10-01

    Interaction between angiotensin II (Ang II) and the fragment peptide 300-320 (fCT300-320) of the rat angiotensin II receptor AT1a was demonstrated by relaxation measurements, NOE effects, chemical shift variations, and CD measurements. The correlation times modulating dipolar interactions for the bound and free forms of Ang II were estimated by the ratio of the nonselective and single-selective longitudinal relaxation rates. The intermolecular NOEs observed in NOESY spectra between HN protons of 9Lys(fCT) and 6His(ang), 10Phe(fCT) and 8Phe(ang), HN proton of 3Tyr(fCT) and Halpha of 4Tyr(ang), 5Phe(fCT)Hdelta and Halpha of 4Tyr(ang) indicated that Ang II aromatic residues are directly involved in the interaction, as also verified by relaxation data. Some fCT300-320 backbone features were inferred by the CSI method and CD experiments revealing that the presence of Ang II enhances the existential probability of helical conformations in the fCT fragment. Restrained molecular dynamics using the simulated annealing protocol was performed with intermolecular NOEs as constraints, imposing an alpha-helix backbone structure to fCT300-320 fragment. In the built model, one strongly preferred interaction was found that allows intermolecular stacking between aromatic rings and forces the peptide to wrap around the 6Leu side chain of the receptor fragment.

  12. Inhibition of angiotensin II-induced contraction of human airway smooth muscle cells by angiotensin-(1-7) via downregulation of the RhoA/ROCK2 signaling pathway.

    Science.gov (United States)

    Li, Ning; Cai, Ruijun; Niu, Yi; Shen, Bin; Xu, Jian; Cheng, Yuanxiong

    2012-10-01

    Sustained renin-angiotensin system (RAS) activation in asthmatic patients plays a crucial role in airway hyperresponsiveness and airflow limitation. Angiotensin II (Ang II), as a key peptide of RAS, contributes to the contraction of human airway smooth muscle by activating the RhoA/Rho-associated coiled-coil containing protein kinase 2 (ROCK2) signaling pathway. Angiotensin-(1-7) [Ang-(1-7)], is a component of the angiotensin I converting enzyme 2 (ACE2)-Ang-(1-7)-Mas axis which counteracts the detrimental effects of the ACE- Ang II-angiotensin type 1 receptor (AT1R) axis in vivo; however, whether Ang-(1-7) can inhibit the effect of Ang II in the contraction of human airway smooth muscle cells (HASMCs) is unknown. In our study, collagen gel lattices and immunofluorescence were used to evaluate the contraction of HASMCs induced by Ang II. Real-time PCR and western blot analysis were performed to confirm the regulatory mechanism and the participating signaling pathway. Ang II caused the contraction of HASMCs; this effect was reversed by Ang‑(1‑7). In addition, irbesartan and A779, which are inhibitors of AT1R and Mas, respectively, attenuated the effect of Ang II and Ang-(1-7). Furthermore, Y-27632, an inhibitor of ROCK2, attenuated the Ang II-induced contraction of HASMCs by blocking the RhoA/ROCK2 signaling pathway which is involved in this contraction, and thus may be a major regulator involved in the basal maintenance of contractility in HASMCs. These data demonstrate that Ang II induces the contraction of HASMCs and that this effect can be reversed by Ang-(1-7), partially through the downregulation of of the RhoA/ROCK2 signaling pathway.

  13. Over-expressed copper/zinc superoxide dismutase localizes to mitochondria in neurons inhibiting the angiotensin II-mediated increase in mitochondrial superoxide.

    Science.gov (United States)

    Li, Shumin; Case, Adam J; Yang, Rui-Fang; Schultz, Harold D; Zimmerman, Matthew C

    2013-01-01

    Angiotensin II (AngII) is the main effector peptide of the renin-angiotensin system (RAS), and contributes to the pathogenesis of cardiovascular disease by exerting its effects on an array of different cell types, including central neurons. AngII intra-neuronal signaling is mediated, at least in part, by reactive oxygen species, particularly superoxide (O2 (•-)). Recently, it has been discovered that mitochondria are a major subcellular source of AngII-induced O2 (•-). We have previously reported that over-expression of manganese superoxide dismutase (MnSOD), a mitochondrial matrix-localized O2 (•-) scavenging enzyme, inhibits AngII intra-neuronal signaling. Interestingly, over-expression of copper/zinc superoxide dismutase (CuZnSOD), which is believed to be primarily localized to the cytoplasm, similarly inhibits AngII intra-neuronal signaling and provides protection against AngII-mediated neurogenic hypertension. Herein, we tested the hypothesis that CuZnSOD over-expression in central neurons localizes to mitochondria and inhibits AngII intra-neuronal signaling by scavenging mitochondrial O2 (•-). Using a neuronal cell culture model (CATH.a neurons), we demonstrate that both endogenous and adenovirus-mediated over-expressed CuZnSOD (AdCuZnSOD) are present in mitochondria. Furthermore, we show that over-expression of CuZnSOD attenuates the AngII-mediated increase in mitochondrial O2 (•-) levels and the AngII-induced inhibition of neuronal potassium current. Taken together, these data clearly show that over-expressed CuZnSOD in neurons localizes in mitochondria, scavenges AngII-induced mitochondrial O2 (•-), and inhibits AngII intra-neuronal signaling.

  14. Over-expressed copper/zinc superoxide dismutase localizes to mitochondria in neurons inhibiting the angiotensin II-mediated increase in mitochondrial superoxide

    Directory of Open Access Journals (Sweden)

    Shumin Li

    2014-01-01

    Full Text Available Angiotensin II (AngII is the main effector peptide of the renin–angiotensin system (RAS, and contributes to the pathogenesis of cardiovascular disease by exerting its effects on an array of different cell types, including central neurons. AngII intra-neuronal signaling is mediated, at least in part, by reactive oxygen species, particularly superoxide (O2·−. Recently, it has been discovered that mitochondria are a major subcellular source of AngII-induced O2·−. We have previously reported that over-expression of manganese superoxide dismutase (MnSOD, a mitochondrial matrix-localized O2·− scavenging enzyme, inhibits AngII intra-neuronal signaling. Interestingly, over-expression of copper/zinc superoxide dismutase (CuZnSOD, which is believed to be primarily localized to the cytoplasm, similarly inhibits AngII intra-neuronal signaling and provides protection against AngII-mediated neurogenic hypertension. Herein, we tested the hypothesis that CuZnSOD over-expression in central neurons localizes to mitochondria and inhibits AngII intra-neuronal signaling by scavenging mitochondrial O2·−. Using a neuronal cell culture model (CATH.a neurons, we demonstrate that both endogenous and adenovirus-mediated over-expressed CuZnSOD (AdCuZnSOD are present in mitochondria. Furthermore, we show that over-expression of CuZnSOD attenuates the AngII-mediated increase in mitochondrial O2·− levels and the AngII-induced inhibition of neuronal potassium current. Taken together, these data clearly show that over-expressed CuZnSOD in neurons localizes in mitochondria, scavenges AngII-induced mitochondrial O2·−, and inhibits AngII intra-neuronal signaling.

  15. The non-peptidic part determines the internalization mechanism and intracellular trafficking of peptide amphiphiles.

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    Dimitris Missirlis

    Full Text Available BACKGROUND: Peptide amphiphiles (PAs are a class of amphiphilic molecules able to self-assemble into nanomaterials that have shown efficient in vivo targeted delivery. Understanding the interactions of PAs with cells and the mechanisms of their internalization and intracellular trafficking is critical in their further development for therapeutic delivery applications. METHODOLOGY/PRINCIPAL FINDINGS: PAs of a novel, cell- and tissue-penetrating peptide were synthesized possessing two different lipophilic tail architectures and their interactions with prostate cancer cells were studied in vitro. Cell uptake of peptides was greatly enhanced post-modification. Internalization occurred via lipid-raft mediated endocytosis and was common for the two analogs studied. On the contrary, we identified the non-peptidic part as the determining factor of differences between intracellular trafficking and retention of PAs. PAs composed of di-stearyl lipid tails linked through poly(ethylene glycol to the peptide exhibited higher exocytosis rates and employed different recycling pathways compared to ones consisting of di-palmitic-coupled peptides. As a result, cell association of the former PAs decreased with time. CONCLUSIONS/SIGNIFICANCE: Control over peptide intracellular localization and retention is possible by appropriate modification with synthetic hydrophobic tails. We propose this as a strategy to design improved peptide-based delivery systems.

  16. Nonpeptidic Delta (δ) Opioid Agonists and Antagonists of the Diarylmethylpiperazine Class: What Have We Learned?

    Science.gov (United States)

    Calderon, Silvia N.

    The discovery of the selective delta (δ) opioid agonists SNC 80 and BW373U86, which possess a diarylmethylpiperazine structure unique among opioids, represented a major advance in the field of δ-opioid ligands. Extensive research has recently been performed to uncover the structure-activity relationships (SAR) of this class of ligands, thereby providing valuable tools for the pharmacological characterization of the δ opioid receptor. This review focuses on the SAR of this unique series of ligands, and provides an overview of the various chemical routes that have been developed and optimized through the years to allow the syntheses of these ligands on a multigram scale. The search for selective δ opioid agonists and antagonists, as well as for those with mixed opioid agonist properties with potential therapeutic value, continues. Several questions regarding the interaction at the molecular level of diphenylmethylpiperazine derivatives and related analogs with opioid receptors and in particular with the δ opioid system still remain unanswered. Indeed, the development and pharmacological characterization of novel nonpeptidic δ opioid ligands remains an active area of research, as it may provide a better understanding of the role of this receptor in multiple disease states and disorders.

  17. Small molecule, non-peptide p75 ligands inhibit Abeta-induced neurodegeneration and synaptic impairment.

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    Tao Yang

    Full Text Available The p75 neurotrophin receptor (p75(NTR is expressed by neurons particularly vulnerable in Alzheimer's disease (AD. We tested the hypothesis that non-peptide, small molecule p75(NTR ligands found to promote survival signaling might prevent Abeta-induced degeneration and synaptic dysfunction. These ligands inhibited Abeta-induced neuritic dystrophy, death of cultured neurons and Abeta-induced death of pyramidal neurons in hippocampal slice cultures. Moreover, ligands inhibited Abeta-induced activation of molecules involved in AD pathology including calpain/cdk5, GSK3beta and c-Jun, and tau phosphorylation, and prevented Abeta-induced inactivation of AKT and CREB. Finally, a p75(NTR ligand blocked Abeta-induced hippocampal LTP impairment. These studies support an extensive intersection between p75(NTR signaling and Abeta pathogenic mechanisms, and introduce a class of specific small molecule ligands with the unique ability to block multiple fundamental AD-related signaling pathways, reverse synaptic impairment and inhibit Abeta-induced neuronal dystrophy and death.

  18. Investigation of CGRP receptors and peptide pharmacology in human coronary arteries. Characterization with a nonpeptide antagonist

    DEFF Research Database (Denmark)

    Hasbak, Philip; Saetrum Opgaard, Ole; Eskesen, Karen

    2003-01-01

    in human coronary arteries. Relaxant responses were studied on isolated segments of coronary arteries after precontraction with U46619 (9,11-dideoxy-11alpha,9alpha-epoxymethano-prostaglandin F(2alpha)). The human peptides alphaCGRP, AM, and amylin induced relaxation with mean pEC50 values of 8.6, 6.......8, and 6.3 M, respectively. Preincubation with alphaCGRP(8-37) (10(-7) -10(-5) M) and a novel nonpeptide CGRP antagonist "Compound 1" (WO98/11128) (10(-7)-10(-5) M) caused a dose-dependent rightward shift of the concentration-response curves for alphaCGRP with pA(2) values of 7.0 and 7.1, respectively....... Preincubation with alphaCGRP(8-37) (10(-6) M) and Compound 1 (10(-6) M) caused significant rightward shift of the concentration-response curves for AM and amylin as well with pK B values between 6.6 and 7.5. Preincubation with AM(22-52) had no antagonistic effect on the AM and amylin response, neither did...

  19. Estudio de la acción proinflamatoria de Angiotensina II y su posible modulación. Papel de Angiotensina II en disfunciones endoteliales.

    OpenAIRE

    Álvarez Ribelles, Ángeles

    2002-01-01

    RESUMEN La acumulación leucocitaria es una característica de los primeros estadios de la lesión aterosclerótica, de infarto agudo de miocardio y de enfermedades renales de diversa etiología. Receptores para Angiotensina-II (Ang-II) han sido hallados en monocitos y Ang-II puede promover la activación y adhesión de estas células. Este proceso podría desencadenar o perpetuar el daño endotelial asociado a aterosclerosis e hipertensión. Los resultados de nuestro estudio demuestran que Ang-II, a...

  20. Angiotensin II counteracts the effects of cAMP/PKA on NHE3 activity and phosphorylation in proximal tubule cells.

    Science.gov (United States)

    Crajoinas, Renato O; Polidoro, Juliano Z; Carneiro de Morais, Carla P A; Castelo-Branco, Regiane C; Girardi, Adriana C C

    2016-11-01

    Binding of angiotensin II (ANG II) to the AT1 receptor (AT1R) in the proximal tubule stimulates Na(+)/H(+) exchanger isoform 3 (NHE3) activity through multiple signaling pathways. However, the effects of ANG II/AT1R-induced inihibitory G protein (Gi) activation and subsequent decrease in cAMP accumulation on NHE3 regulation are not well established. We therefore tested the hypothesis that ANG II reduces cAMP/PKA-mediated phosphorylation of NHE3 on serine 552 and, in doing so, stimulates NHE3 activity. Under basal conditions, ANG II stimulated NHE3 activity but did not affect PKA-mediated NHE3 phosphorylation at serine 552 in opossum kidney (OKP) cells. However, in the presence of the cAMP-elevating agent forskolin (FSK), ANG II blocked FSK-induced NHE3 inhibition, reduced intracellular cAMP concentrations, lowered PKA activity, and prevented the FSK-mediated increase in NHE3 serine 552 phosphorylation. All effects of ANG II were blocked by pretreating OKP cells with the AT1R antagonist losartan, highlighting the contribution of the AT1R/Gi pathway in ANG II-mediated NHE3 upregulation under cAMP-elevating conditions. Accordingly, Gi inhibition by pertussis toxin treatment decreased NHE3 activity both in vitro and in vivo and, more importantly, prevented the stimulatory effect of ANG II on NHE3 activity in rat proximal tubules. Collectively, our results suggest that ANG II counteracts the effects of cAMP/PKA on NHE3 phosphorylation and inhibition by activating the AT1R/Gi pathway. Moreover, these findings support the notion that NHE3 dephosphorylation at serine 552 may represent a key event in the regulation of renal proximal tubule sodium handling by ANG II in the presence of natriuretic hormones that promote cAMP accumulation and transporter phosphorylation.

  1. Statins inhibit angiotensin II/Smad pathway and related vascular fibrosis, by a TGF-β-independent process.

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    Raúl Rodrigues Díez

    Full Text Available We have recently described that in an experimental model of atherosclerosis and in vascular smooth muscle cells (VSMCs statins increased the activation of the Smad pathway by transforming growth factor-β (TGF-β, leading to an increase in TGF-β-dependent matrix accumulation and plaque stabilization. Angiotensin II (AngII activates the Smad pathway and contributes to vascular fibrosis, although the in vivo contribution of TGF-β has not been completely elucidated. Our aim was to further investigate the mechanisms involved in AngII-induced Smad activation in the vasculature, and to clarify the beneficial effects of statins on AngII-induced vascular fibrosis. Infusion of AngII into rats for 3 days activates the Smad pathway and increases fibrotic-related factors, independently of TGF-β, in rat aorta. Treatment with atorvastatin or simvastatin inhibited AngII-induced Smad activation and related-fibrosis. In cultured rat VSMCs, direct AngII/Smad pathway activation was mediated by p38 MAPK and ROCK activation. Preincubation of VSMCs with statins inhibited AngII-induced Smad activation at all time points studied (from 20 minutes to 24 hours. All these data show that statins inhibited several AngII-activated intracellular signaling systems, including p38-MAPK and ROCK, which regulates the AngII/Smad pathway and related profibrotic factors and matrix proteins, independently of TGF-β responses. The inhibitory effect of statins on the AngII/Smad pathway could explain, at least in part, their beneficial effects on hypertension-induced vascular damage.

  2. Roles of Caveolin-1 in Angiotensin II-Induced Hypertrophy and Inward Remodeling of Cerebral Pial Arterioles.

    Science.gov (United States)

    Umesalma, Shaikamjad; Houwen, Frederick Keith; Baumbach, Gary L; Chan, Siu-Lung

    2016-03-01

    Angiotensin II (Ang II) is a major determinant of inward remodeling and hypertrophy in pial arterioles that may have an important role in stroke during chronic hypertension. Previously, we found that epidermal growth factor receptor is critical in Ang II-mediated hypertrophy that may involve caveolin-1 (Cav-1). In this study, we examined the effects of Cav-1 and matrix metalloproteinase-9 (MMP9) on Ang II-mediated structural changes in pial arterioles. Cav-1-deficient (Cav-1(-/-)), MMP9-deficient (MMP9(-/-)), and wild-type mice were infused with either Ang II (1000 ng/kg per minute) or saline via osmotic minipumps for 28 days (n=6-8 per group). Systolic arterial pressure was measured by a tail-cuff method. Pressure and diameter of pial arterioles were measured through an open cranial window in anesthetized mice. Cross-sectional area of the wall was determined histologically in pressurized fixed pial arterioles. Expression of Cav-1, MMP9, phosphorylated epidermal growth factor receptor, and Akt was determined by Western blotting and immunohistochemistry. Deficiency of Cav-1 or MMP9 did not affect Ang II-induced hypertension. Ang II increased the expression of Cav-1, phosphorylated epidermal growth factor receptor, and Akt in wild-type mice, which was attenuated in Cav-1(-/-) mice. Ang II-induced hypertrophy, inward remodeling, and increased MMP9 expression in pial arterioles were prevented in Cav-1(-/-) mice. Ang II-mediated increases in MMP9 expression and inward remodeling, but not hypertrophy, were prevented in MMP9(-/-) mice. In conclusion, Cav-1 is essential in Ang II-mediated inward remodeling and hypertrophy in pial arterioles. Cav-1-induced MMP9 is exclusively involved in inward remodeling, not hypertrophy. Further studies are needed to determine the role of Akt in Ang II-mediated hypertrophy. © 2016 American Heart Association, Inc.

  3. Mas receptor overexpression increased Ang-(1-7) relaxation response in renovascular hypertensive rat carotid.

    Science.gov (United States)

    Olivon, V C; Aires, R D; Santiago, L B; Ramalho, L Z N; Cortes, S F; Lemos, V S

    2015-09-01

    Renin-angiotensin system (RAS) is an important factor in the pathophysiology of hypertension. Mas receptor, Angiotensin-(1-7) [Ang-(1-7)]-activated receptor, is an important RAS component and exerts protective effects in the vasculature. Ang-(1-7) vascular effects and Mas receptor expression in carotid from renovascular hypertensive (2K-1C) rats is not clear. In the present study we investigated Mas receptor vasodilator response activated by Ang-(1-7) in the carotid rings from sham and 2K-1C rats. Changes in isometric tension were recorded on organ chamber. Mas receptors expression was investigated in carotid by Western blot. Nitric oxide production was evaluated by 2,3-diaminonaphthalene (DAN) and eNOS expression and activity by immunofluoresce and western blot, respectively. Ang-(1-7) induced concentration-dependent vasodilator effect in carotid rings from sham and 2K-1C, which the hypertension increased vasodilatation response. In the 2K-1C carotid rings, A-779 (Mas receptor antagonist) reduced but not abolish the vasodilator effect of Ang-(1-7). Corroborating, Mas receptor protein expression was significantly increased in the 2K-1C rats. L-NAME and ibuprofen decreased Ang-(1-7) vasodilator response and L-NAME plus ibuprofen practically abolish the remaining vasodilatation response. Nitric oxide production is increased due increased of eNOS expression and pSer(1177) activity. Our results demonstrated that renovascular hypertension increased Mas receptors expression and nitric oxide production in the rats carotid which, consequently increased Ang-(1-7)-vasorelaxant response. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Increased angiotensin II receptors in brain nuclei of DOCA-salt hypertensive rats

    Energy Technology Data Exchange (ETDEWEB)

    Gutkind, J.S.; Kurihara, M.; Saavedra, J.M.

    1988-09-01

    We analyzed angiotensin II (ANG II) receptors by in vitro autoradiography in selective brain nuclei of control, salt-treated (1% NaCl in drinking water), deoxycorticosterone acetate (DOCA)-treated (DOCA pivalate, 25 mg/kg sc weekly), and DOCA-salt-treated (DOCA + salt treatments) uninephrectomized male Wistar-Kyoto rats. After 4 wk of treatment, only the DOCA-salt group developed hypertension. ANG II binding increased in median preoptic nucleus and subfornical organ of salt- and DOCA-treated rats. DOCA-treated rats also showed increased ANG II binding in paraventricular nucleus. DOCA-salt-treated rats showed higher ANG II binding in nucleus of the solitary tract and area postrema, as well as in the areas mentioned before. Although salt and/or DOCA treatments alone increased ANG II receptors in some brain nuclei, after combined DOCA-salt treatment there was significantly higher ANG II binding in all areas, except the median preoptic nucleus. These results suggest that increased ANG II receptors in selected brain areas may play a role in the pathophysiology of mineralocorticoid-salt experimental hypertension.

  5. TRIF promotes angiotensin II-induced cross-talk between fibroblasts and macrophages in atrial fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Xiao-Qing; Zhang, Dao-Liang [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai (China); Zhang, Ming-Jian; Guo, Meng; Zhan, Yang-Yang; Liu, Fang [National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai (China); Jiang, Wei-Feng; Zhou, Li [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai (China); Zhao, Liang, E-mail: zhaol_zg@163.com [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai (China); Wang, Quan-Xing, E-mail: wqxejd@126.com [National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai (China); Liu, Xu, E-mail: liuxu_xk@163.com [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai (China)

    2015-08-14

    Aims: Atrial fibroblasts and macrophages have long been thought to participate in atrial fibrillation (AF). However, which specific mediator may regulate the interaction between them remains unclear. Methods and results: We provided the evidence for the involvement of Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF), an important inflammation-related molecule, in the pathophysiology of AF. Patients with AF showed higher levels of angiotensin II (AngII) and TRIF expression and larger number of macrophages infiltration in left atria appendage than individuals with sinus rhythm (SR). In the cell study, AngII induced chemokines expressions in mouse atrial fibroblasts and AngII-stimulated atrial fibroblasts induced the chemotaxis of macrophages, which were reduced by losartan and TRIF siRNA. Meanwhile, AngII-stimulated atrial fibroblasts proliferation was enhanced by macrophages. Conclusions: Our data demonstrated that TRIF may be a crucial factor promoting the interaction between atrial fibroblasts and macrophages, leading to atrial fibrosis. - Highlights: • Compared with SR, AF showed higher TRIF expression in left atrial appendage. • TRIF siRNA reversed macrophage chemotaxis induced by AngII-treated fibroblast. • TRIF siRNA reversed chemokines expressions induced by AngII in fibroblast. • AngII-stimulated atrial fibroblast proliferation was enhanced by macrophage.

  6. Ets-1 upregulation mediates angiotensin II-related cardiac fibrosis.

    Science.gov (United States)

    Hao, Guanghua; Han, Zhenhua; Meng, Zhe; Wei, Jin; Gao, Dengfeng; Zhang, Hong; Wang, Nanping

    2015-01-01

    Ets-1, the prototypical member of the family of Ets transcription factors, has been shown to participate in tissue fibrotic remodeling. However, its role in cardiac fibrosis has not been established. The aim of this study was to investigate the role of Ets-1 in profibrotic actions of angiotensin II (Ang II) in cardiac fibroblasts (CFs) and in the in vivo heart. In growth-arrested CFs, Ang II induced Ets-1 expression in a time- and concentration-dependent manner. Pretreatment with Ang II type 1 receptor blocker losartan, protein kinase C inhibitor bisindolylmaleimide I, extracellular signal-regulated kinase (ERK) inhibitor PD98059, or c-Jun NH(2)-terminal kinase (JNK) inhibitor SP600125 partly inhibited this induction accompanied with impaired cell proliferation and production of plasminogen activator inhibitor-1 (PAI-1) and connective tissue growth factor (CTGF) protein, the two downstream targets of Ets-1. Knockdown of Ets-1 by siRNA significantly inhibited the inductive effects of Ang II on cell proliferation and expression of CTGF and PAI-1. Moreover, the levels of Ets-1, PAI-1 and CTGF protein were simultaneously upregulated in left ventricle of Ang II-infused rats in parallel with an increase in the activation of ERK and JNK. Our data suggest that Ets-1 may mediate Ang II-induced cardiac fibrotic effects.

  7. Central Renin-Angiotensin System Activation and Inflammation Induced by High-Fat Diet Sensitize Angiotensin II-Elicited Hypertension.

    Science.gov (United States)

    Xue, Baojian; Thunhorst, Robert L; Yu, Yang; Guo, Fang; Beltz, Terry G; Felder, Robert B; Johnson, Alan Kim

    2016-01-01

    Obesity has been shown to promote renin-angiotensin system activity and inflammation in the brain and to be accompanied by increased sympathetic activity and blood pressure. Our previous studies demonstrated that administration of a subpressor dose of angiotensin (Ang) II sensitizes subsequent Ang II-elicited hypertension. The present study tested whether high-fat diet (HFD) feeding also sensitizes the Ang II-elicited hypertensive response and whether HFD-induced sensitization is mediated by an increase in renin-angiotensin system activity and inflammatory mechanisms in the brain. HFD did not increase baseline blood pressure, but enhanced the hypertensive response to Ang II compared with a normal-fat diet. The sensitization produced by the HFD was abolished by concomitant central infusions of either a tumor necrosis factor-α synthesis inhibitor, pentoxifylline, an Ang II type 1 receptor blocker, irbesartan, or an inhibitor of microglial activation, minocycline. Furthermore, central pretreatment with tumor necrosis factor-α mimicked the sensitizing action of a central subpressor dose of Ang II, whereas central pentoxifylline or minocycline abolished this Ang II-induced sensitization. Real-time quantitative reverse transcription-polymerase chain reaction analysis of lamina terminalis tissue indicated that HFD feeding, central tumor necrosis factor-α, or a central subpressor dose of Ang II upregulated mRNA expression of several components of the renin-angiotensin system and proinflammatory cytokines, whereas inhibition of Ang II type 1 receptor and of inflammation reversed these changes. The results suggest that HFD-induced sensitization of Ang II-elicited hypertension is mediated by upregulation of the brain renin-angiotensin system and of central proinflammatory cytokines.

  8. Role of EGFR transactivation in angiotensin II signaling to extracellular regulated kinase in preglomerular smooth muscle cells.

    Science.gov (United States)

    Andresen, Bradley T; Linnoila, Jenny J; Jackson, Edwin K; Romero, Guillermo G

    2003-03-01

    Angiotensin (Ang) II promotes the phosphorylation of extracellular regulated kinase (ERK); however, the mechanisms leading to Ang II-induced ERK phosphorylation are debated. The currently accepted theory involves transactivation of epidermal growth factor receptor (EGFR). We have shown that generation of phosphatidic acid (PA) is required for the recruitment of Raf to membranes and the activation of ERK by multiple agonists, including Ang II. In the present report, we confirm that phospholipase D-dependent generation of PA is required for Ang II-mediated phosphorylation of ERK in Wistar-Kyoto and spontaneously hypertensive rat preglomerular smooth muscle cells (PGSMCs). However, EGF stimulation does not activate phospholipase D or generate PA. These observations indicate that EGF recruits Raf to membranes via a mechanism that does not involve PA, and thus, Ang II-mediated phosphorylation of ERK is partially independent of EGFR-mediated signaling cascades. We hypothesized that phosphoinositide-3-kinase (PI3K) can also act to recruit Raf to membranes; therefore, inhibition of PI3K should inhibit EGF signaling to ERK. Wortmannin, a PI3K inhibitor, inhibited EGF-mediated phosphorylation of ERK (IC50, approximately 14 nmol/L). To examine the role of the EGFR in Ang II-mediated phosphorylation of ERK we utilized 100 nmol/L wortmannin to inhibit EGFR signaling to ERK and T19N RhoA to block Ang II-mediated ERK phosphorylation. Wortmannin treatment inhibited EGF-mediated but not Ang II-mediated phosphorylation of ERK. Furthermore, T19N RhoA inhibited Ang II-mediated ERK phosphorylation, whereas T19N RhoA had significantly less effect on EGF-mediated ERK phosphorylation. We conclude that transactivation of the EGFR is not primarily responsible for Ang II-mediated activation of ERK in PGSMCs.

  9. Exercise intensity modulates capillary perfusion in correspondence with ACE I/D modulated serum angiotensin II levels

    Directory of Open Access Journals (Sweden)

    Sander van Ginkel

    2015-03-01

    Full Text Available During exercise the renin–angiotensin system is stimulated. We hypothesized that the increase in serum angiotensin II (AngII levels after exercise is dependent on exercise intensity and duration and secondly that people with the ACE-II genotype will show a higher increase in AngII serum levels. We also assumed that perfusion of upper limbs is transiently reduced with maximal cycling exercise and that subjects with the ACE-II compared to the ACE-ID/DD genotype will have a higher capillary perfusion due to lower AngII levels. Ten healthy subjects completed a maximal exercise test, a 12-min exercise test at ventilatory threshold and a 3-min test at the respiratory compensation point. AngII serum levels and capillary recruitment of the skin in the third finger were measured before and after exercise and breath-by-breath gas exchange during exercise was assessed. Baseline levels of AngII levels were lower prior to the 3-min test which took place on average 5 days after the last exercise. A two-fold increase compared to baseline levels was found for AngII only immediately after the 3-min test and not after the maximal exercise test and 12-min of exercise. Subjects without the I allele showed a decrease in AngII values after the maximal test in contrast to subjects with the ACE-II/ID genotype. Subjects with the ACE-II genotype had a 1.8 times significant higher capillary perfusion in the finger after exercise. A trend was observed for a 34.3% decreased capillary recruitment in the ACE-ID/DD genotype after exercise. We conclude that the rise in AngII after exercise is intensity dependent and that variability in serum AngII and capillary perfusion is related to the ACE I/D polymorphism.

  10. The development of non-peptide glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes.

    Science.gov (United States)

    Moon, Ho-Sang; Kim, Mi-Kyung; Son, Moon-Ho

    2011-07-01

    Glucagon-like peptide-1 (GLP-1) is the main member of the incretin family and stimulates insulin secretion by binding with its specific receptor on pancreatic β-cells. In addition, GLP-1 exerts broad beneficial effects on the glucose regulation by suppressing food intake and delaying stomach emptying. Now, long acting GLP-1 analogs including exenatide and liraglutide have been approved for the treatment of diabetes mellitus type 2, however long-term injection can limit their use for these chronic patients. In this report, the authors provide a review on the development of non-peptide GLP-1 receptor agonists and introduce a novel agonist DA-15864.

  11. Pro-Cognitive Effects of Non-Peptide Analogues of Soluble Amyloid Peptide Precursor Fragment sAPP.

    Science.gov (United States)

    Tiunova, A A; Komissarova, N V; Nenaidenko, V G; Makhmutova, A A; Beznosko, B K; Bachurin, S O; Anokhin, K V

    2016-08-01

    We studied pro-cognitive effect of two heterocyclic low-molecular-weight compounds that serve as non-peptide analogues of soluble fragment of amyloid peptide precursor (sAPP). Intracerebroventricular and systemic administration of peptide mimetics P2 and P5 improved weak memory on the model of passive avoidance in chicks and in the object location task in mice. Both compounds were effective if administered close to the moment of training or 4 h after it. The time windows and dose range for the pro-cognitive effects of the mimetics were similar to those observed in previous studies with sAPP peptide fragments.

  12. Angiotensin II stimulates thick ascending limb NO production via AT(2) receptors and Akt1-dependent nitric-oxide synthase 3 (NOS3) activation.

    Science.gov (United States)

    Herrera, Marcela; Garvin, Jeffrey L

    2010-05-14

    Angiotensin II (Ang II) acutely stimulates thick ascending limb (TAL) NO via an unknown mechanism. In endothelial cells, activation of Ang II type 2 receptor (AT(2)) stimulates NO. Akt1 activates NOS3 by direct phosphorylation. We hypothesized that Ang II stimulates TAL NO production via AT(2)-mediated Akt1 activation, which phosphorylates NOS3 at serine 1177. We measured NO production by fluorescence microscopy. In isolated TALs, Ang II (100 nm) increased NO production by 1.1 +/- 0.2 fluorescence units/min (p NOS3 at serine 1177 by 130% (p NOS3 phosphorylation. We concluded that Ang II enhances TAL NO production via activation of AT(2) and Akt1-dependent phosphorylation of NOS3 at serines 1177 and 633.

  13. Angiotensin II Stimulates Thick Ascending Limb NO Production via AT2 Receptors and Akt1-dependent Nitric-oxide Synthase 3 (NOS3) Activation*

    Science.gov (United States)

    Herrera, Marcela; Garvin, Jeffrey L.

    2010-01-01

    Angiotensin II (Ang II) acutely stimulates thick ascending limb (TAL) NO via an unknown mechanism. In endothelial cells, activation of Ang II type 2 receptor (AT2) stimulates NO. Akt1 activates NOS3 by direct phosphorylation. We hypothesized that Ang II stimulates TAL NO production via AT2-mediated Akt1 activation, which phosphorylates NOS3 at serine 1177. We measured NO production by fluorescence microscopy. In isolated TALs, Ang II (100 nm) increased NO production by 1.1 ± 0.2 fluorescence units/min (p NOS3 at serine 1177 by 130% (p NOS3 phosphorylation. We concluded that Ang II enhances TAL NO production via activation of AT2 and Akt1-dependent phosphorylation of NOS3 at serines 1177 and 633. PMID:20299462

  14. SNC 80, a selective, nonpeptidic and systemically active opioid delta agonist.

    Science.gov (United States)

    Bilsky, E J; Calderon, S N; Wang, T; Bernstein, R N; Davis, P; Hruby, V J; McNutt, R W; Rothman, R B; Rice, K C; Porreca, F

    1995-04-01

    The present study has investigated the pharmacology of SNC 80, a nonpeptidic ligand proposed to be a selective delta agonist in vitro and in vivo. SNC 80 was potent in producing inhibition of electrically induced contractions of mouse vas deferens, but not in inhibiting contractions of the guinea pig isolated ileum (IC50 values of 2.73 nM and 5457 nM, respectively). The delta selective antagonist ICI 174,864 (1 microM) and the mu selective antagonist CTAP (1 microM) produced 236- and 1.9-fold increases, respectively, in the SNC 80 IC50 value in the mouse vas deferens. SNC 80 preferentially competed against sites labeled by [3H]naltrindole (delta receptors) rather than against those labeled by [3H]DAMGO (mu receptors) or [3H]U69, 593 kappa receptors) in mouse whole-brain assays. The ratios of the calculated Ki values for SNC 80 at mu/delta and kappa/delta sites were 495- and 248-fold, respectively, which indicates a significant degree of delta selectivity for this compound in radioligand binding assays. SNC 80 produced dose- and time-related antinociception in the mouse warm-water tail-flick test after i.c.v., i.th. and i.p. administration. The calculated A50 values (and 95% C.I.) for SNC 80 administered i.c.v., i.th. and i.p. were 104.9 (63.7-172.7) nmol, 69 (51.8-92.1) nmol and 57 (44.5-73.1) mg/kg, respectively. The i.c.v. administration of SNC 80 also produced dose- and time-related antinociception in the hot-plate test, with a calculated A50 value (and 95% C.I.) of 91.9 (60.3-140.0) nmol.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Angiotensin II upregulates endothelial lipase expression via the NF-kappa B and MAPK signaling pathways.

    Directory of Open Access Journals (Sweden)

    Xiaoli Zhang

    Full Text Available BACKGROUND: Angiotensin II (AngII participates in endothelial damage and inflammation, and accelerates atherosclerosis. Endothelial lipase (EL is involved in the metabolism and clearance of high density lipoproteins (HDL, the serum levels of which correlate negatively with the onset of cardiovascular diseases including atherosclerosis. However, the relationship between AngII and EL is not yet fully understood. In this study, we investigated the effects of AngII on the expression of EL and the signaling pathways that mediate its effects in human umbilical vein endothelial cells (HUVECs. METHODS AND FINDINGS: HUVECs were cultured in vitro with different treatments as follows: 1 The control group without any treatment; 2 AngII treatment for 0 h, 4 h, 8 h, 12 h and 24 h; 3 NF-κB activation inhibitor pyrrolidine dithiocarbamate (PDTC pretreatment for 1 h before AngII treatment; and 4 mitogen-activated protein kinase (MAPK p38 inhibitor (SB203580 pretreatment for 1 h before AngII treatment. EL levels in each group were detected by immunocytochemical staining and western blotting. HUVECs proliferation was detected by MTT and proliferating cell nuclear antigen (PCNA immunofluorescence staining. NF-kappa B (NF-κB p65, MAPK p38, c-Jun N-terminal kinase (JNK, extracellular signal-regulated kinase (ERK and phosphorylated extracellular signal-regulated kinase (p-ERK expression levels were assayed by western blotting. The results showed that the protein levels of EL, NF-κB p65, MAPK p38, JNK, and p-ERK protein levels, in addition to the proliferation of HUVECs, were increased by AngII. Both the NF-kB inhibitor (PDTC and the MAPK p38 inhibitor (SB203580 partially inhibited the effects of AngII on EL expression. CONCLUSION: AngII may upregulate EL protein expression via the NF-κB and MAPK signaling pathways.

  16. Targeting metastatic breast cancer with ANG1005, a novel peptide-paclitaxel conjugate that crosses the blood-brain-barrier (BBB

    Directory of Open Access Journals (Sweden)

    Fei Li

    2017-03-01

    Full Text Available We devoted this short interview piece with Dr Shou-Ching Tang at Augusta University to feature some promising results from a clinical phase II trial on a novel brain-penetrating peptide-paclitaxel-conjugate, ANG1005, in treating brain metastatic breast cancer. These results were presented by Dr. Tang at the recent annual meeting of the European Society for Medical Oncology (ESMO 2016 Congress. This development heralds an important step forward towards the development of effective chemotherapeutic agents, which can cross the blood-brain-barrier and effectively treat and prevent the brain metastatic cancers.

  17. "Graafika IN" kui klots ANG piltmõistatuses / Anu Allas

    Index Scriptorium Estoniae

    Allas, Anu, 1977-

    2005-01-01

    9. IN Graafika festivalist "Man-Machine" Pärnus Muuseumiaidas 8.-16. I, Pärnu kontserdimajas 8. I-12. II TÜ kolledzhis ja Endla teatri Küüni koridorigaleriis 8. I kuni veebruari lõpuni ning Academia Non Gratast (J. Köleri nim. Positivistlikust Kunsttööstuskoolist)

  18. "Graafika IN" kui klots ANG piltmõistatuses / Anu Allas

    Index Scriptorium Estoniae

    Allas, Anu, 1977-

    2005-01-01

    9. IN Graafika festivalist "Man-Machine" Pärnus Muuseumiaidas 8.-16. I, Pärnu kontserdimajas 8. I-12. II TÜ kolledzhis ja Endla teatri Küüni koridorigaleriis 8. I kuni veebruari lõpuni ning Academia Non Gratast (J. Köleri nim. Positivistlikust Kunsttööstuskoolist)

  19. Angiotensin II increases matrix metalloproteinase 2 expression in human aortic smooth muscle cells via AT1R and ERK1/2.

    Science.gov (United States)

    Wang, Chunmao; Qian, Xiangyang; Sun, Xiaogang; Chang, Qian

    2015-12-01

    Increased levels of angiotensin II (Ang II) and activated matrix metalloproteinase 2 (MMP-2) produced by human aortic smooth muscle cells (human ASMCs) have recently been implicated in the pathogenesis of thoracic aortic aneurysm (TAA). Additionally, angiotensin II type 1 receptor (AT1R)-mediated extracellular signal-regulated kinase (ERK)1/2 activation contributes to TAA development in Marfan Syndrome. However, there is scant data regarding the relationship between Ang II and MMP-2 expression in human ASMCs. Therefore, we investigated the effect of Ang II on MMP-2 expression in human ASMCs and used Western blotting to identify the Ang II receptors and intracellular signaling pathways involved. Reverse transcription polymerase chain reaction (RT-PCR) and immunofluorescence data demonstrated that Ang II receptors were expressed on human ASMCs. Additionally, Ang II increased the expression of Ang II type 2 receptor (AT2R) but not AT1R at both the transcriptional and translational levels. Furthermore, Western blotting showed that Ang II increased MMP-2 expression in human ASMCs in a dose- and time-dependent manner. This response was completely inhibited by the AT1R inhibitor candesartan but not by the AT2R blocker PD123319. In addition, Ang II-induced upregulation of MMP-2 was mediated by the activation of ERK1/2, whereas p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) had no effect on this process. In conclusion, these results indicate that Ang II can increase the expression of MMP-2 via AT1 receptor and ERK1/2 signaling pathways in human ASMCs and suggest that antagonists of AT1R and ERK1/2 may be useful for treating TAAs.

  20. Combination of angiotensin II and l-NG-nitroarginine methyl ester exacerbates mitochondrial dysfunction and oxidative stress to cause heart failure.

    Science.gov (United States)

    Hamilton, Dale J; Zhang, Aijun; Li, Shumin; Cao, Tram N; Smith, Jessie A; Vedula, Indira; Cordero-Reyes, Andrea M; Youker, Keith A; Torre-Amione, Guillermo; Gupte, Anisha A

    2016-03-15

    Mitochondrial dysfunction has been implicated as a cause of energy deprivation in heart failure (HF). Herein, we tested individual and combined effects of two pathogenic factors of nonischemic HF, inhibition of nitric oxide synthesis [with l-N(G)-nitroarginine methyl ester (l-NAME)] and hypertension [with angiotensin II (AngII)], on myocardial mitochondrial function, oxidative stress, and metabolic gene expression. l-NAME and AngII were administered individually and in combination to mice for 5 wk. Although all treatments increased blood pressure and reduced cardiac contractile function, the l-NAME + AngII group was associated with the most severe HF, as characterized by edema, hypertrophy, oxidative stress, increased expression of Nppa and Nppb, and decreased expression of Atp2a2 and Camk2b. l-NAME + AngII-treated mice exhibited robust deterioration of cardiac mitochondrial function, as observed by reduced respiratory control ratios in subsarcolemmal mitochondria and reduced state 3 levels in interfibrillar mitochondria for complex I but not for complex II substrates. Cardiac myofibrils showed reduced ADP-supported and oligomycin-inhibited oxygen consumption. Mitochondrial functional impairment was accompanied by reduced mitochondrial DNA content and activities of pyruvate dehydrogenase and complex I but increased H2O2 production and tissue protein carbonyls in hearts from AngII and l-NAME + AngII groups. Microarray analyses revealed the majority of the gene changes attributed to the l-NAME + AngII group. Pathway analyses indicated significant changes in metabolic pathways, such as oxidative phosphorylation, mitochondrial function, cardiac hypertrophy, and fatty acid metabolism in l-NAME + AngII hearts. We conclude that l-NAME + AngII is associated with impaired mitochondrial respiratory function and increased oxidative stress compared with either l-NAME or AngII alone, resulting in nonischemic HF.

  1. Polychlorinated biphenyl 77 augments angiotensin II-induced atherosclerosis and abdominal aortic aneurysms in male apolipoprotein E deficient mice

    Energy Technology Data Exchange (ETDEWEB)

    Arsenescu, Violeta [Graduate Center for Nutritional Sciences, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States); Arsenescu, Razvan [Digestive Diseases and Nutrition, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States); Parulkar, Madhura; Karounos, Michael [Graduate Center for Nutritional Sciences, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States); Zhang, Xuan [Graduate Center for Toxicology, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States); Baker, Nicki [Graduate Center for Nutritional Sciences, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States); Cassis, Lisa A., E-mail: lcassis@uky.edu [Graduate Center for Nutritional Sciences, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States)

    2011-11-15

    Infusion of angiotensin II (AngII) to hyperlipidemic mice augments atherosclerosis and causes formation of abdominal aortic aneurysms (AAAs). Each of these AngII-induced vascular pathologies exhibit pronounced inflammation. Previous studies demonstrated that coplanar polychlorinated biphenyls (PCBs) promote inflammation in endothelial cells and adipocytes, two cell types implicated in AngII-induced vascular pathologies. The purpose of this study was to test the hypothesis that administration of PCB77 to male apolipoprotein E (ApoE) -/- mice promotes AngII-induced atherosclerosis and AAA formation. Male ApoE-/- mice were administered vehicle or PCB77 (49 mg/kg, i.p.) during week 1 and 4 (2 divided doses/week) of AngII infusion. Body weights and total serum cholesterol concentrations were not influenced by administration of PCB77. Systolic blood pressure was increased in AngII-infused mice administered PCB77 compared to vehicle (156 {+-} 6 vs 137 {+-} 5 mmHg, respectively). The percentage of aortic arch covered by atherosclerotic lesions was increased in AngII-infused mice administered PCB77 compared to vehicle (2.0 {+-} 0.4 vs 0.9 {+-} 0.1%, respectively). Lumen diameters of abdominal aortas determined by in vivo ultrasound and external diameters of excised suprarenal aortas were increased in AngII-infused mice administered PCB77 compared to vehicle. In addition, AAA incidence increased from 47 to 85% in AngII-infused mice administered PCB77. Adipose tissue in close proximity to AAAs from mice administered PCB77 exhibited increased mRNA abundance of proinflammatory cytokines and elevated expression of components of the renin-angiotensin system (angiotensinogen, angiotensin type 1a receptor (AT1aR)). These results demonstrate that PCB77 augments AngII-induced atherosclerosis and AAA formation. -- Highlights: Black-Right-Pointing-Pointer Polychlorinated biphenyl 77 (PCB77) promotes AngII-induced hypertension. Black-Right-Pointing-Pointer PCB77 augments AngII

  2. Clinical Significance of Tumor Ang-2 for Lung Cancer Detection%肿瘤标志物--Ang-2对肺癌临床检测意义

    Institute of Scientific and Technical Information of China (English)

    李明琦; 石学魁; 尤琦; 王大为; 贾云鹤; 王锡山; 张鹏宇

    2015-01-01

    Objective: To evaluate the clinical value of angiopoietin-2 in diagnose of lung cancer. Methods: Patients with lung cancer (n=116) and healthy volunteers (n=16) were enrolled. Serum angiopoietin-2 concentrations were measured using en-zyme-linked immunosorbent assay.Serum carcinoembryonic antigen (CEA)、neuron specific enolase;neurone specific enolase (NSE)、cytokeratin fragment 19 (CYFRA21-1) concentrations were measured by electrochemiluminescence(ECL). Serum squamous cell carci-noma antigen (SCC) concentrations were measured by microparticle enzyme immunoassay(MEIA). Results: Patients with lung cancer had higher serum angiopoietin-2 (p<0.05) levels than the control group. With stage progression in nonsmall-cell lung cancer (NSCLC), serum angiopoietin-2 levels increased, and patients with distant metastasis had higher levels than those without metastasis (p<0.005). The combined test of angiopoietin-2 with other tumor markers increased the sensitivity of diagnosis. Conclusions: Our study suggests that serum angiopoietin-2 is a useful clinical marker for detecting lung cancer with distant metastasis and is of potential prognostic value. The combined measurement of CEA、NSE、CYFRA21-1、SCC and angiopoietin-2 was helpful in the diagnosis of lung cancer.%目的:探讨一种新型肿瘤标志物促血管生成素-2(Ang-2)对肺癌诊断、治疗监测、预后判断的应用价值。方法:对112例肺癌患者,包括鳞癌(squamous cell carcinoma ,SC)患者42例、腺癌(adenocarcinoma of lung ,AC)46例、小细胞肺癌(small-cell lung cancer,SCLC)24例,以及16例健康者健康体检者以血清促血管生成素2(Ang-2)检测为主体,同步测定其他相关肿瘤标志物血清癌胚抗原(CEA)、神经元特异性烯醇酶(NSE)、角蛋白19片段(CYFRA21-1)、鳞状细胞癌相关抗原(SCC)。比较病理分型、临床分期及远处转移对血清Ang-2的影响。评价CEA、NSE、CYFRA21-1、SCC与Ang-2

  3. Angústia de uma perda: caso Maria: uma abordagem terapêutica

    OpenAIRE

    Mónica Costa; Catarina Pinheiro Mota; Cláudia Milheiro

    2013-01-01

    O presente estudo de caso procura discutir a vivência de Maria, de 32 anos de idade, onde está patente uma dinâmica emocional e relacional marcada por sentimentos de angústia. A avaliação revelou uma vivência afetiva de tipo neurótico, apresentando sinais clínicos evidentes da angústia da perda do objeto e da separação afetiva, revelando fortes sentimentos de culpabilidade frente a conflitos internos. É proposta uma intervenção psicológica no sentido de facilitar a vivência do luto passando p...

  4. Angústia de uma perda - caso Maria: uma abordagem terapêutica

    OpenAIRE

    Mónica Costa; Catarina Pinheiro Mota; Cláudia Milheiro

    2013-01-01

    O presente estudo de caso procura discutir a vivência de Maria, de 32 anos de idade, onde está patente uma dinâmica emocional e relacional marcada por sentimentos de angústia. A avaliação revelou uma vivência afetiva de tipo neurótico, apresentando sinais clínicos evidentes da angústia da perda do objeto e da separação afetiva, revelando fortes sentimentos de culpabilidade frente a conflitos internos. É proposta uma intervenção psicológica no sentido de facilitar a vivência do luto passando p...

  5. Non-peptide ligand binding to the formyl peptide receptor FPR2--A comparison to peptide ligand binding modes.

    Science.gov (United States)

    Stepniewski, Tomasz M; Filipek, Slawomir

    2015-07-15

    Ligands of the FPR2 receptor initiate many signaling pathways including activation of phospholipase C, protein kinase C, the mitogen-activated protein kinase, and phosphatidylinositol 3-kinase/protein kinase B pathway. The possible actions include also calcium flux, superoxide generation, as well as migration and proliferation of monocytes. FPR2 activation may induce a pro- and anti-inflammatory effect depending on the ligand type. It is also found that this receptor is involved in tumor growth. Most of currently known FPR2 ligands are agonists since they were designed based on N-formyl peptides, which are natural agonists of formyl receptors. Since the non-peptide drugs are indispensable for effective treatment strategies, we performed a docking study of such ligands employing a generated dual template homology model of the FPR2 receptor. The study revealed different binding modes of particular classes of these drugs. Based on the obtained docking poses we proposed a detailed location of three hydrophobic pockets in orthosteric binding site of FPR2. Our model emphasizes the importance of aromatic stacking, especially with regard to residues His102(3.29) and Phe257(6.51), for binding of FPR2 ligands. We also identified other residues important for non-peptide ligand binding in the binding site of FPR2. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Hyperthermic responses to central injections of some peptide and non-peptide opioids in the guinea-pig

    Science.gov (United States)

    Kandasamy, S. B.; Williams, B. A.

    1983-01-01

    The intracerebroventricular administration of prototype nonpeptide opioid receptor (mu, kappa, and sigma) agonists, morphine, ketocyclazocine, and N-allyl normetazocine and an agonist at both kappa and sigma receptors, pentazocine, was found to induce hyperthermia in guinea pigs. The similar administration of peptide opioids like beta endorphin, methionine endkephalin, leucine endkephaline, and several of their synthetic analogues was also found to cause hyperthermia. Only the liver-like transport system of the three anion transport systems (iodide, hippurate, and liver-like) present in the choroid plexus was determined to be important to the central inactivation of beta-endorphin and two synthetic analogues. Prostaglandins and norepinephrine (NE) as well as cAMP were not involved in peptide and nonpeptide opioid-induced hyperthermia. Naloxone-sensitive receptors were found to be involved in the induction of hyperthermia by morphine and beta-endorphin, while hyperthermic responses to ketocyclazocine, N-allyl normetazocine, pentazocine, Met-enkephalin, Leu-enkephalin, and two of the synthetic analogues were not antagonized by nalozone. The lack of antagonism of naloxone on pyrogen, arachidonic acid, PGE2, dibutyryl cAMP, and NE-induced hyperthermia shows that endogenous opioid peptides are not likely to be central mediators of the hyperthermia induced by these agents.

  7. Delayed cardioprotection is mediated via a non-peptide delta opioid agonist, SNC-121, independent of opioid receptor stimulation.

    Science.gov (United States)

    Patel, Hemal H; Hsu, Anna; Gross, Garrett J

    2004-01-01

    Acute cardioprotection is mediated primarily through delta opioid receptor stimulation independent of micro or kappa opioid receptor stimulation. Delayed cardioprotection is mediated by delta opioid receptor agonists but ambiguity remains about direct receptor involvement. Therefore, we investigated the potential of SNC-121, a non-peptide delta opioid agonist, to produce delayed cardioprotection and characterized the role of opioid receptors in this delayed response. All rats underwent 30 minutes of ischemia followed by 2 hours of reperfusion. SNC-121 induced a significant delayed cardioprotective effect. To determine the nature of this SNC-121-induced delayed cardioprotection, rats were treated with specific opioids receptor antagonists and underwent pertussis toxin (PT) treatment prior to opioid agonist stimulation. Control rats were injected with saline and allowed to recover for 24 hours. Pretreatment and early treatment with opioid receptor antagonists failed to inhibit the delayed protective effects of SNC-121, as did pretreatment with PT. Treatment with a free radical scavenger, 2-mercaptopropionyl glycine, at the time of opioid stimulation attenuated the delayed cardioprotective effects of SNC-121. These data suggest that delayed cardioprotection is stimulated via non-peptide delta opioid agonists by a mechanism unrelated to opioid receptor activation. The mechanism appears to be a non-opioid receptor mediated production of reactive oxygen species that triggers the signaling cascade leading to delayed cardioprotection.

  8. Central estrogen inhibition of angiotensin II-induced hypertension in male mice and the role of reactive oxygen species.

    Science.gov (United States)

    Xue, Baojian; Zhao, Yuanzi; Johnson, Alan Kim; Hay, Meredith

    2008-09-01

    It has been shown that reactive oxygen species (ROS) contribute to the central effect of ANG II on blood pressure (BP). Recent studies have implicated an antihypertensive action of estrogen in ANG II-infused female mice. The present study used in vivo telemetry recording and in vitro living mouse brain slices to test the hypothesis that the central activation of estrogen receptors in male mice inhibits ANG II-induced hypertension via the modulation of the central ROS production. In male wild-type mice, the systemic infusion of ANG II induced a significant increase in BP (Delta30.1 +/- 2.5 mmHg). Either central infusion of Tempol or 17beta-estradiol (E2) attenuated the pressor effect of ANG II (Delta10.9 +/- 2.3 and Delta4.5 +/- 1.4 mmHg), and the protective effect of E2 was prevented by the coadministration of an estrogen receptor, antagonist ICI-182780 (Delta23.6 +/- 3.1 mmHg). Moreover, the ganglionic blockade on day 7 after the start of ANG II infusions resulted in a smaller reduction of BP in central Tempol- and in central E2-treated males, suggesting that estrogen inhibits the central ANG II-induced increases in sympathetic outflow. In subfornical organ slices, the application of ANG II resulted in a 21.5 +/- 2.5% increase in ROS production. The coadministration of irbesartan, an ANG II type 1 receptor antagonist, or the preincubation of brain slices with Tempol blocked ANG II-induced increases in ROS production (-1.8 +/- 1.6% and -1.0 +/- 1.8%). The ROS response to ANG II was also blocked by E2 (-3.2 +/- 2.4%). The results suggest that the central actions of E2 are involved in the protection from ANG II-induced hypertension and that estrogen modulation of the ANG II-induced effects may involve interactions with ROS production.

  9. Coordination Environment of Cu(II) Ions Bound to N-Terminal Peptide Fragments of Angiogenin Protein.

    Science.gov (United States)

    Magrì, Antonio; Munzone, Alessia; Peana, Massimiliano; Medici, Serenella; Zoroddu, Maria Antonietta; Hansson, Orjan; Satriano, Cristina; Rizzarelli, Enrico; La Mendola, Diego

    2016-08-01

    Angiogenin (Ang) is a potent angiogenic factor, strongly overexpressed in patients affected by different types of cancers. The specific Ang cellular receptors have not been identified, but it is known that Ang-actin interaction induces changes both in the cell cytoskeleton and in the extracellular matrix. Most in vitro studies use the recombinant form (r-Ang) instead of the form that is normally present in vivo ("wild-type", wt-Ang). The first residue of r-Ang is a methionine, with a free amino group, whereas wt-Ang has a glutamic acid, whose amino group spontaneously cyclizes in the pyro-glutamate form. The Ang biological activity is influenced by copper ions. To elucidate the role of such a free amino group on the protein-copper binding, we scrutinized the copper(II) complexes with the peptide fragments Ang(1-17) and AcAng(1-17), which encompass the sequence 1-17 of angiogenin (QDNSRYTHFLTQHYDAK-NH₂), with free amino and acetylated N-terminus, respectively. Potentiometric, ultraviolet-visible (UV-vis), nuclear magnetic resonance (NMR) and circular dichroism (CD) studies demonstrate that the two peptides show a different metal coordination environment. Confocal microscopy imaging of neuroblastoma cells with the actin staining supports the spectroscopic results, with the finding of different responses in the cytoskeleton organization upon the interaction, in the presence or not of copper ions, with the free amino and the acetylated N-terminus peptides.

  10. Direct Activation of ENaC by Angiotensin II: Recent Advances and New Insights

    OpenAIRE

    Zaika, Oleg; Mamenko, Mykola; Staruschenko, Alexander; Pochynyuk, Oleh

    2013-01-01

    Angiotensin II (Ang II) is the principal effector of the renin-angiotensin-aldosterone system (RAAS). It initiates myriad processes in multiple organs integrated to increase circulating volume and elevate systemic blood pressure. In the kidney, Ang II stimulates renal tubular water and salt reabsorption causing antinatriuresis and antidiuresis. Activation of RAAS is known to enhance activity of the epithelial Na+ channel (ENaC) in the aldosterone-sensitive distal nephron. In addition to its w...

  11. SIRT1 Functions as an Important Regulator of Estrogen-Mediated Cardiomyocyte Protection in Angiotensin II-Induced Heart Hypertrophy

    Directory of Open Access Journals (Sweden)

    Tao Shen

    2014-01-01

    Full Text Available Background. Sirtuin 1 (SIRT1 is a member of the sirtuin family, which could activate cell survival machinery and has been shown to be protective in regulation of heart function. Here, we determined the mechanism by which SIRT1 regulates Angiotensin II- (AngII- induced cardiac hypertrophy and injury in vivo and in vitro. Methods. We analyzed SIRT1 expression in the hearts of control and AngII-induced mouse hypertrophy. Female C57BL/6 mice were ovariectomized and pretreated with 17β-estradiol to measure SIRT1 expression. Protein synthesis, cardiomyocyte surface area analysis, qRT-PCR, TUNEL staining, and Western blot were performed on AngII-induced mouse heart hypertrophy samples and cultured neonatal rat ventricular myocytes (NRVMs to investigate the function of SIRT1. Results. SIRT1 expression was slightly upregulated in AngII-induced mouse heart hypertrophy in vivo and in vitro, accompanied by elevated cardiomyocyte apoptosis. SIRT1 overexpression relieves AngII-induced cardiomyocyte hypertrophy and apoptosis. 17β-Estradiol was able to protect cardiomyocytes from AngII-induced injury with a profound upregulation of SIRT1 and activation of AMPK. Moreover, estrogen receptor inhibitor ICI 182,780 and SIRT1 inhibitor niacinamide could block SIRT1’s protective effect. Conclusions. These results indicate that SIRT1 functions as an important regulator of estrogen-mediated cardiomyocyte protection during AngII-induced heart hypertrophy and injury.

  12. ACE2/ANG-(1-7)/Mas pathway in the brain: the axis of good

    National Research Council Canada - National Science Library

    Xu, Ping; Sriramula, Srinivas; Lazartigues, Eric

    2011-01-01

    ...). Among them, angiotensin converting enzyme-2 (ACE2) and the Mas receptor have forced a reevaluation of the original cascade and led to the emergence of a new arm of the RAS: the ACE2/ANG-(1-7)/Mas axis...

  13. Periodic solutions of delayed predator-prey model with the Beddington-DeAngelis functional response

    Energy Technology Data Exchange (ETDEWEB)

    Huo Haifeng [Institute of Applied Mathematics, Lanzhou University of Technology, Lanzhou, Gansu 730050 (China)]. E-mail: hfhuo@lut.cn; Li Wantong [Department of Mathematics, Lanzhou University Lanzhou, Gansu 730000 (China)]. E-mail: wtli@lzu.edu.cn; Nieto, Juan J. [Departamento de Analisis Matematico, Facultad de Matematicas, Universidad de Santiago de Compostela 15782 (Spain)]. E-mail: amnieto@usc.es

    2007-07-15

    By using the continuation theorem based on Gaines and Mawhin's coincidence degree, sufficient and realistic conditions are obtained for the global existence of positive periodic solutions for a delayed predator-prey model with the Beddington-DeAngelis functional response. Our results are applicable to state dependent and distributed delays.

  14. Protease-activated receptor 1 and 2 contribute to angiotensin II-induced activation of adventitial fibroblasts from rat aorta

    Energy Technology Data Exchange (ETDEWEB)

    He, Rui-Qing; Tang, Xiao-Feng; Zhang, Bao-Li [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Shanghai Institute of Hypertension, Shanghai (China); Li, Xiao-Dong [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai (China); Shanghai Institute of Hypertension, Shanghai (China); Hong, Mo-Na [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Shanghai Institute of Hypertension, Shanghai (China); Chen, Qi-Zhi [Shanghai Institute of Hypertension, Shanghai (China); Han, Wei-Qing, E-mail: whan020@gmail.com [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai (China); Shanghai Institute of Hypertension, Shanghai (China); Gao, Ping-Jin, E-mail: gaopingjin@sibs.ac.cn [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai (China); Shanghai Institute of Hypertension, Shanghai (China)

    2016-04-29

    Adventitial fibroblasts (AFs) can be activated by angiotensin II (Ang II) and exert pro-fibrotic and pro-inflammatory effects in vascular remodeling. Protease-activated receptor (PAR) 1 and 2 play a significant role in fibrogenic and inflammatory diseases. The present study hypothesized that PAR1 and PAR2 are involved in Ang II-induced AF activation and contribute to adventitial remodeling. We found that direct activation of PAR1 and PAR2 with PAR1-AP and PAR2-AP led to AF activation, including proliferation and differentiation of AFs, extracellular matrix synthesis, as well as production of pro-fibrotic cytokine TGF-β and pro-inflammatory cytokines IL-6 and MCP-1. Furthermore, PAR1 and PAR2 mediated Ang II-induced AF activation, since both PAR1 and PAR2 antagonists inhibited Ang II-induced proliferation, migration, differentiation, extracellular matrix synthesis and production of pro-fibrotic and pro-inflammatory cytokines in AFs. Finally, mechanistic study showed that Ang II, via Ang II type I receptor (AT1R), upregulated both PAR1 and PAR2 expression, and transactivated PAR1 and PAR2, as denoted by internalization of both proteins. In conclusion, our results suggest that PAR1 and PAR2 play a critical role in Ang II-induced AF activation, and this may contribute to adventitia-related pathological changes. - Highlights: • Direct activation of PAR1 and PAR2 led to adventitial fibroblast (AF) activation. • PAR1 and PAR2 antagonists attenuated Ang II-induced AF activation. • Ang II induced the upregulation and transactivation of PAR1/PAR2 in AFs.

  15. Adrenomedullin is a potent inhibitor of angiotensin II-induced migration of human coronary artery smooth muscle cells.

    Science.gov (United States)

    Kohno, M; Yokokawa, K; Kano, H; Yasunari, K; Minami, M; Hanehira, T; Yoshikawa, J

    1997-06-01

    The migration of coronary artery medial smooth muscle cells (SMCs) into the intima is proposed to be an important process of intimal thickening in coronary atherosclerotic lesions. In the current study, we examined the possible interaction of adrenomedullin, a novel vasorelaxant peptide, and angiotensin II (Ang II) on human coronary artery SMC migration using Boyden's chamber method. Ang II stimulated SMC migration in a concentration-dependent manner between 10(6) and 10(8) mol/L. This stimulation was clearly blocked by the Ang II type 1 receptor antagonist losartan but not by the type 2 receptor antagonist PD 123319. The migration stimulatory effect of Ang II was chemotactic in nature for cultured human coronary artery SMCs but was not chemokinetic. Human adrenomedullin clearly inhibited Ang II-induced migration in a concentration-dependent manner. Human adrenomedullin stimulated cAMP formation in these cells. Inhibition by adrenomedullin of Ang II-induced SMC migration was paralleled by an increase in the cellular level of cAMP. 8-Bromo-cAMP, a cAMP analogue, and forskolin, an activator of adenylate cyclase, inhibited the Ang II-induced SMC migration. These results suggest that Ang II stimulates SMC migration via type 1 receptors in human coronary artery and adrenomedullin inhibits Ang II-induced migration at least partly through a cAMP-dependent mechanism. Taken together with the finding that adrenomedullin is synthesized in and secreted from vascular endothelial cells, this peptide may play a role as a local antimigration factor in certain pathological conditions.

  16. Development of nonfibrotic left ventricular hypertrophy in an ANG II-induced chronic ovine hypertension model

    DEFF Research Database (Denmark)

    Klatt, Niklas; Scherschel, Katharina; Schad, Claudia

    2016-01-01

    by picrosirius red and H&E staining on myocardial full thickness paraffin sections of both atria and ventricles. Measurements of plasma high-sensitivity C-reactive protein and urinary 8-iso-prostaglandin F2α were inconspicuous in all animals. Furthermore, multielectrode surface mapping of the heart did not show...

  17. Influence of angiotensin II receptor subtypes of the paraventricular nucleus on the physiological responses induced by angiotensin II injection into the medial septal area

    Directory of Open Access Journals (Sweden)

    Saad Wilson Abrão

    2003-01-01

    Full Text Available OBJECTIVE: We determined the effects of losartan and PD 123319 (antagonists of the AT1 and AT2 angiotensin receptors, respectively, and [Sar¹, Ala8] ANG II (a relatively peptide antagonist of angiotensin receptors injected into the paraventricular nucleus (PVN on water and 3% NaCl intake, and the diuretic, natriuretic, and pressor effects induced by administration of angiotensin II (ANG II into the medial septal area (MSA of conscious rats. METHODS: Holtzman rats were used . Animals were anesthetized with tribromoethanol (20 mg per 100 grams of body weight, ip. A stainless steel guide cannula was implanted into the MSA and PVN. All drugs were injected in 0.5-mul volumes for 10-15 seconds. Seven days after brain surgery, water and 3% NaCl intake, urine and sodium excretion, and arterial blood pressure were measured. RESULTS: Losartan (40 nmol and [Sar¹, Ala8] ANG II (40 nmol completely eliminated whereas PD 123319 (40 nmol partially blocked the increase in water and sodium intake and the increase in arterial blood pressure induced by ANG II (10 nmol injected into the MSA. The PVN administration of PD 123319 and [Sar¹, Ala8] ANG II blocked whereas losartan attenuated the diuresis and natriuresis induced by MSA administration of ANG II. CONCLUSION: MSA involvement with PVN on water and sodium homeostasis and arterial pressure modulation utilizing ANGII receptors is suggested.

  18. Ang2基因RNA干扰慢病毒表达载体的构建与鉴定%Construction and Identification of RNAi Lentiviral Expression Vector for Ang2 Gene

    Institute of Scientific and Technical Information of China (English)

    王彪; 张炜强; 单秀英; 刘照亮; 郭国祥; 庄福连

    2011-01-01

    Objective To construct and identify the RNAi lentiviral expression vector for angiopoietin ( Ang )2 gene, and identify its validity. Methods pSilenser 1.0-U6 - Ang2-siRNA reccombinant plasmid to ploymorphonuclear neutrophilic leukocyte-effective green fluorescence protein( pNL-EGFP )vector, which were digested and electorphoresis identified by using enzyme Xha Ⅰ , were joined to get pNL-EGFP-U6-Ang2 -siRNA lentiviral transfer plamid , then the PNL-EGFP-U6-Ang2-siRNA lentiviral transfer plasmid , vesicular stomatitis virus G-protein envelope plasmid and pHelper packaging plasmid were cotransfected into 293T cells , resulting in lentivirus. The virus supernatant were collected and the viral titer was determined.Results The lentiviral transfer plasmids of pNL-EGFP-U6-Ang2 -siRNA were constructed successfully and identified by using enzyme digestion electrophoresis of Xba Ⅰ and sequencing analysis,proved the correctness of the inserted Ang2-siRNA nudeotide sequence. EGFP-Ang2-siRNA virus were produced hy using the three plasmid lentiviral packaging system. The virus supernatant was collected and viral titers measured for the 9 ×103/μL. Conclusion The RNAi lentiviral expression vectors for Ang2 gene were constructed successfully ,and would be useful for the further research of the next research of interfering the Ang2 expression in malignant melanoma in vivo and vitro.%目的 构建促血管生成素(Ang)2基因的RNAi慢病毒表达载体,并鉴定其正确性.方法 将经XbaⅠ酶切电泳鉴定的pSilencer 1.0-U6-Ang2-siRNA重组质粒与经XbaⅠ酶切电泳鉴定的嗜中性多形核白细胞-绿色荧光蛋白转移质粒(pNL-EGFP)载体连接,产生pNL-EGFP-U6-Ang2-siRNA慢病毒转移质粒,再以pNL-EGFP-U6-Ang2-siRNA慢病毒转移质粒、水疱性口炎病毒G蛋白包膜质粒和包装质粒三质粒共转染293T细胞产生慢病毒,收集病毒上清液并测定病毒滴度.结果 成功构建pNL-EGFP-U6-Ang2-siRNA慢病毒转移质粒2条,通

  19. Angiotensin II directly stimulates macula densa Na-2Cl-K cotransport via apical AT(1) receptors.

    Science.gov (United States)

    Kovács, Gergely; Peti-Peterdi, János; Rosivall, László; Bell, P Darwin

    2002-02-01

    ANG II is a modulator of tubuloglomerular feedback (TGF); however, the site of its action remains unknown. Macula densa (MD) cells sense changes in luminal NaCl concentration ([NaCl](L)) via a Na-2Cl-K cotransporter, and these cells do possess ANG II receptors. We tested whether ANG II regulates Na-2Cl-K cotransport in MD cells. MD cell Na(+) concentration ([Na(+)](i)) was measured using sodium-binding benzofuran isophthalate with fluorescence microscopy. Resting [Na(+)](i) in MD cells was 27.7 +/- 1.05 mM (n = 138) and increased (Delta[Na(+)](i)) by 18.5 +/- 1.14 mM (n = 17) at an initial rate (Delta[Na(+)](i)/Deltat) of 5.54 +/- 0.53 x 10(-4) U/s with an increase in [NaCl](L) from 25 to 150 mM. Both Delta[Na(+)](i) and Delta[Na(+)](i)/Deltat were inhibited by 80% with 100 microM luminal furosemide. ANG II (10(-9) or 10(-12) M) added to the lumen increased MD resting [Na(+)](i) and [NaCl](L)-dependent Delta[Na(+)](i) and caused a twofold increase in Delta[Na(+)](i)/Deltat. Bath (10(-9) M) ANG II also stimulated cotransport activity, and there was no additive effect of simultaneous addition of ANG II to bath and lumen. The effects of luminal ANG II were furosemide sensitive and abolished by the AT(1) receptor blocker candesartan. ANG II at 10(-6) M failed to stimulate the cotransporter, whereas increased cotransport activity could be restored by blocking AT(2) receptors with PD-123, 319. Thus ANG II may modulate TGF responses via alterations in MD Na-2Cl-K cotransport activity.

  20. Guanylyl cyclase/natriuretic peptide receptor-A gene disruption causes increased adrenal angiotensin II and aldosterone levels.

    Science.gov (United States)

    Zhao, Di; Vellaichamy, Elangovan; Somanna, Naveen K; Pandey, Kailash N

    2007-07-01

    Disruption of the guanylyl cyclase-A/natriuretic peptide receptor-A (GC-A/NPRA) gene leads to elevated arterial blood pressure and congestive heart failure in mice lacking NPRA. This study was aimed at determining whether Npr1 (coding for GC-A/NPRA) gene copy number affects adrenal ANG II and aldosterone (Aldo) levels in a gene-dose-dependent manner in Npr1 gene-targeted mice. Adrenal ANG II and Aldo levels increased in 1-copy mice compared with 2-copy mice, but decreased in 3-copy and 4-copy mice. In contrast, renal ANG II levels decreased in 1-copy (25%), 3-copy (38%), and 4-copy (39%) mice compared with 2-copy mice. The low-salt diet stimulated adrenal ANG II and Aldo levels in 1-copy (20 and 2,441%), 2-copy (15 and 2,339%), 3-copy (20 and 424%), and 4-copy (31 and 486%) mice, respectively. The high-salt diet suppressed adrenal ANG II and Aldo levels in 1-copy (46 and 29%) and 2-copy (38 and 17%) mice. On the other hand, the low-salt diet stimulated renal ANG II levels in 1-copy (45%), 2-copy (45%), 3-copy (59%), and 4-copy (48%) mice. However, the high-salt diet suppressed renal ANG II levels in 1-copy (28%) and 2-copy (27%) mice. In conclusion, NPRA signaling antagonizes adrenal ANG II and Aldo levels in a gene-dose dependent manner. Increased adrenal ANG II and Aldo levels may play an important role in elevated arterial blood pressure and progressive hypertension, leading to renal and vascular injury in Npr1 gene-disrupted mice.

  1. Angiotensin II increases CTGF expression via MAPKs/TGF-{beta}1/TRAF6 pathway in atrial fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Gu, Jun [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of medicine, Shanghai (China); Liu, Xu, E-mail: xkliuxu@yahoo.cn [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of medicine, Shanghai (China); Wang, Quan-xing, E-mail: shmywqx@126.com [National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai (China); Tan, Hong-wei [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of medicine, Shanghai (China); Guo, Meng [National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai (China); Jiang, Wei-feng; Zhou, Li [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of medicine, Shanghai (China)

    2012-10-01

    The activation of transforming growth factor-{beta}1(TGF-{beta}1)/Smad signaling pathway and increased expression of connective tissue growth factor (CTGF) induced by angiotensin II (AngII) have been proposed as a mechanism for atrial fibrosis. However, whether TGF{beta}1/non-Smad signaling pathways involved in AngII-induced fibrogenetic factor expression remained unknown. Recently tumor necrosis factor receptor associated factor 6 (TRAF6)/TGF{beta}-associated kinase 1 (TAK1) has been shown to be crucial for the activation of TGF-{beta}1/non-Smad signaling pathways. In the present study, we explored the role of TGF-{beta}1/TRAF6 pathway in AngII-induced CTGF expression in cultured adult atrial fibroblasts. AngII (1 {mu}M) provoked the activation of P38 mitogen activated protein kinase (P38 MAPK), extracellular signal-regulated kinase 1/2(ERK1/2) and c-Jun NH(2)-terminal kinase (JNK). AngII (1 {mu}M) also promoted TGF{beta}1, TRAF6, CTGF expression and TAK1 phosphorylation, which were suppressed by angiotensin type I receptor antagonist (Losartan) as well as p38 MAPK inhibitor (SB202190), ERK1/2 inhibitor (PD98059) and JNK inhibitor (SP600125). Meanwhile, both TGF{beta}1 antibody and TRAF6 siRNA decreased the stimulatory effect of AngII on TRAF6, CTGF expression and TAK1 phosphorylation, which also attenuated AngII-induced atrial fibroblasts proliferation. In summary, the MAPKs/TGF{beta}1/TRAF6 pathway is an important signaling pathway in AngII-induced CTGF expression, and inhibition of TRAF6 may therefore represent a new target for reversing Ang II-induced atrial fibrosis. -- Highlights: Black-Right-Pointing-Pointer MAPKs/TGF{beta}1/TRAF6 participates in AngII-induced CTGF expression in atrial fibroblasts. Black-Right-Pointing-Pointer TGF{beta}1/TRAF6 participates in AngII-induced atrial fibroblasts proliferation. Black-Right-Pointing-Pointer TRAF6 may represent a new target for reversing Ang II-induced atrial fibrosis.

  2. High sodium augments angiotensin II-induced vascular smooth muscle cell proliferation through the ERK 1/2-dependent pathway.

    Science.gov (United States)

    Liu, Gang; Hitomi, Hirofumi; Rahman, Asadur; Nakano, Daisuke; Mori, Hirohito; Masaki, Tsutomu; Ma, Hong; Iwamoto, Takahiro; Kobori, Hiroyuki; Nishiyama, Akira

    2014-01-01

    Angiotensin II (Ang II)-induced vascular injury is exacerbated by high-salt diets. This study examined the effects of high-sodium level on Ang II-induced cell proliferation in rat vascular smooth muscle cells (VSMCs). The cells were cultured in a standard medium containing 137.5 mmol l(-1) of sodium. The high-sodium medium (140 mmol l(-1)) contained additional sodium chloride. Extracellular signal-regulated kinase (ERK) 1/2 phosphorylation was determined by western blot analysis. Cell proliferation was evaluated by [(3)H]-thymidine incorporation. Ang II (100 nmol l(-1)) significantly increased ERK 1/2 phosphorylation and cell proliferation in the both medium containing standard sodium and high sodium. High-sodium level augmented Ang II-induced ERK 1/2 phosphorylation and cell proliferation compared with standard sodium. Pre-treatment with candesartan (1 μmol l(-1), Ang II type 1 receptor blocker) or PD98095 (10 μmol l(-1), ERK kinase iinhibitor) abolished the proliferative effect induced by high sodium/Ang II. Pre-treatment with 5-N,N-hexamethylene amiloride (30 μmol l(-1), Na(+)/H(+) exchanger type 1 (NHE-1) inhibitor), but not SN-6 (10 μmol l(-1), Na(+)/Ca(2+) exchanger inhibitor) or ouabain (1 mmol l(-1), Na(+)/K(+)-ATPase inhibitor) attenuated ERK 1/2 phosphorylation or cell proliferation. Osmotic pressure or chloride had no effect on Ang II-induced proliferative changes. High-sodium level did not affect Ang II receptor expression. Ang II increased intracellular pH via NHE-1 activation, and high-sodium level augmented the pH increase induced by Ang II. These data suggest that high-sodium level directly augments Ang II-induced VSMC proliferation through NHE-1- and ERK 1/2-dependent pathways and may offer new insights into the mechanisms of vascular remodeling by high-sodium/Ang II.

  3. The role of mAKAPβ in the process of cardiomyocyte hypertrophy induced by angiotensin II.

    Science.gov (United States)

    Guo, Huixin; Liu, Baoxin; Hou, Lei; The, Erlinda; Li, Gang; Wang, Dongzhi; Jie, Qiqiang; Che, Wenliang; Wei, Yidong

    2015-05-01

    Angiotensin II (AngII) is the central product of the renin-angiotensin system (RAS) and this octapeptide contributes to the pathophysiology of cardiac hypertrophy and remodeling. mAKAPβ is an A-kinase anchoring protein (AKAP) that has the function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. In this study, we aimed to investigate the role of mAKAPβ in AngII‑induced cardiomyocyte hypertrophy and the possible mechanisms involved. Cultured cardiomyocytes from neonatal rats were treated with AngII. Subsequently, the morphology of the cardiomyocytes was observed and the expression of mAKAPβ and cardiomyocyte hypertrophic markers was measured. mAKAPβ‑shRNA was constructed for RNA interference; the expression of mAKAPβ and hypertrophic markers, the cell surface area and the [3H]Leucine incorporation rate in the AngII‑treated rat cardiomyocytes were detected following RNA interference. Simultaneously, changes in the expression levels of phosphorylated extracellular signal-regulated kinase (p-ERK)2 in the cardiomyocytes were assessed. The cell size of the AngII-treated cardiaomyocytes was significantly larger than that of the untreated cardiomyocytes. The expression of hypertrophic markers and p-ERK2, the cell surface area and the [3H]Leucine incorporation rate were all significantly increased in the AngII‑treated cells. However, the expression of mAKAPβ remained unaltered in this process. RNA interference simultaneously inhibited the protein expression of mAKAPβ and p‑ERK2, and the hypertrophy of the cardiomyocytes induced by AngII was attenuated. These results demonstrate that AngII induces hypertrophy in cardiomyocytes, and mAKAPβ is possibly involved in this process. The effects of mAKAPβ on AngII‑induced cardiomyocyte hypertrophy may be associated with p-ERK2 expression.

  4. Localization of the angiotensin II and its receptor subtype expression in human endometrium and identification of a novel high-affinity angiotensin II binding site.

    OpenAIRE

    Ahmed, A.; Li, X F; M Shams; Gregory, J; Rollason, T.; Barnes, N. M.; Newton, J. R.

    1995-01-01

    Angiotensin (ANG) II is not only a potent vasoconstrictor but may also be involved in the regeneration of new blood vessels. In proliferative endometrium, ANG II-like immunoreactivity was detected in glandular epithelium and stroma with negligible staining around the vascular endothelium. In contrast, in secretory endometrium intense immunostaining was seen in the perivascular stromal cells around the endometrial spiral arterioles with negligible staining of the other cell types. Quantitative...

  5. Carbohydrate-Binding Non-Peptidic Pradimicins for the Treatment of Acute Sleeping Sickness in Murine Models

    Science.gov (United States)

    Castillo-Acosta, Víctor M.; Ruiz-Pérez, Luis M.; Reichardt, Niels C.; Igarashi, Yasuhiro; Liekens, Sandra; Balzarini, Jan

    2016-01-01

    Current treatments available for African sleeping sickness or human African trypanosomiasis (HAT) are limited, with poor efficacy and unacceptable safety profiles. Here, we report a new approach to address treatment of this disease based on the use of compounds that bind to parasite surface glycans leading to rapid killing of trypanosomes. Pradimicin and its derivatives are non-peptidic carbohydrate-binding agents that adhere to the carbohydrate moiety of the parasite surface glycoproteins inducing parasite lysis in vitro. Notably, pradimicin S has good pharmaceutical properties and enables cure of an acute form of the disease in mice. By inducing resistance in vitro we have established that the composition of the sugars attached to the variant surface glycoproteins are critical to the mode of action of pradimicins and play an important role in infectivity. The compounds identified represent a novel approach to develop drugs to treat HAT. PMID:27662652

  6. Human rhinovirus 3C protease: generation of pharmacophore models for peptidic and nonpeptidic inhibitors and their application in virtual screening.

    Science.gov (United States)

    Steindl, Theodora; Laggner, Christian; Langer, Thierry

    2005-01-01

    Three-dimensional pharmacophore models for peptidic and small organic nonpeptidic inhibitors of the human rhinovirus 3C protease were generated in a structure-based as well as in a ligand-based approach, using the software package Catalyst. The inhibitors possess an electrophilic moiety, often a Michael acceptor function, which covalently binds to a cysteine in the active site of the enzyme. Since this process presents the key step for virus inactivation, the creation of a new function in Catalyst was required in order to include this decisive functionality into the pharmacophore models. In the present study we focus on this feature definition process because it presents an innovative strategy to expand the pharmacophore description ability of the Catalyst software to also include covalent bonds between ligand and binding site. The resulting hypotheses were then used for virtual screening of 3D databases in order to verify their quality and to search for structurally diverse, possible new lead substances.

  7. Nitrosonifedipine ameliorates angiotensin II-induced vascular remodeling via antioxidative effects.

    Science.gov (United States)

    Sakurada, Takumi; Ishizawa, Keisuke; Imanishi, Masaki; Izawa-Ishizawa, Yuki; Fujii, Shoko; Tominaga, Erika; Tsuneishi, Teppei; Horinouchi, Yuya; Kihira, Yoshitaka; Ikeda, Yasumasa; Tomita, Shuhei; Aihara, Ken-ichi; Minakuchi, Kazuo; Tsuchiya, Koichiro; Tamaki, Toshiaki

    2013-01-01

    Nifedipine is unstable under light and decomposes to a stable nitroso analog, nitrosonifedipine (NO-NIF). The ability of NO-NIF to block calcium channels is quite weak compared with that of nifedipine. Recently, we have demonstrated that NO-NIF reacts with unsaturated fatty acid leading to generate NO-NIF radical, which acquires radical scavenging activity. However, the effects of NO-NIF on the pathogenesis related with oxidative stress, such as atherosclerosis and hypertension, are unclear. In this study, we investigated the effects of NO-NIF on angiotensin II (Ang II)-induced vascular remodeling. Ang II-induced thickening and fibrosis of aorta were inhibited by NO-NIF in mice. NO-NIF decreased reactive oxygen species (ROS) in the aorta and urinary 8-hydroxy-20-deoxyguanosine. Ang II-stimulated mRNA expressions of p22(phox), CD68, F4/80, monocyte chemoattractant protein-1, and collagen I in the aorta were inhibited by NO-NIF. Moreover, NO-NIF inhibited Ang II-induced cell migration and proliferation of vascular smooth muscle cells (VSMCs). NO-NIF reduced Ang II-induced ROS to the control level detected by dihydroethidium staining and lucigenin chemiluminescence assay in VSMCs. NO-NIF suppressed phosphorylations of Akt and epidermal growth factor receptor induced by Ang II. However, NO-NIF had no effects on intracellular Ca(2+) increase and protein kinase C-δ phosphorylation induced by Ang II in VSMCs. The electron paramagnetic resonance spectra indicated the continuous generation of NO-NIF radical of reaction with cultured VSMCs. These findings suggest that NO-NIF improves Ang II-induced vascular remodeling via the attenuation of oxidative stress.

  8. Vasopressin and angiotensin II in reflex regulation of ACTH, glucocorticoids, and renin: effect of water deprivation

    Science.gov (United States)

    Brooks, V. L.; Keil, L. C.

    1992-01-01

    Angiotensin II (ANG II) and vasopressin participate in baroreflex regulation of adrenocorticotropic hormone (ACTH), glucocorticoid, and renin secretion. The purpose of this study was to determine whether this participation is enhanced in water-deprived dogs, with chronically elevated plasma ANG II and vasopressin levels, compared with water-replete dogs. The baroreflex was assessed by infusing increasing doses of nitroprusside (0.3, 0.6, 1.5, and 3.0 micrograms.kg-1.min-1) in both groups of animals. To quantitate the participation of ANG II and vasopressin, the dogs were untreated or pretreated with the competitive ANG II antagonist saralasin, a V1-vasopressin antagonist, or combined V1/V2-vasopressin antagonist, either alone or in combination. The findings were as follows. 1) Larger reflex increases in ANG II, vasopressin, and glucocorticoids, but not ACTH, were produced in water-deprived dogs compared with water-replete dogs. 2) ANG II blockade blunted the glucocorticoid and ACTH responses to hypotension in water-deprived dogs, but not water-replete dogs. In contrast, vasopressin blockade reduced the ACTH response only in water-replete dogs. 3) Vasopressin or combined vasopressin and ANG II blockade reduced the plasma level of glucocorticoids related either to the fall in arterial pressure or to the increase in plasma ACTH concentration in water-replete dogs, and this effect was enhanced in water-deprived dogs. 4) In both water-deprived and water-replete animals, saralasin and/or a V1-antagonist increased the renin response to hypotension, but a combined V1/V2-antagonist did not. These results reemphasize the importance of endogenous ANG II and vasopressin in the regulation of ACTH, glucocorticoid, and renin secretion.(ABSTRACT TRUNCATED AT 250 WORDS).

  9. Roscovitine inhibits ERK1/2 activation induced by angiotensin II in vascular smooth muscle cells.

    Science.gov (United States)

    Li, Ai-Ying; Han, Mei; Zheng, Bin; Wen, Jin-Kun

    2008-01-23

    Roscovitine is a potent CDK inhibitor often used as a biological tool in cell-cycle studies, but its working mechanism and real targets in vascular smooth muscle cells (VSMCs) remain unclear. In this study, we observed that ERK1/2 phosphorylation induced by Ang II was abrogated by pretreating VSMCs with roscovitine for 15h. Pretreating VSMCs with roscovitine also inhibited Ang II-induced c-Jun expression and phosphorylation. We further demonstrated that roscovitine could suppress the DNA binding activity of c-Jun and activation of angiotensinogen promoter by Ang II. These results suggest that roscovitine represses Ang II-induced angiotensinogen expression by inhibiting activation of ERK1/2 and c-Jun.

  10. Transcriptional network analysis reveals that AT1 and AT2 angiotensin II receptors are both involved in the regulation of genes essential for glioma progression.

    Science.gov (United States)

    Azevedo, Hátylas; Fujita, André; Bando, Silvia Yumi; Iamashita, Priscila; Moreira-Filho, Carlos Alberto

    2014-01-01

    Gliomas are aggressive primary brain tumors with high infiltrative potential. The expression of Angiotensin II (Ang II) receptors has been associated with poor prognosis in human astrocytomas, the most common type of glioma. In this study, we investigated the role of Angiotensin II in glioma malignancy through transcriptional profiling and network analysis of cultured C6 rat glioma cells exposed to Ang II and to inhibitors of its membrane receptor subtypes. C6 cells were treated with Ang II and specific antagonists of AT1 and AT2 receptors. Total RNA was isolated after three and six hours of Ang II treatment and analyzed by oligonucleotide microarray technology. Gene expression data was evaluated through transcriptional network modeling to identify how differentially expressed (DE) genes are connected to each other. Moreover, other genes co-expressing with the DE genes were considered in these analyses in order to support the identification of enriched functions and pathways. A hub-based network analysis showed that the most connected nodes in Ang II-related networks exert functions associated with cell proliferation, migration and invasion, key aspects for glioma progression. The subsequent functional enrichment analysis of these central genes highlighted their participation in signaling pathways that are frequently deregulated in gliomas such as ErbB, MAPK and p53. Noteworthy, either AT1 or AT2 inhibitions were able to down-regulate different sets of hub genes involved in protumoral functions, suggesting that both Ang II receptors could be therapeutic targets for intervention in glioma. Taken together, our results point out multiple actions of Ang II in glioma pathogenesis and reveal the participation of both Ang II receptors in the regulation of genes relevant for glioma progression. This study is the first one to provide systems-level molecular data for better understanding the protumoral effects of Ang II in the proliferative and infiltrative behavior of

  11. Transcriptional network analysis reveals that AT1 and AT2 angiotensin II receptors are both involved in the regulation of genes essential for glioma progression.

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    Hátylas Azevedo

    Full Text Available Gliomas are aggressive primary brain tumors with high infiltrative potential. The expression of Angiotensin II (Ang II receptors has been associated with poor prognosis in human astrocytomas, the most common type of glioma. In this study, we investigated the role of Angiotensin II in glioma malignancy through transcriptional profiling and network analysis of cultured C6 rat glioma cells exposed to Ang II and to inhibitors of its membrane receptor subtypes. C6 cells were treated with Ang II and specific antagonists of AT1 and AT2 receptors. Total RNA was isolated after three and six hours of Ang II treatment and analyzed by oligonucleotide microarray technology. Gene expression data was evaluated through transcriptional network modeling to identify how differentially expressed (DE genes are connected to each other. Moreover, other genes co-expressing with the DE genes were considered in these analyses in order to support the identification of enriched functions and pathways. A hub-based network analysis showed that the most connected nodes in Ang II-related networks exert functions associated with cell proliferation, migration and invasion, key aspects for glioma progression. The subsequent functional enrichment analysis of these central genes highlighted their participation in signaling pathways that are frequently deregulated in gliomas such as ErbB, MAPK and p53. Noteworthy, either AT1 or AT2 inhibitions were able to down-regulate different sets of hub genes involved in protumoral functions, suggesting that both Ang II receptors could be therapeutic targets for intervention in glioma. Taken together, our results point out multiple actions of Ang II in glioma pathogenesis and reveal the participation of both Ang II receptors in the regulation of genes relevant for glioma progression. This study is the first one to provide systems-level molecular data for better understanding the protumoral effects of Ang II in the proliferative and infiltrative

  12. Mitochondrial aldehyde dehydrogenase prevents ROS-induced vascular contraction in angiotensin-II hypertensive mice.

    Science.gov (United States)

    Choi, Hyehun; Tostes, Rita C; Webb, R Clinton

    2011-01-01

    Mitochondrial aldehyde dehydrogenase (ALDH2) is an enzyme that detoxifies aldehydes to carboxylic acids. ALDH2 deficiency is known to increase oxidative stress, which is the imbalance between reactive oxygen species (ROS) generation and antioxidant defense activity. Increased ROS contribute to vascular dysfunction and structural remodeling in hypertension. We hypothesized that ALDH2 plays a protective role to reduce vascular contraction in angiotensin-II (AngII) hypertensive mice. Endothelium-denuded aortic rings from C57BL6 mice, treated with AngII (3.6 μg/kg/min, 14 days), were used to measure isometric force development. Rings treated with daidzin (10 μmol/L), an ALDH2 inhibitor, potentiated contractile responses to phenylephrine (PE) in AngII mice. Tempol (1 mmol/L) and catalase (600 U/mL) attenuated the augmented contractile effect of daidzin. In normotensive mice, contraction to PE in the presence of the daidzin was not different from control, untreated values. AngII aortic rings transfected with ALDH2 recombinant protein decreased contractile responses to PE compared with control. These data suggest that ALDH2 reduces vascular contraction in AngII hypertensive mice. Because tempol and catalase blocked the contractile response of the ALDH2 inhibitor, ROS generation by AngII may be decreased by ALDH2, thereby preventing ROS-induced contraction.

  13. Salvianolic Acid B Attenuates Rat Hepatic Fibrosis via Downregulating Angiotensin II Signaling

    Science.gov (United States)

    Li, Shu; Wang, Lina; Yan, Xiuchuan; Wang, Qinglan; Tao, Yanyan; Li, Junxia; Peng, Yuan; Liu, Ping; Liu, Chenghai

    2012-01-01

    The renin-angiotensin system (RAS) plays an important role in hepatic fibrosis. Salvianolic acid B (Sal B), one of the water-soluble components from Radix Salviae miltiorrhizae, has been used to treat hepatic fibrosis, but it is still not clear whether the effect of Sal B is related to angiotensin II (Ang II) signaling pathway. In the present study, we studied Sal B effect on rat liver fibrosis and Ang-II related signaling mediators in dimethylnitrosamine-(DMN-) induced rat fibrotic model in vivo and Ang-II stimulated hepatic stellate cells (HSCs) in vitro, with perindopril or losartan as control drug, respectively. The results showed that Sal B and perindopril inhibited rat hepatic fibrosis and reduced expression of Ang II receptor type 1 (AT1R) and ERK activation in fibrotic liver. Sal B and losartan also inhibited Ang II-stimulated HSC activation including cell proliferation and expression of type I collagen I (Col-I) and α-smooth muscle actin (α-SMA) production in vitro, reduced the gene expression of transforming growth factor beta (TGF-β), and downregulated AT1R expression and ERK and c-Jun phosphorylation. In conclusion, our results indicate that Sal B may exert an antihepatic fibrosis effect via downregulating Ang II signaling in HSC activation. PMID:23243430

  14. Salvianolic Acid B Attenuates Rat Hepatic Fibrosis via Downregulating Angiotensin II Signaling

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    Shu Li

    2012-01-01

    Full Text Available The renin-angiotensin system (RAS plays an important role in hepatic fibrosis. Salvianolic acid B (Sal B, one of the water-soluble components from Radix Salviae miltiorrhizae, has been used to treat hepatic fibrosis, but it is still not clear whether the effect of Sal B is related to angiotensin II (Ang II signaling pathway. In the present study, we studied Sal B effect on rat liver fibrosis and Ang-II related signaling mediators in dimethylnitrosamine-(DMN- induced rat fibrotic model in vivo and Ang-II stimulated hepatic stellate cells (HSCs in vitro, with perindopril or losartan as control drug, respectively. The results showed that Sal B and perindopril inhibited rat hepatic fibrosis and reduced expression of Ang II receptor type 1 (AT1R and ERK activation in fibrotic liver. Sal B and losartan also inhibited Ang II-stimulated HSC activation including cell proliferation and expression of type I collagen I (Col-I and α-smooth muscle actin (α-SMA production in vitro, reduced the gene expression of transforming growth factor beta (TGF-β, and downregulated AT1R expression and ERK and c-Jun phosphorylation. In conclusion, our results indicate that Sal B may exert an antihepatic fibrosis effect via downregulating Ang II signaling in HSC activation.

  15. Sex differences in T-lymphocyte tissue infiltration and development of angiotensin II hypertension.

    Science.gov (United States)

    Pollow, Dennis P; Uhrlaub, Jennifer; Romero-Aleshire, Melissa J; Sandberg, Kathryn; Nikolich-Zugich, Janko; Brooks, Heddwen L; Hay, Meredith

    2014-08-01

    There is extensive evidence that activation of the immune system is both necessary and required for the development of angiotensin II (Ang II)-induced hypertension in males. The purpose of this study was to determine whether sex differences exist in the ability of the adaptive immune system to induce Ang II-dependent hypertension and whether central and renal T-cell infiltration during Ang II-induced hypertension is sex dependent. Recombinant activating gene-1 (Rag-1)(-/-) mice, lacking both T and B cells, were used. Male and female Rag-1(-/-) mice received adoptive transfer of male CD3(+) T cells 3 weeks before 14-day Ang II infusion (490 ng/kg per minute). Blood pressure was monitored via tail cuff. In the absence of T cells, systolic blood pressure responses to Ang II were similar between sexes (Δ22.1 mm Hg males versus Δ18 mm : Hg females). After adoptive transfer of male T cells, Ang II significantly increased systolic blood pressure in males (Δ37.7 mm : Hg; Phypertension when compared with their male counterparts, and this protection may involve sex differences in the magnitude of T-cell infiltration of the kidney and brain.

  16. 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.

  17. Sex differences in the development of angiotensin II-induced hypertension in conscious mice.

    Science.gov (United States)

    Xue, Baojian; Pamidimukkala, Jaya; Hay, Meredith

    2005-05-01

    Sex has an important influence on blood pressure (BP) regulation. There is increasing evidence that sex hormones interfere with the renin-angiotensin system. Thus the purpose of this study was to determine whether there are sex differences in the development of ANG II-induced hypertension in conscious male and female mice. We used telemetry implants to measure aortic BP and heart rate (HR) in conscious, freely moving animals. ANG II (800 ng.kg(-1).min(-1)) was delivered via an osmotic pump implanted subcutaneously. Our results showed baseline BP in male and female mice to be similar. Chronic systemic infusion of ANG II induced a greater increase in BP in male (35.1 +/- 5.7 mmHg) than in female mice (7.2 +/- 2.0 mmHg). Gonadectomy attenuated ANG II-induced hypertension in male mice (15.2 +/- 2.4 mmHg) and augmented it in female mice (23.1 +/- 1.0 mmHg). Baseline HR was significantly higher in females relative to males (630.1 +/- 7.9 vs. 544.8 +/- 16.2 beats/min). In females, ANG II infusion significantly decreased HR. However, the increase in BP with ANG II did not result in the expected decrease in HR in either intact male or gonadectomized mice. Moreover, the slope of the baroreflex bradycardia to phenylephrine was blunted in males (-5.6 +/- 0.3 to -2.9 +/- 0.5) but not in females (-6.5 +/- 0.5 to -5.6 +/- 0.3) during infusion of ANG II, suggesting that, in male mice, infusion of ANG II results in a resetting of the baroreflex control of HR. Ganglionic blockade resulted in greater reduction in BP on day 7 after ANG II infusion in males compared with females (-61.0 +/- 8.9 vs. -36.6 +/- 6.6 mmHg), suggesting an increased contribution of sympathetic nerve activity in arterial BP maintenance in male mice. Together, these data indicate that there are sex differences in the development of chronic ANG II-induced hypertension in conscious mice and that females may be protected from the increases in BP induced by ANG II.

  18. The first winter solstice observed at the meridian line of Santa Maria degli Angeli in Rome

    CERN Document Server

    Sigismondi, Costantino

    2014-01-01

    The page written by the astronomer Francesco Bianchini (1662-1729) and containing the data of the 1701 winter solstice observed at Santa Maria degli Angeli is presented for the first time in figure 2 and widely discussed along this paper. The great meridian line in the Basilica of Santa Maria degli Angeli in Rome was built in 1701/1702 with the scope to measure the Obliquity of the Earth's orbit in the following eight centuries, upon the will of pope Clement XI. During the winter solstice of 1701 the first measurements of the obliquity have been realized by Francesco Bianchini, the astronomer who designed the meridian line, upgrading the similar instrument realized by Giandomenico Cassini in San Petronio, Bononia. In this paper the accuracy of the data observed by Francesco Bianchini is discussed and compared with up-to-date ephemerides. The modern situation of this historical instrument is also presented.

  19. Oposição e conflito na metapsicologia da angústia

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    Paulo de Carvalho Ribeiro

    Full Text Available Partindo da existência de diferentes graus e efeitos da angústia, busca-se estabelecer uma associação da angústia psicótica com a prevalência de uma oposição não conflitiva entre as forças pulsionais disruptivas e os elementos de ligação, transformados em exigências de um supereu tirânico e aberrante. Algumas idéias de Jean Laplanche sobre a exclusividade das forças de desligamento no inconsciente são criticadas, levando, assim, à discussão sobre o recalcamento, bem como a questões relacionadas com a presença do conflito nas neuroses e sua ausência nas psicoses.

  20. Vinte Poemas de Amor - Uma leitura da angústia na perspectiva freudiana

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    Vanessa Aparecida Alves Lima

    2015-07-01

    Full Text Available Este é o momento do encontro de uma parte da teoria freudiana com a obra do grande poeta latino americano Pablo Neruda. Trata-se de uma livre associação ao lançar um olhar sobre a teoria freudiana da angústia para vê-la caracterizada no poema “Vinte Poemas de Amor e Uma Canção Desesperada” de Pablo Neruda.

  1. Contribution of renal purinergic receptors to renal vasoconstriction in angiotensin II-induced hypertensive rats.

    Science.gov (United States)

    Franco, Martha; Bautista, Rocio; Tapia, Edilia; Soto, Virgilia; Santamaría, José; Osorio, Horacio; Pacheco, Ursino; Sánchez-Lozada, L Gabriela; Kobori, Hiroyuki; Navar, L Gabriel

    2011-06-01

    To investigate the participation of purinergic P2 receptors in the regulation of renal function in ANG II-dependent hypertension, renal and glomerular hemodynamics were evaluated in chronic ANG II-infused (14 days) and Sham rats during acute blockade of P2 receptors with PPADS. In addition, P2X1 and P2Y1 protein and mRNA expression were compared in ANG II-infused and Sham rats. Chronic ANG II-infused rats exhibited increased afferent and efferent arteriolar resistances and reductions in glomerular blood flow, glomerular filtration rate (GFR), single-nephron GFR (SNGFR), and glomerular ultrafiltration coefficient. PPADS restored afferent and efferent resistances as well as glomerular blood flow and SNGFR, but did not ameliorate the elevated arterial blood pressure. In Sham rats, PPADS increased afferent and efferent arteriolar resistances and reduced GFR and SNGFR. Since purinergic blockade may influence nitric oxide (NO) release, we evaluated the role of NO in the response to PPADS. Acute blockade with N(ω)-nitro-l-arginine methyl ester (l-NAME) reversed the vasodilatory effects of PPADS and reduced urinary nitrate excretion (NO(2)(-)/NO(3)(-)) in ANG II-infused rats, indicating a NO-mediated vasodilation during PPADS treatment. In Sham rats, PPADS induced renal vasoconstriction which was not modified by l-NAME, suggesting blockade of a P2X receptor subtype linked to the NO pathway; the response was similar to that obtained with l-NAME alone. P2X1 receptor expression in the renal cortex was increased by chronic ANG II infusion, but there were no changes in P2Y1 receptor abundance. These findings indicate that there is an enhanced P2 receptor-mediated vasoconstriction of afferent and efferent arterioles in chronic ANG II-infused rats, which contributes to the increased renal vascular resistance observed in ANG II-dependent hypertension.

  2. Angiotensin II Induced Cardiac Dysfunction on a Chip.

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    Renita E Horton

    Full Text Available In vitro disease models offer the ability to study specific systemic features in isolation to better understand underlying mechanisms that lead to dysfunction. Here, we present a cardiac dysfunction model using angiotensin II (ANG II to elicit pathological responses in a heart-on-a-chip platform that recapitulates native laminar cardiac tissue structure. Our platform, composed of arrays of muscular thin films (MTF, allows for functional comparisons of healthy and diseased tissues by tracking film deflections resulting from contracting tissues. To test our model, we measured gene expression profiles, morphological remodeling, calcium transients, and contractile stress generation in response to ANG II exposure and compared against previous experimental and clinical results. We found that ANG II induced pathological gene expression profiles including over-expression of natriuretic peptide B, Rho GTPase 1, and T-type calcium channels. ANG II exposure also increased proarrhythmic early after depolarization events and significantly reduced peak systolic stresses. Although ANG II has been shown to induce structural remodeling, we control tissue architecture via microcontact printing, and show pathological genetic profiles and functional impairment precede significant morphological changes. We assert that our in vitro model is a useful tool for evaluating tissue health and can serve as a platform for studying disease mechanisms and identifying novel therapeutics.

  3. Angiotensin II Induced Cardiac Dysfunction on a Chip.

    Science.gov (United States)

    Horton, Renita E; Yadid, Moran; McCain, Megan L; Sheehy, Sean P; Pasqualini, Francesco S; Park, Sung-Jin; Cho, Alexander; Campbell, Patrick; Parker, Kevin Kit

    2016-01-01

    In vitro disease models offer the ability to study specific systemic features in isolation to better understand underlying mechanisms that lead to dysfunction. Here, we present a cardiac dysfunction model using angiotensin II (ANG II) to elicit pathological responses in a heart-on-a-chip platform that recapitulates native laminar cardiac tissue structure. Our platform, composed of arrays of muscular thin films (MTF), allows for functional comparisons of healthy and diseased tissues by tracking film deflections resulting from contracting tissues. To test our model, we measured gene expression profiles, morphological remodeling, calcium transients, and contractile stress generation in response to ANG II exposure and compared against previous experimental and clinical results. We found that ANG II induced pathological gene expression profiles including over-expression of natriuretic peptide B, Rho GTPase 1, and T-type calcium channels. ANG II exposure also increased proarrhythmic early after depolarization events and significantly reduced peak systolic stresses. Although ANG II has been shown to induce structural remodeling, we control tissue architecture via microcontact printing, and show pathological genetic profiles and functional impairment precede significant morphological changes. We assert that our in vitro model is a useful tool for evaluating tissue health and can serve as a platform for studying disease mechanisms and identifying novel therapeutics.

  4. Small Molecule AngIV-based Analogs to Treat Alzheimers Disease

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    John W Wright

    2016-06-01

    Full Text Available Alzheimer’s disease (AD patients are presently without adequate treatment thus new therapeutic approaches are needed to slow and hopefully reverse disease progression. Neurotrophic agents such as nerve growth factor and brain-derived neurotrophic factor have received research attention concerning their potential to treat AD but have not progressed to clinical trials due to their large size, inability to penetrate the blood-brain barrier (BBB, and the high cost of synthesis. This review focuses on one over looked neurotrophin, hepatocyte growth factor (HGF that acts via the Type 1 tyrosine kinase receptor Met to mediate stem cell differentiation, synaptogenesis, neurogenesis, and protect against tissue insults in a wide range of cell types including neurons. We have determined that the brain angiotensin and HGF/c-Met systems interact in such a way that angiotensin IV (AngIV-based analogs including Nle1-AngIV, Norleual-AngIV, Dihexa, and others influence HGF dimerization which is a prerequisite to binding at the Met receptor. Several of these analogs have shown the ability to facilitate the formation of new functional synaptic connections in hippocampal slices, promote neurogenesis, and augment memory consolidation and retrieval in animal models of AD. This family of compounds represents a new class of drugs with lead candidates that are orally active, penetrate the BBB sufficiently to reach therapeutic concentrations, and reverse memory deficits seen in animal models of dementia.

  5. Angiotensin II infusion induces marked diaphragmatic skeletal muscle atrophy.

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    Bashir M Rezk

    Full Text Available Advanced congestive heart failure (CHF and chronic kidney disease (CKD are characterized by increased angiotensin II (Ang II levels and are often accompanied by significant skeletal muscle wasting that negatively impacts mortality and morbidity. Both CHF and CKD patients have respiratory muscle dysfunction, however the potential effects of Ang II on respiratory muscles are unknown. We investigated the effects of Ang II on diaphragm muscle in FVB mice. Ang II induced significant diaphragm muscle wasting (18.7±1.6% decrease in weight at one week and reduction in fiber cross-sectional area. Expression of the E3 ubiquitin ligases atrogin-1 and muscle ring finger-1 (MuRF-1 and of the pro-apoptotic factor BAX was increased after 24 h of Ang II infusion (4.4±0.3 fold, 3.1±0.5 fold and 1.6±0.2 fold, respectively, compared to sham infused control suggesting increased muscle protein degradation and apoptosis. In Ang II infused animals, there was significant regeneration of injured diaphragm muscles at 7 days as indicated by an increase in the number of myofibers with centralized nuclei and high expression of embryonic myosin heavy chain (E-MyHC, 11.2±3.3 fold increase and of the satellite cell marker M-cadherin (59.2±22.2% increase. Furthermore, there was an increase in expression of insulin-like growth factor-1 (IGF-1, 1.8±0.3 fold increase in Ang II infused diaphragm, suggesting the involvement of IGF-1 in diaphragm muscle regeneration. Bone-marrow transplantation experiments indicated that although there was recruitment of bone-marrow derived cells to the injured diaphragm in Ang II infused mice (267.0±74.6% increase, those cells did not express markers of muscle stem cells or regenerating myofibers. In conclusion, Ang II causes marked diaphragm muscle wasting, which may be important for the pathophysiology of respiratory muscle dysfunction and cachexia in conditions such as CHF and CKD.

  6. Central interactions of aldosterone and angiotensin II in aldosterone- and angiotensin II-induced hypertension.

    Science.gov (United States)

    Xue, Baojian; Beltz, Terry G; Yu, Yang; Guo, Fang; Gomez-Sanchez, Celso E; Hay, Meredith; Johnson, Alan Kim

    2011-02-01

    Many studies have implicated both angiotensin II (ANG II) and aldosterone (Aldo) in the pathogenesis of hypertension, the progression of renal injury, and cardiac remodeling after myocardial infarction. In several cases, ANG II and Aldo have been shown to have synergistic interactions in the periphery. In the present studies, we tested the hypothesis that ANG II and Aldo interact centrally in Aldo- and ANG II-induced hypertension in male rats. In rats with blood pressure (BP) and heart rate (HR) measured by DSI telemetry, intracerebroventricular (icv) infusions of the mineralocorticoid receptor (MR) antagonists spironolactone and RU28318 or the angiotensin type 1 receptor (AT1R) antagonist irbesartan significantly inhibited Aldo-induced hypertension. In ANG II-induced hypertension, icv infusion of RU28318 significantly reduced the increase in BP. Moreover, icv infusions of the reactive oxygen species (ROS) scavenger tempol or the NADPH oxidase inhibitor apocynin attenuated Aldo-induced hypertension. To confirm these effects of pharmacological antagonists, icv injections of either recombinant adeno-associated virus carrying siRNA silencers of AT1aR (AT1aR-siRNA) or MR (MR-siRNA) significantly attenuated the development of Aldo-induced hypertension. The immunohistochemical and Western blot analyses of AT1aR-siRNA- or MR-siRNA-injected rats showed a marked reduction in the expression of AT1R or MR in the paraventricular nucleus compared with scrambled siRNA rats. When animals from all studies underwent ganglionic blockade with hexamethonium, there was a smaller reduction in the fall of BP in animals receiving icv AT1R or MR antagonists. These results suggest that ANG II and Aldo interact in the brain in a mutually cooperative manner such that the functional integrity of both brain AT1R and MR are necessary for hypertension to be induced by either systemic ANG II or Aldo. The pressor effects produced by systemic ANG II or Aldo involve increased central ROS and

  7. Exendin-4 Prevents Vascular Smooth Muscle Cell Proliferation and Migration by Angiotensin II via the Inhibition of ERK1/2 and JNK Signaling Pathways.

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    Kosuke Nagayama

    Full Text Available Angiotensin II (Ang II is a main pathophysiological culprit peptide for hypertension and atherosclerosis by causing vascular smooth muscle cell (VSMC proliferation and migration. Exendin-4, a glucagon-like peptide-1 (GLP-1 receptor agonist, is currently used for the treatment of type-2 diabetes, and is believed to have beneficial effects for cardiovascular diseases. However, the vascular protective mechanisms of GLP-1 receptor agonists remain largely unexplained. In the present study, we examined the effect of exendin-4 on Ang II-induced proliferation and migration of cultured rat aortic smooth muscle cells (RASMC. The major findings of the present study are as follows: (1 Ang II caused a phenotypic switch of RASMC from contractile type to synthetic proliferative type cells; (2 Ang II caused concentration-dependent RASMC proliferation, which was significantly inhibited by the pretreatment with exendin-4; (3 Ang II caused concentration-dependent RASMC migration, which was effectively inhibited by the pretreatment with exendin-4; (4 exendin-4 inhibited Ang II-induced phosphorylation of ERK1/2 and JNK in a pre-incubation time-dependent manner; and (5 U0126 (an ERK1/2 kinase inhibitor and SP600125 (a JNK inhibitor also inhibited both RASMC proliferation and migration induced by Ang II stimulation. These results suggest that exendin-4 prevented Ang II-induced VSMC proliferation and migration through the inhibition of ERK1/2 and JNK phosphorylation caused by Ang II stimulation. This indicates that GLP-1 receptor agonists should be considered for use in the treatment of cardiovascular diseases in addition to their current use in the treatment of diabetes mellitus.

  8. HMG-CoA reductase inhibitors decrease angiotensin II-induced vascular fibrosis: role of RhoA/ROCK and MAPK pathways.

    Science.gov (United States)

    Rupérez, Mónica; Rodrigues-Díez, Raquel; Blanco-Colio, Luis Miguel; Sánchez-López, Elsa; Rodríguez-Vita, Juan; Esteban, Vanesa; Carvajal, Gisselle; Plaza, Juan José; Egido, Jesús; Ruiz-Ortega, Marta

    2007-08-01

    3-Hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) present beneficial effects in cardiovascular diseases. Angiotensin II (Ang II) contributes to cardiovascular damage through the production of profibrotic factors, such as connective tissue growth factor (CTGF). Our aim was to investigate whether HMG-CoA reductase inhibitors could modulate Ang II responses, evaluating CTGF expression and the mechanisms underlying this process. In cultured vascular smooth muscle cells (VSMCs) atorvastatin and simvastatin inhibited Ang II-induced CTGF production. The inhibitory effect of statins on CTGF upregulation was reversed by mevalonate and geranylgeranylpyrophosphate, suggesting that RhoA inhibition could be involved in this process. In VSMCs, statins inhibited Ang II-induced Rho membrane localization and activation. In these cells Ang II regulated CTGF via RhoA/Rho kinase activation, as shown by inhibition of Rho with C3 exoenzyme, RhoA dominant-negative overexpression, and Rho kinase inhibition. Furthermore, activation of p38MAPK and JNK, and redox process were also involved in Ang II-mediated CTGF upregulation, and were downregulated by statins. In rats infused with Ang II (100 ng/kg per minute) for 2 weeks, treatment with atorvastatin (5 mg/kg per day) diminished aortic CTGF and Rho activation without blood pressure modification. Rho kinase inhibition decreased CTGF upregulation in rat aorta, mimicking statin effect. CTGF is a vascular fibrosis mediator. Statins diminished extracellular matrix (ECM) overexpression caused by Ang II in vivo and in vitro. In summary, HMG-CoA reductase inhibitors inhibit several intracellular signaling systems activated by Ang II (RhoA/Rho kinase and MAPK pathways and redox process) involved in the regulation of CTGF. Our results may explain, at least in part, some beneficial effects of statins in cardiovascular diseases.

  9. A continued saga of Boc5, the first non-peptidic glucagon-like peptide-1 receptor agonist with in vivo activities.

    Science.gov (United States)

    He, Min; Guan, Ni; Gao, Wei-wei; Liu, Qing; Wu, Xiao-yan; Ma, Da-wei; Zhong, Da-fang; Ge, Guang-bo; Li, Chuan; Chen, Xiao-yan; Yang, Ling; Liao, Jia-yu; Wang, Ming-wei

    2012-02-01

    Glucagon-like peptide-1 (GLP-1)-based therapy presents a promising option for treating type 2 diabetes. However, there are several limitations relative to the peptidic GLP-1 mimetics currently on the market or under development. This concern has led to a continued interest in the search for non-peptidic agonists for GLP-1 receptor (GLP-1R). Here, we briefly review the discovery, characterization and current status of a novel class of cyclobutane-derivative-based non-peptidic agonists for GLP-1R, including Boc5 and its newly discovered analogue WB4-24. Although the oral bioavailability of such compounds still poses great challenges, the progress made so far encourages us to identify a truly 'druggable' small molecule agonist for GLP-1R.

  10. A continued saga of Boc5, the first non-peptidic glucagon-like peptide-1 receptor agonist with in vivo activities

    Institute of Scientific and Technical Information of China (English)

    Min HE; Xiao-yan CHEN; Ling YANG; Jia-yu LIAO; Ming-wei WANG; Ni GUAN; Wei-wei GAO; Qing LIU; Xiao-yan WU; Da-wei MA; Da-fang ZHONG; Guang-bo GE; Chuan LI

    2012-01-01

    Glucagon-like peptide-1 (GLP-1)-based therapy presents a promising option for treating type 2 diabetes.However,there are several limitations relative to the peptidic GLP-1 mimetics currently on the market or under development.This concern has led to a continued interest in the search for non-peptidic agonists for GLP-1 receptor (GLP-1R).Here,we briefly review the discovery,characterization and current status of a novel class of cyclobutane-derivative-based non-peptidic agonists for GLP-1R,including Boc5 and its newly discovered analogue WB4-24.Although the oral bioavailability of such compounds still poses great challenges,the progress made so far encourages us to identify a truly 'druggable' small molecule agonist for GLP-1R.

  11. Angiotensin II or epinephrine hemodynamic and metabolic responses in the liver of L-NAME induced hypertension and spontaneous hypertensive rats

    Science.gov (United States)

    Kimura, Debora Conte; Nagaoka, Marcia Regina; Borges, Durval Rosa; Kouyoumdjian, Maria

    2017-01-01

    AIM To study hepatic vasoconstriction and glucose release induced by angiotensin (Ang)II or Epi in rats with pharmacological hypertension and spontaneously hypertensive rat (SHR). METHODS Isolated liver perfusion was performed following portal vein and vena cava cannulation; AngII or epinephrine (Epi) was injected in bolus and portal pressure monitored; glucose release was measured in perfusate aliquots. RESULTS The portal hypertensive response (PHR) and the glucose release induced by AngII of L-NAME were similar to normal rats (WIS). On the other hand, the PHR induced by Epi in L-NAME was higher whereas the glucose release was lower compared to WIS. Despite the similar glycogen content, glucose release induced by AngII was lower in SHR compared to Wistar-Kyoto rats although both PHR and glucose release induced by Epi in were similar. CONCLUSION AngII and Epi responses are altered in different ways in these hypertension models. Our results suggest that inhibition of NO production seems to be involved in the hepatic effects induced by Epi but not by AngII; the diminished glucose release induced by AngII in SHR is not related to glycogen content. PMID:28660012

  12. Cross talk between AT1 receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus.

    Science.gov (United States)

    Biancardi, Vinicia Campana; Stranahan, Alexis M; Krause, Eric G; de Kloet, Annette D; Stern, Javier E

    2016-02-01

    ANG II is thought to increase sympathetic outflow by increasing oxidative stress and promoting local inflammation in the paraventricular nucleus (PVN) of the hypothalamus. However, the relative contributions of inflammation and oxidative stress to sympathetic drive remain poorly understood, and the underlying cellular and molecular targets have yet to be examined. ANG II has been shown to enhance Toll-like receptor (TLR)4-mediated signaling on microglia. Thus, in the present study, we aimed to determine whether ANG II-mediated activation of microglial TLR4 signaling is a key molecular target initiating local oxidative stress in the PVN. We found TLR4 and ANG II type 1 (AT1) receptor mRNA expression in hypothalamic microglia, providing molecular evidence for the potential interaction between these two receptors. In hypothalamic slices, ANG II induced microglial activation within the PVN (∼65% increase, P microglia) to ANG II-driven ROS production in the PVN. Taken together, these results support functional interactions between AT1 receptors and TLR4 in mediating ANG II-dependent microglial activation and oxidative stress within the PVN. More broadly, our results support a functional interaction between the central renin-angiotensin system and innate immunity in the regulation of neurohumoral outflows from the PVN.

  13. Binding of trans-acting protein AngCP to the CCAAT-containing motifs in Aspergillus niger glaA promoter

    Institute of Scientific and Technical Information of China (English)

    ZHU Xingguo; QIU Runxiang; LIU Li; TANG Guomin

    2004-01-01

    CCAAT-binding proteins AngCP1 and AngCP2 of Aspergillus niger binding to DC(- 489- - 414 bp)and PC(- 390~ - 345 bp)of A.Niger glaA gene were respectively purified by 20 % ~ 40 % saturated ammonium sulfate,gel filtration,Heparin SepharoseC1-6B chromatography and DNA sequence-specific affinity chromatography.Gel filtration and SDS-PAGE revealed that both AngCP1 and AngCP2 were of 120 kD,comprised of two suhunits of 34 kD and 50 kD.Western blot showed that the 34 kD subunits of both AngCP1 and AngCP2 cross-reacted specifically with the anti-AngHAPC antiserum.Further electrophoretic mobility shift assay identified that AngCP1 and AngCP2 were the same protein,designated AngCP.Southwestern blot showed that the affinity of the 34 kD subunit to DC was stronger than that of the 50 kD subunit to PC.These results suggested that interaction between AngCP,DC and PC plays an important role in the regulation of transcription of Aspergillus niger glaA gene.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-02-01

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

  15. In vitro cultivation of rat bone marrow mesenchymal stem cells and establishment of pEGFP/Ang-1 transfection method

    Directory of Open Access Journals (Sweden)

    Xiu-Qun Zhang

    2014-09-01

    Conclusions: Adherence screening method and density gradient centrifugation can be effective methods to obtain BMSCs with high purity and rapid proliferation. Besides, the expression of transfected recombinant plasmid pEGFP/Ang-1 in rat BMSCs is satisfactory.

  16. Angiotensin II-induced oxidative stress resets the Ca2+ dependence of Ca2+-calmodulin protein kinase II and promotes a death pathway conserved across different species.

    Science.gov (United States)

    Palomeque, Julieta; Rueda, Omar Velez; Sapia, Luciana; Valverde, Carlos A; Salas, Margarita; Petroff, Martin Vila; Mattiazzi, Alicia

    2009-12-04

    Angiotensin (Ang) II-induced apoptosis was reported to be mediated by different signaling molecules. Whether these molecules are either interconnected in a single pathway or constitute different and alternative cascades by which Ang II exerts its apoptotic action, is not known. To investigate in cultured myocytes from adult cat and rat, 2 species in which Ang II has opposite inotropic effects, the signaling cascade involved in Ang II-induced apoptosis. Ang II (1 micromol/L) reduced cat/rat myocytes viability by approximately 40%, in part, because of apoptosis (TUNEL/caspase-3 activity). In both species, apoptosis was associated with reactive oxygen species (ROS) production, Ca(2+)/calmodulin-dependent protein kinase (CaMK)II, and p38 mitogen-activated protein kinase (p38MAPK) activation and was prevented by the ROS scavenger MPG (2-mercaptopropionylglycine) or the NADPH oxidase inhibitor DPI (diphenyleneiodonium) by CaMKII inhibitors (KN-93 and AIP [autocamtide 2-related inhibitory peptide]) or in transgenic mice expressing a CaMKII inhibitory peptide and by the p38MAPK inhibitor, SB202190. Furthermore, p38MAPK overexpression exacerbated Ang II-induced cell mortality. Moreover, although KN-93 did not affect Ang II-induced ROS production, it prevented p38MAPK activation. Results further show that CaMKII can be activated by Ang II or H(2)O(2), even in the presence of the Ca(2+) chelator BAPTA-AM, in myocytes and in EGTA-Ca(2+)-free solutions in the presence of the calmodulin inhibitor W-7 in in vitro experiments. (1) The Ang II-induced apoptotic cascade converges in both species, in a common pathway mediated by ROS-dependent CaMKII activation which results in p38MAPK activation and apoptosis. (2) In the presence of Ang II or ROS, CaMKII may be activated at subdiastolic Ca(2+) concentrations, suggesting a new mechanism by which ROS reset the Ca(2+) dependence of CaMKII to extremely low Ca(2+) levels.

  17. Lipid rafts are required for signal transduction by angiotensin II receptor type 1 in neonatal glomerular mesangial cells

    Energy Technology Data Exchange (ETDEWEB)

    Adebiyi, Adebowale, E-mail: aadebiyi@uthsc.edu; Soni, Hitesh; John, Theresa A.; Yang, Fen

    2014-05-15

    Angiotensin II (ANG-II) receptors (AGTRs) contribute to renal physiology and pathophysiology, but the underlying mechanisms that regulate AGTR function in glomerular mesangium are poorly understood. Here, we show that AGTR1 is the functional AGTR subtype expressed in neonatal pig glomerular mesangial cells (GMCs). Cyclodextrin (CDX)-mediated cholesterol depletion attenuated cell surface AGTR1 protein expression and ANG-II-induced intracellular Ca{sup 2+} ([Ca{sup 2+}]{sub i}) elevation in the cells. The COOH-terminus of porcine AGTR1 contains a caveolin (CAV)-binding motif. However, neonatal GMCs express CAV-1, but not CAV-2 and CAV-3. Colocalization and in situ proximity ligation assay detected an association between endogenous AGTR1 and CAV-1 in the cells. A synthetic peptide corresponding to the CAV-1 scaffolding domain (CSD) sequence also reduced ANG-II-induced [Ca{sup 2+}]{sub i} elevation in the cells. Real-time imaging of cell growth revealed that ANG-II stimulates neonatal GMC proliferation. ANG-II-induced GMC growth was attenuated by EMD 66684, an AGTR1 antagonist; BAPTA, a [Ca{sup 2+}]{sub i} chelator; KN-93, a Ca{sup 2+}/calmodulin-dependent protein kinase II inhibitor; CDX; and a CSD peptide, but not PD 123319, a selective AGTR2 antagonist. Collectively, our data demonstrate [Ca{sup 2+}]{sub i}-dependent proliferative effect of ANG-II and highlight a critical role for lipid raft microdomains in AGTR1-mediated signal transduction in neonatal GMCs. - Highlights: • AGTR1 is the functional AGTR subtype expressed in neonatal mesangial cells. • Endogenous AGTR1 associates with CAV-1 in neonatal mesangial cells. • Lipid raft disruption attenuates cell surface AGTR1 protein expression. • Lipid raft disruption reduces ANG-II-induced [Ca{sup 2+}]{sub i} elevation in neonatal mesangial cells. • Lipid raft disruption inhibits ANG-II-induced neonatal mesangial cell growth.

  18. Influence of antihypertensive drugs on aortic and coronary effects of Ang-(1-7 in pressure-overloaded rats

    Directory of Open Access Journals (Sweden)

    A.D.C. Nunes

    Full Text Available This study investigated the influence of antihypertensive drugs, such as angiotensin-converting enzyme inhibitors (ACEIs, AT1 receptor blockers (ARBs, voltage-gated L-type calcium channel blockers, and mineralocorticoid receptor antagonists (MRAs, on the effects of angiotensin-(1-7 [Ang-(1-7] on aorta and coronary arteries from pressure-overloaded rats. Pressure overload was induced by abdominal aortic banding (AB. To evaluate the role of antihypertensive drugs on the effect of Ang-(1-7, AB male Wistar rats weighing 250–300 g were treated with vehicle or low doses (5 mg·kg-1·day-1, gavage of losartan, captopril, amlodipine, or spironolactone. Isolated aortic rings and isolated perfused hearts under constant flow were used to evaluate the effect of Ang-(1-7 in thoracic aorta and coronary arteries, respectively. Ang-(1-7 induced a significant relaxation in the aorta of sham animals, but this effect was reduced in the aortas of AB rats. Chronic treatments with losartan, captopril or amlodipine, but not with spironolactone, restored the Ang-(1-7-induced aorta relaxation in AB rats. The coronary vasodilatation evoked by Ang-(1-7 in sham rats was blunted in hypertrophic rats. Only the treatment with losartan restored the coronary vasodilatory effect of Ang-(1-7 in AB rat hearts. These data support a beneficial vascular effect of an association of Ang-(1-7 and some antihypertensive drugs. Thus, this association may have potential as a new therapeutic strategy for cardiovascular diseases.

  19. Lipid rafts are required for signal transduction by angiotensin II receptor type 1 in neonatal glomerular mesangial cells.

    Science.gov (United States)

    Adebiyi, Adebowale; Soni, Hitesh; John, Theresa A; Yang, Fen

    2014-05-15

    Angiotensin II (ANG-II) receptors (AGTRs) contribute to renal physiology and pathophysiology, but the underlying mechanisms that regulate AGTR function in glomerular mesangium are poorly understood. Here, we show that AGTR1 is the functional AGTR subtype expressed in neonatal pig glomerular mesangial cells (GMCs). Cyclodextrin (CDX)-mediated cholesterol depletion attenuated cell surface AGTR1 protein expression and ANG-II-induced intracellular Ca(2+) ([Ca(2+)]i) elevation in the cells. The COOH-terminus of porcine AGTR1 contains a caveolin (CAV)-binding motif. However, neonatal GMCs express CAV-1, but not CAV-2 and CAV-3. Colocalization and in situ proximity ligation assay detected an association between endogenous AGTR1 and CAV-1 in the cells. A synthetic peptide corresponding to the CAV-1 scaffolding domain (CSD) sequence also reduced ANG-II-induced [Ca(2+)]i elevation in the cells. Real-time imaging of cell growth revealed that ANG-II stimulates neonatal GMC proliferation. ANG-II-induced GMC growth was attenuated by EMD 66684, an AGTR1 antagonist; BAPTA, a [Ca(2+)]i chelator; KN-93, a Ca(2+)/calmodulin-dependent protein kinase II inhibitor; CDX; and a CSD peptide, but not PD 123319, a selective AGTR2 antagonist. Collectively, our data demonstrate [Ca(2+)]i-dependent proliferative effect of ANG-II and highlight a critical role for lipid raft microdomains in AGTR1-mediated signal transduction in neonatal GMCs. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. 醛固酮通过调节ACE2-Ang(1-7)-Mas受体轴诱导内皮细胞凋亡的研究%Aldosterone induced endothelial cell apoptosis via modulation of ACE2-Ang (1-7)-Mas receptor axis

    Institute of Scientific and Technical Information of China (English)

    张霞; 潘瑜; 金惠敏

    2013-01-01

    ACE2 receptor and Mas receptor was determined by Western blotting, the contents of AngII and Ang ( 1-7) protein and caspase-3 activity in the supernatant of culture fluid were measured by ELISA, and cell apoptosis was detected by flow cytometry with FITC-Annexin V/PI fluorescein staining. Results Compared with control group, the expression of ACE2 receptor and Mas receptor in cells in aldosterone group significantly decreased in a dose-dependent manner (P <0.01). In 100 nmol/L aldosterone group, the expression of ACE2 receptor and Mas receptor in cells significantly decreased in a time-dependent manner (P <0.01) , while the expression of ACE2 receptor and Mas receptor in cells in aldosterone antagonist group was significantly higher than that in 100 nmol/L aldosterone group (P <0.01). The content of Ang II and caspase-3 activity in the supernatant of culture fluid in aldosterone group significantly increased with the time, while the content of Ang (1-7) significantly decreased. The apoptosis rate in aldosterone group was significantly higher than that in control group, while the apoptosis rate in aldosterone antagonist group was significantly lower than that in aldosterone group ( P < 0. 05).Conclusion Aldosterone may regulate ACE2 - Ang (1-7) - Mas receptor axis, which may play a role in inducing endothelial cell apoptosis.

  1. Optimization of transfection parameters for ultrasound/SonoVue microbubble-mediated hAng-1 gene delivery in vitro.

    Science.gov (United States)

    Zhou, Qing; Chen, Jin-Ling; Chen, Qian; Wang, Xiao; Deng, Qing; Hu, Bo; Guo, Rui-Qiang

    2012-12-01

    This study aimed to explore the effects of microbubble concentration, gene dosage, cell-microbubble mixing mode and fetal bovine serum (FBS) on gene delivery. 293T cells were transfected with Sonovue microbubbles carrying the hAng-1 gene via ultrasound irradiation. Various ultrasound exposure parameters and microbubble and DNA concentrations were investigated. In addition, FBS and the cell suspension or adherent mode was explored. Transfection efficiency and cell viability were used to determine the optimal transfection parameters. hAng-1 gene transfection efficiency gradually increased with elongation of ultrasound exposure and increasing microbubble concentration. However, if ultrasound irradiation exceeded 1.5 W/cm² and 30 sec or the microbubble concentration was over 20%, hAng-1 gene expression was significantly decreased, coupled with extensive cell death. Gene transfection levels were low under DNA concentrations less than 15 µg/ml. Furthermore, the gene transfer rate was significantly increased under cell suspension mode; FBS had no effect on hAng-1 gene transfection. The integrity of hAng-1 DNA was not affected by ultrasonic irradiation under optimal conditions. The optimal transfection parameters for the hAng-1 gene and Sonovue microbubble were ultrasound exposure of 1.5 W/cm² and 30 sec, 20% microbubbles, 15 µg/ml of DNA and under cell suspension mode.

  2. In vitro cultivation of rat bone marrow mesenchymal stem cells and establishment of pEGFP/Ang-1 transfection method

    Institute of Scientific and Technical Information of China (English)

    Xiu-Qun Zhang; Long Wang; Shu-Li Zhao; Wei Xu

    2014-01-01

    Objective:To obtain the bone marrow mesenchymal stem cells (BMSCs), complete phenotypic identification and successfully transfect rat BMSCs by recombinant plasmid pEGFP/Ang-1. Methods:BMSCs were isolated from bone marrow using density gradient centrifugation method and adherence screening method, and purified. Then the recombinant plasmid pEGFP/Ang-1 was used to transfect BMSCs and the positive clones were obtained by the screen of G418 and observed under light microscopy inversely. Green fluorescent exhibited by protein was enhanced to measure the change time of the expression amount of Ang-1. Results: BMSCs cell lines were obtained successfully by adherence screening method and density gradient centrifugation. Ang-1 recombinant plasmid was transfected smoothly into rat BMSCs, which can express Ang-1 for 3 d and decreased after 7 d. Conclusions:Adherence screening method and density gradient centrifugation can be effective methods to obtain BMSCs with high purity and rapid proliferation. Besides, the expression of transfected recombinant plasmid pEGFP/Ang-1 in rat BMSCs is satisfactory.

  3. The neurogenic phase of angiotensin II-salt hypertension is prevented by chronic intracerebroventricular administration of benzamil.

    Science.gov (United States)

    Osborn, John W; Olson, Dalay M; Guzman, Pilar; Toney, Glenn M; Fink, Gregory D

    2014-02-01

    Hypertension induced by chronic administration of angiotensin II (AngII) is exacerbated by high-salt intake. Previous studies have demonstrated that this salt-sensitive component is due to increased activity of the sympathetic nervous system, suggesting an interaction of plasma AngII with sodium-sensitive regions of the brain. This study tested the hypothesis that the salt-sensitive component of AngII-induced hypertension would be prevented by intracerebroventricular (ICV) administration of the sodium channel/transporter blocker benzamil. Male Sprague Dawley rats were instrumented to measure mean arterial pressure (MAP) by radio telemetry and for ICV administration of benzamil or vehicle and placed in metabolic cages for measurement of sodium and water intake and excretion. In rats consuming a high-salt diet (2.0% NaCl) and treated with ICV vehicle, administration of AngII (150 ng/kg/min, sc) for 13 days increased MAP by ~30 mmHg. ICV administration of benzamil (16 nmol/day) had no effect during the first 5 days of AngII, but returned MAP to control levels by Day 13. There were minimal or no differences between ICV vehicle or benzamil groups in regards to sodium and water balance. A lower dose of ICV benzamil administered ICV at 8 nmol/day had no effect on the MAP response to AngII in rats on a high-salt diet. Finally, in contrast to rats on a high-salt diet, AngII had negligible effects on MAP in rats consuming a low-salt diet (0.1% NaCl) and there were no differences in any variable between ICV benzamil (16 nmol/day) and ICV vehicle-treated groups. We conclude that the salt-sensitive component of AngII-induced hypertension is dependent on benzamil blockable sodium channels or transporters in the brain.

  4. Preventive effect of gomisin J from Schisandra chinensis on angiotensin II-induced hypertension via an increased nitric oxide bioavailability.

    Science.gov (United States)

    Ye, Byeong Hyeok; Lee, Seung Jin; Choi, Young Whan; Park, So Youn; Kim, Chi Dae

    2015-03-01

    Gomisin J (GJ) is a small molecular weight lignan found in Schisandra chinensis and has been demonstrated to have vasodilatory activity. In this study, the authors investigated the effect of GJ on blood pressure (BP) in angiotensin II (Ang II)-induced hypertensive mice. In addition, we determined the relative potencies of gomisin A (GA) and GJ with respect to vasodilatory activity and antihypertensive effects. C57/BL6 mice infused s.c. with Ang II (2 μg kg(-1) min(-1) for 2 weeks) showed an increase in BP and a decrease in plasma nitric oxide (NO) metabolites. In the thoracic aortas of Ang II-induced hypertensive mice, a decrease in vascular NO was accompanied by an increase in reactive oxygen species (ROS) production. Furthermore, these alterations in BP, plasma concentrations of NO metabolites and in the vascular productions of NO and ROS in Ang II-treated mice were reversed by the co-administration of GJ (1 and 3 μg kg(-1) min(-1)). In in vitro studies, Ang II decreased the cellular concentration of NO, which was accompanied by a reduction in phosphorylated endothelial nitric oxide synthase (eNOS) and an increase in ROS production. These eNOS phosphorylation and ROS production changes in Ang II-treated cells were also reversed by GJ pretreatment (0-3 μg ml(-1)). Interestingly, the vasodilatory and antihypertensive effects of GJ were more prominent than those of GA. Collectively, an increase in BP in mice treated with Ang II was markedly attenuated by GJ, which was attributed to the preservations of vascular NO bioavailability and eNOS function, and to the inhibition of ROS production in Ang II-induced hypertensive mice.

  5. Heme oxygenase attenuates angiotensin II-mediated superoxide production in cultured mouse thick ascending loop of Henle cells.

    Science.gov (United States)

    Kelsen, Silvia; Patel, Bijal J; Parker, Lawson B; Vera, Trinity; Rimoldi, John M; Gadepalli, Rama S V; Drummond, Heather A; Stec, David E

    2008-10-01

    Heme oxygenase (HO)-1 induction can attenuate the development of angiotensin II (ANG II)-dependent hypertension. However, the mechanism by which HO-1 lowers blood pressure is not clear. The goal of this study was to test the hypothesis that induction of HO-1 can reduce the ANG II-mediated increase in superoxide production in cultured thick ascending loop of Henle (TALH) cells. Studies were performed on an immortalized cell line of mouse TALH (mTALH) cells. HO-1 was induced in cultured mTALH cells by treatment with cobalt protoporphyrin (CoPP, 10 microM) or hemin (50 microM) or by transfection with a plasmid containing the human HO-1 isoform. Treatment of mTALH cells with 10(-9) M ANG II increased dihydroethidium (DHE) fluorescence (an index of superoxide levels) from 35.5+/-5 to 136+/-18 relative fluorescence units (RFU)/microm2. Induction of HO-1 via CoPP, hemin, or overexpression of the human HO-1 isoform significantly reduced ANG II-induced DHE fluorescence to 64+/-5, 64+/-8, and 41+/-4 RFU/microm2, respectively. To determine which metabolite of HO-1 is responsible for reducing ANG II-mediated increases in superoxide production in mTALH cells, cells were preincubated with bilirubin or carbon monoxide (CO)-releasing molecule (CORM)-A1 (each at 100 microM) before exposure to ANG II. DHE fluorescence averaged 80+/-7 RFU/microm2 after incubation with ANG II and was significantly decreased to 55+/-7 and 53+/-4 RFU/microm2 after pretreatment with bilirubin and CORM-A1. These results demonstrate that induction of HO-1 in mTALH cells reduces the levels of ANG II-mediated superoxide production through the production of both bilirubin and CO.

  6. Arterial and venous endothelia display differential functional fractalkine (CX3CL1) expression by angiotensin-II.

    Science.gov (United States)

    Rius, Cristina; Piqueras, Laura; González-Navarro, Herminia; Albertos, Fernando; Company, Chantal; López-Ginés, Concha; Ludwig, Andreas; Blanes, Jose-Ignacio; Morcillo, Esteban J; Sanz, Maria-Jesus

    2013-01-01

    Angiotensin-II (Ang-II) promotes the interaction of mononuclear cells with arterioles and neutrophils with postcapillary venules. To investigate the mechanisms underlying this dissimilar response, the involvement of fractalkine (CX(3)CL1) was explored. Enhanced CX(3)CL1 expression was detected in both cremasteric arterioles and postcapillary venules 24 hours after Ang-II intrascrotal injection. Arteriolar leukocyte adhesion was the unique parameter significantly reduced (83%) in animals lacking CX(3)CL1 receptor (CX(3)CR1). Human umbilical arterial and venous endothelial cell stimulation with 1 μmol/L Ang-II increased CX(3)CL1 expression, yet neutralization of CX(3)CL1 activity only significantly inhibited Ang-II-induced mononuclear cell-human umbilical arterial endothelial cell interactions (73%) but not with human umbilical venous endothelial cells. The use of small interfering RNA revealed the involvement of tumor necrosis factor-α in Ang-II-induced CX(3)CL1 upregulation and mononuclear cell arrest. Nox5 knockdown with small interfering RNA or pharmacological inhibition of extracellular signal-regulated kinases1/2, p38 mitogen-activated protein kinase, and nuclear factor-κB also abolished these responses. Finally, when human umbilical arterial endothelial cells were costimulated with Ang-II, tumor necrosis factor-α, and interferon-γ, CX(3)CL1 expression and mononuclear cell adhesiveness were more pronounced than when each stimulus was provided alone. These results suggest that Ang-II induces functional CX(3)CL1 expression in arterial but not in venous endothelia. Thus, targeting endothelial CX(3)CL1-mononuclear leukocyte CX(3)CR1 interactions may constitute a new therapeutic strategy in the treatment of Ang-II-associated cardiovascular diseases.

  7. Ang2-siRNA 慢病毒干预裸鼠移植性恶性黑色素瘤的研究%Ang2-siRNA Lentivirus Interference on Melanoma Xenograft in Nude Mice

    Institute of Scientific and Technical Information of China (English)

    王彪; 林建鸿; 张炜强; 张明凤; 刘照亮; 单秀英; 王美水; 庄福连

    2012-01-01

    目的 研究血管生成素2小干扰 RNA(Ang2-siRNA)对裸鼠移植性恶性黑色素瘤血管形成及其生长的影响.方法 建立人恶性黑色素肿瘤裸鼠异种移植瘤模型.在体内使用 pNL-EGFP-Ang2-siRNA 慢病毒干扰裸鼠移植性恶性黑色素瘤 Ang2 基因的表达,观察统计各组肿瘤(空白组、空载组、实验组)生长情况.应用实时荧光定量 RT-PCR 检测肿瘤组织中 Ang2 基因的 mRNA 表达水平;CD34 单克隆抗体作为血管内皮标志物,免疫组织化学法检测其表达,以评价肿瘤微血管密度.结果 成功建立了恶性黑色素瘤裸鼠异种移植瘤模型,实验组肿瘤 Ang2 基因 mRNA 水平、微血管密度、肿瘤体积显著小于空白组和空载组(P0.05).结论 pNL-EGFP-Ang2-siRNA 慢病毒能沉默Ang2 的表达,显著抑制恶性黑色素瘤血管的形成和肿瘤的生长,可能为临床恶性黑色素肿瘤的基因治疗开辟新的途径.%Objective Research the influence of Ang2-siRNA on angiogenesis and growth of transplanted melanoma tumors in nude mice. Methods Human malignant melanoma ( MM ) trans-plantation tumor model was established in nude mice . Interference of Ang2 gene expression by pNL-EGFP-Ang2-siRNA lentivirus in transplanted MM was observed and recorded by comparison of tumor growth between the PBS control group, the Vector control group , and the experimental RNAi group. The expression levels of Ang2 gene in transplanted tumors was detected by Real -time RT-PCR. CD34, as one of the vascular endothelial markers , was detected by CD34 monoclonal antibodies to evaluate the microvessel de Nsity of transplanted tumor using Immunohistochemical method. Results The human MM transplanted tumor nude mice model was successfully established . The Ang2 gene mRNA level, microvassel de Nsity, and tumor size in RNAi group were significantly deceased , compared to those in the PBS and Vector control groups (P 0. 05 ) . Conclusion PNL-EGFP-Ang2-siRNA lentivirus can reduce

  8. The Effects of Hydroalchoholic Extract of Teucrium polium L. on Hypertension Induced by Angiotensin II in Rats

    Directory of Open Access Journals (Sweden)

    Maryam Mahmoudabady

    2014-01-01

    Conclusions: It seems TP extract could be effective in preventing of high blood pressure induced by Ang II pathway activation but could not have remarkable efficacy for improving the created tachycardia.

  9. Aldosterone breakthrough caused by chronic blockage of angiotensin II type 1 receptors in human adrenocortical cells: Possible involvement of bone morphogenetic protein-6 actions

    OpenAIRE

    Otani, Hiroyuki; Otsuka, Fumio; Inagaki, Kenichi; Suzuki, Jiro; Miyoshi, Tomoko; KANO, YOSHIHIRO; GOTO, Junko; Ogura, Toshio; Makino, Hirofumi

    2008-01-01

    Circulating aldosterone concentrations occasionally increase after initial suppression with angiotensin II (Ang II) converting enzyme inhibitors or Ang II type 1 receptor blockers (ARBs), a phenomenon referred to as aldosterone breakthrough. However, the underlying mechanism causing the aldosterone breakthrough remains unknown. Here we investigated whether aldosterone breakthrough occurs in human adrenocortical H295R cells in vitro. We recently reported that bone morphogenetic protein (BMP)-6...

  10. Angiotensin II and 1-7 during aging in Metabolic Syndrome rats. Expression of AT1, AT2 and Mas receptors in abdominal white adipose tissue.

    Science.gov (United States)

    Rubio-Ruíz, M E; Del Valle-Mondragón, L; Castrejón-Tellez, V; Carreón-Torres, E; Díaz-Díaz, E; Guarner-Lans, V

    2014-07-01

    Renin-Angiotensin System (RAS) plays an important role in the development of Metabolic Syndrome (MS) and in aging. Angiotensin 1-7 (Ang 1-7) has opposite effects to Ang II. All of the components of RAS are expressed locally in adipose tissue and there is over-activation of adipose RAS in obesity and hypertension. We determined serum and abdominal adipose tissue Ang II and Ang 1-7 in control and MS rats during aging and the expression of AT1, AT2 and Mas in white adipose tissue. MS was induced by sucrose ingestion during 6, 12 and 18 months. During aging, an increase in body weight, abdominal fat and dyslipidemia were found but increases in aging MS rats were higher. Control and MS concentrations of serum Ang II from 6-month old rats were similar. Aging did not modify Ang II seric concentration in control rats but decreased it in MS rats. Ang II levels increased in WAT from both groups of rats. Serum and adipose tissue Ang 1-7 increased during aging in MS rats. Western blot analysis revealed that AT1 expression increased in the control group during aging while AT2 and Mas remained unchanged. In MS rats, AT1 and AT2 expression decreased significantly in aged rats. The high concentration of Ang 1-7 and adiponectin in old MS rats might be associated to an increased expression of PPAR-γ. PPAR-γ was increased in adipose tissue from MS rats. It decreased with aging in control rats and showed no changes during aging in MS rats. Ang 1-7/Mas axis was the predominant pathway in WAT from old MS animals and could represent a potential target for therapeutical strategies in the treatment of MS during aging.

  11. Ca2+ -regulated lysosome fusion mediates angiotensin II-induced lipid raft clustering in mesenteric endothelial cells.

    Science.gov (United States)

    Han, Wei-Qing; Chen, Wen-Dong; Zhang, Ke; Liu, Jian-Jun; Wu, Yong-Jie; Gao, Ping-Jin

    2016-04-01

    It has been reported that intracellular Ca2+ is involved in lysosome fusion and membrane repair in skeletal cells. Given that angiotensin II (Ang II) elicits an increase in intracellular Ca2+ and that lysosome fusion is a crucial mediator of lipid raft (LR) clustering, we hypothesized that Ang II induces lysosome fusion and activates LR formation in rat mesenteric endothelial cells (MECs). We found that Ang II acutely increased intracellular Ca2+ content, an effect that was inhibited by the extracellular Ca2+ chelator ethylene glycol tetraacetic acid (EGTA) and the inositol 1,4,5-trisphosphate (IP3)-induced Ca2+ release inhibitor 2-aminoethoxydiphenyl borate (2-APB). Further study showed that EGTA almost completely blocked Ang II-induced lysosome fusion, the translocation of acid sphingomyelinase (ASMase) to LR clusters, ASMase activation and NADPH (nicotinamide adenine dinucleotide phosphate) oxidase activation. In contrast, 2-APB had a slight inhibitory effect. Functionally, both the lysosome inhibitor bafilomycin A1 and the ASMase inhibitor amitriptyline reversed Ang II-induced impairment of vasodilation. We conclude that Ca2+ -regulated lysosome fusion mediates the Ang II-induced regulation of the LR-redox signaling pathway and mesenteric endothelial dysfunction.

  12. Angiotensin-II-induced Muscle Wasting is Mediated by 25-Hydroxycholesterol via GSK3β Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Congcong Shen

    2017-02-01

    Full Text Available While angiotensin II (ang II has been implicated in the pathogenesis of cardiac cachexia (CC, the molecules that mediate ang II's wasting effect have not been identified. It is known TNF-α level is increased in patients with CC, and TNF-α release is triggered by ang II. We therefore hypothesized that ang II induced muscle wasting is mediated by TNF-α. Ang II infusion led to skeletal muscle wasting in wild type (WT but not in TNF alpha type 1 receptor knockout (TNFR1KO mice, suggesting that ang II induced muscle loss is mediated by TNF-α through its type 1 receptor. Microarray analysis identified cholesterol 25-hydroxylase (Ch25h as the down stream target of TNF-α. Intraperitoneal injection of 25-hydroxycholesterol (25-OHC, the product of Ch25h, resulted in muscle loss in C57BL/6 mice, accompanied by increased expression of atrogin-1, MuRF1 and suppression of IGF-1/Akt signaling pathway. The identification of 25-OHC as an inducer of muscle wasting has implications for the development of specific treatment strategies in preventing muscle loss.

  13. Melatonin attenuates angiotensin II-induced cardiomyocyte hypertrophy through the CyPA/CD147 signaling pathway.

    Science.gov (United States)

    Su, Hongyan; Li, Jingyuan; Chen, Tongshuai; Li, Na; Xiao, Jie; Wang, Shujian; Guo, Xiaobin; Yang, Yi; Bu, Peili

    2016-11-01

    Melatonin is well known for its cardioprotective effects; however, whether melatonin exerts therapeutic effects on cardiomyocyte hypertrophy remains to be investigated, as do the mechanisms underlying these effects, if they exist. Cyclophilin A (CyPA) and its corresponding receptor, CD147, which exists in a variety of cells, play crucial roles in modulating reactive oxygen species (ROS) production. In this study, we explored the role of the CyPA/CD147 signaling pathway in angiotensin II (Ang II)-induced cardiomyocyte hypertrophy and the protective effects exerted by melatonin against Ang II-induced injury in cultured H9C2 cells. Cyclosporine A, a specific CyPA/CD147 signaling pathway inhibitor, was used to manipulate CyPA/CD147 activity. H9C2 cells were then subjected to Ang II or CyPA treatment in either the absence or presence of melatonin. Our results indicate that Ang II induces cardiomyocyte hypertrophy through the CyPA/CD147 signaling pathway and promotes ROS production, which can be blocked by melatonin pretreatment in a concentration-dependent manner, in cultured H9C2 cells and that CyPA/CD147 signaling pathway inhibition protects against Ang II-induced cardiomyocyte hypertrophy. The protective effects of melatonin against Ang II-induced cardiomyocyte hypertrophy depend at least partially on CyPA/CD147 inhibition.

  14. Antihypertensive effect of gomisin A from Schisandra chinensis on angiotensin II-induced hypertension via preservation of nitric oxide bioavailability.

    Science.gov (United States)

    Young Park, Ji; Wook Yun, Jung; Whan Choi, Young; Ung Bae, Jin; Won Seo, Kyo; Jin Lee, Seung; Youn Park, So; Whan Hong, Ki; Kim, Chi Dae

    2012-09-01

    Gomisin A (GA) is a small molecular weight lignan present in Schisandra chinensis, and has been demonstrated to have vasodilatory activity. In the present study, we investigated the effect of GA on blood pressure (BP) in angiotensin II (Ang II)-induced hypertensive mice. C57/BL6 mice infused subcutaneously with Ang II (1 and 2 μg kg⁻¹ per min for 2 weeks) showed an increase in BP with a decrease in nitric oxide (NO) metabolites in plasma, and a negative correlation between these two parameters was demonstrated. In the thoracic aorta from Ang II-induced hypertensive mice, a decrease in vascular NO that was accompanied by a diminution of phosphorylated endothelial nitric oxide synthase (eNOS), as well as by increased reactive oxygen species (ROS) production, was demonstrated. These alterations in BP, eNOS phosphorylation and ROS production in the vasculature of Ang II-treated mice were markedly and dose-dependently reversed by simultaneous administration of GA (2 and 10 μg kg⁻¹ per min). In addition, Ang II-induced ROS production in cultured vascular cells such as endothelial cells and vascular smooth muscle cells was markedly attenuated by GA. These results suggested that GA attenuated the increase in BP via preservation of vascular NO bioavailability not only by inhibiting ROS production but also by preventing the impairment of eNOS function in the vasculature of Ang II-induced hypertensive mice.

  15. Functional cross-talk between angiotensin II and epidermal growth factor receptors in NIH3T3 fibroblasts.

    Science.gov (United States)

    De Paolis, Paola; Porcellini, Antonio; Savoia, Carmine; Lombardi, Alessia; Gigante, Bruna; Frati, Giacomo; Rubattu, Speranza; Musumeci, Beatrice; Volpe, Massimo

    2002-04-01

    The main angiotensin (Ang) II subtype receptors (AT1R and AT2R) are involved in cellular growth processes and exert functionally antagonistic effects. To characterize the mechanisms by which Ang II receptors influence growth, by investigating the interactions between Ang II subtype receptors and epidermal growth factor (EGF) receptors on mitogen-activated protein kinase (MAPK) pathway activation. The experiments were performed using a mouse fibroblast cell line, NIH3T3, by transient co-transfection with rat AT1R or AT2R expression vectors, or both. Extracellular-signal-regulated kinase (ERK)1/2 phosphorylation was analysed by western blot and the ERK activity was evaluated using PathDetect, an in-vivo signal transduction pathway trans-reporting system. Selective Ang II receptor antagonists (losartan for AT1R and PD123319 for AT2R) were used to investigate the contributions of each receptor to the response observed. Our data show that, in this cellular model, both Ang II receptors phosphorylate ERK1/2. However, in the cells expressing AT1R, the EGF-induced MAPK pathway was enhanced in the presence of Ang II in a synergistic fashion. In contrast, a reduction of EGF-induced MAPK activation was observed in the cells expressing AT2R. In cells expressing both Ang II subtype receptors, Ang II promoted an enhancement of EGF-induced MAPK activation. However, in the presence of the AT1R antagonist, losartan, the effect of EGF was reduced. These data indicate the existence of an opposite cross-talk of AT1R and AT2R with EGF receptors, and suggest a complex functional interaction between these pathways in the regulation of cellular growth processes.

  16. Actions of Angeli's salt, a nitroxyl (HNO) donor, on ion transport across mucosa-submucosa preparations from rat distal colon.

    Science.gov (United States)

    Pouokam, Ervice; Bell, Anna; Diener, Martin

    2013-09-05

    The aim of this study was to investigate whether nitroxyl (HNO), a redox variant of the radical gasotransmitter nitric oxide (NO) with therapeutically promising properties, affects colonic ion transport. Changes in short-circuit current (Isc) induced by the HNO donor Angeli's salt were recorded in Ussing chambers. Cytosolic Ca(2+) concentration was measured with fura-2. The nitroxyl donor induced a concentration-dependent increase in Isc across rat distal colon which was due to a stimulation of chloride secretion. The secretion induced by Angeli's salt (5×10(-4)mol/l) was not altered by the NO scavenger 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide (carboxy-PTIO), but was abolished by the HNO scavenger l-cysteine. The response was not dependent on the activity of soluble guanylate cyclase or enteric neurons, but was inhibited by indomethacin. Experiments with apically permeabilized epithelia revealed the activation of basolateral K(+) channels and a stimulation of the current carried by the basolateral Na(+)-K(+)-pump by Angeli's salt. The secretion induced by Angeli's salt was reduced in the absence of extracellular Ca(2+). A prominent increase in the cytosolic Ca(2+) concentration was evoked by Angeli's salt predominantly in subepithelial cells within the submucosa, which had the same dependence on extracellular Ca(2+) as the Angeli's salt-induced Cl(-) secretion. Consequently, Angeli's salt induces a soluble guanylate cyclase-independent, Ca(2+)-dependent Cl(-) secretion via activation of the Na(+)-K(+)-ATPase and of basolateral K(+) channels. Cyclooxygenase metabolites produced within the submucosa seem to be involved in this response.

  17. Dynamical behavior of a three species food chain model with Beddington-DeAngelis functional response

    Energy Technology Data Exchange (ETDEWEB)

    Naji, Raid Kamel [Department of Mathematics, College of Science, University of Baghdad (Iraq)]. E-mail: rknaji@yahoo.com; Balasim, Alla Tariq [Department of Mathematics, College of Science, University of Baghdad (Iraq)]. E-mail: alkhazrejy@yahoo.com

    2007-06-15

    A three species food chain model with Beddington-DeAngelis functional response is investigated. The local stability analysis is carried out and global behavior is simulated numerically for a biologically feasible choice of parameters. The persistence conditions of a food chain model are established. The bifurcation diagrams are obtained for different parameters of the model after intensive numerical simulations. The results of simulations show that the model could exhibit chaotic dynamics for realistic and biologically feasible parametric values. Finally, the effect of immigration within prey species is investigated. It is observed that adding small amount of constant immigration to prey species stabilize the system.

  18. Ang-1基因修饰的骨髓间质干细胞移植治疗脑梗死的实验研究%Therapeutic efficacy of Ang-1 gene-modified MSCs in cerebral infarction

    Institute of Scientific and Technical Information of China (English)

    陈柏龄; 陈东平; 张志坚; 黄东煜; 吴秀丽; 张彦定

    2009-01-01

    目的:观察血管生成素-1(Ang-1)和骨髓间质干细胞(MSCs)对脑梗死的联合治疗作用.方法:构建带有大鼠Ang-1基因的慢病毒载体,感染大鼠骨髓间质干细胞(rMSCs)获得可表达具有生物活性Ang-1蛋白的rMSCs(Ang-rMSCs).制备大鼠大脑中动脉栓塞模型,随机分为对照组、Ang-rMSCs组及空载体-rMSCs(pNL-rMSCs)组.脑栓塞术后24 h进行细胞移植.各组大鼠分别于术后24 h、移植后1周、1月及3月用mNSS量表评价神经功能状况,移植后1周应用伊文思蓝(EB)检测血脑屏障通透性,应用荧光激发及荧光免疫组化观察移植细胞在脑内的存活、分化情况,并经组织学观察有无成瘤迹象.结果: 与对照组相比,移植后1周、1月,pNL-rMSCs及Ang-rMSCs组神经功能改善明显(P0.05).EB检测示血脑屏障通透性在pNL-rMSCs及Ang-rMSCs组低于对照组(P<0.01),Ang-rMSCs组低于pNL-rMSCs组(P<0.01).移植后1周、1月及3月,Ang-rMSCs和pNL-rMSCs组在荧光激发下均见移植细胞在梗死灶及其周边区聚集并存活.荧光免疫组化检测示Ang- rMSCs组中移植细胞大量表达Ang-1,两移植组中均有部分细胞可同时表达神经元特异性烯醇化酶(NSE)、神经丝蛋白(NF)或星形胶质细胞标志物神经胶质纤维酸性蛋白(GFAP).未观察到移植细胞异常增殖等成瘤迹象.结论:Ang-1基因修饰的rMSCs移植后可迁移至脑梗死灶周围,分化表达神经细胞标志物并较长期存活.MSCs移植与其分泌的Ang-1蛋白可协同促进脑梗死后神经功能恢复.

  19. Angiotensin II-induced hypertension blunts thick ascending limb NO production by reducing NO synthase 3 expression and enhancing threonine 495 phosphorylation

    Science.gov (United States)

    Ramseyer, Vanesa D.; Gonzalez-Vicente, Agustin; Carretero, Oscar A.

    2014-01-01

    Thick ascending limbs reabsorb 30% of the filtered NaCl load. Nitric oxide (NO) produced by NO synthase 3 (NOS3) inhibits NaCl transport by this segment. In contrast, chronic angiotensin II (ANG II) infusion increases net thick ascending limb transport. NOS3 activity is regulated by changes in expression and phosphorylation at threonine 495 (T495) and serine 1177 (S1177), inhibitory and stimulatory sites, respectively. We hypothesized that NO production by thick ascending limbs is impaired by chronic ANG II infusion, due to reduced NOS3 expression, increased phosphorylation of T495, and decreased phosphorylation of S1177. Rats were infused with 200 ng·kg−1·min−1 ANG II or vehicle for 1 and 5 days. ANG II infusion for 5 days decreased NOS3 expression by 40 ± 12% (P NOS3 expression and altered phosphorylation. PMID:25377910

  20. Protective actions of estrogen on angiotensin II-induced hypertension: role of central nitric oxide.

    Science.gov (United States)

    Xue, Baojian; Singh, Minati; Guo, Fang; Hay, Meredith; Johnson, Alan Kim

    2009-11-01

    The present study tested the hypotheses that 1) nitric oxide (NO) is involved in attenuated responses to ANG II in female mice, and 2) there is differential expression of neuronal NO synthase (nNOS) in the subfornical organ (SFO) and paraventricular nucleus (PVN) in response to systemic infusions of ANG II in males vs. females. Aortic blood pressure (BP) was measured in conscious mice with telemetry implants. N(G)-nitro-l-arginine methyl ester (l-NAME; 100 microg x kg(.-1)day(-1)), an inhibitor of NOS, was administrated into the lateral cerebral ventricle for 14 days before and during ANG II pump implantation. Central infusion of l-NAME augmented the pressor effects of systemic ANG II in females (Delta21.5 + or - 2.2 vs. Delta9.2 + or - 1.5 mmHg) but not in males (Delta29.4 + or - 2.5 vs. Delta30.1 + or - 2.5 mmHg). Central administration of N(5)-(1-imino-3-butenyl)-l-ornithine (l-VNIO), a selective nNOS inhibitor, also significantly potentiated the increase in BP induced by ANG II in females (Delta17.5 + or - 3.2 vs. Delta9.2 + or - 1.5 mmHg). In gonadectomized mice, central l-NAME infusion did not affect the pressor response to ANG II in either males or females. Ganglionic blockade after ANG II infusion resulted in a greater reduction in BP in central l-NAME- or l-VNIO-treated females compared with control females. Western blot analysis of nNOS protein expression indicated that levels were approximately 12-fold higher in both the SFO and PVN of intact females compared with those in intact males. Seven days of ANG II treatment resulted in a further increase in nNOS protein expression only in intact females (PVN, to approximately 51-fold). Immunohistochemical studies revealed colocalization of nNOS and estrogen receptors in the SFO and PVN. These results suggest that NO attenuates the increase in BP induced by ANG II through reduced sympathetic outflow in females and that increased nNOS protein expression associated with the presence of female sex hormones plays a

  1. Cellular and molecular mechanisms of ACE2/Ang1-7/Mas in ALI/ARDS%ACE2/Ang1-7/Mas在ALI/ARDS中作用机制研究

    Institute of Scientific and Technical Information of China (English)

    孙佳; 朱彪

    2016-01-01

    Renin-angiotensin system(RAS)plays important roles in the pathogenesis of acute lung injury(ALI)/acute respiratory distress syndrome(ARDS).About 60% of ARDS patients are shown to develop pulmonary fibrosis with increased mortality rate.Recent researches have demonstrated potent inhibitory of angiotensin-converting enzyme 2 (ACE2)/angiotensin 1-7 (Ang1-7)/Mas axis on ALI/ARDS.This review summarizes the beneficial action of ACE2/Ang1-7/Mas on ALI/ARDS and research progress on relative signaling pathway.%肾素-血管紧张素系统在 ALI/ARDS的病理过程中有重要作用。大约60% ARDS患者进展成肺纤维化且其病死率明显增加。目前研究显示 ACE/AngⅡ/AT1 R 与 ALI/ARDS 发病机制有关,而ACE2/Ang1-7/Mas起负向调节作用———ACE2和Ang1-7对ALI/ARDS有保护作用。因此,本文就 ACE2/Ang1-7/Mas在 ALI/ARDS中的保护作用和相关信号传导通路等方面最新研究进展作一阐述。

  2. Induction of micronuclei by a new non-peptidic mimetic farnesyltransferase inhibitor RPR-115135: role of gene mutations.

    Science.gov (United States)

    Ottoboni, C; Crippa, A; Falugi, C; Russo, P

    2001-09-01

    To investigate the relationship between oncogene activation and induction of micronuclei by a new non-peptidic mimetic farnesyltransferase inhibitor, RPR-115135, two isogenic cell lines, human colon cancer line HCT-116, which harbors a K-ras mutation, and spontaneously immortalized human breast epithelial cell line MCF-10A, were utilized. HCT-116 cells were transfected with an empty control pCMV vector (clone CMV-2) or with a dominant negative mutated p53 transgene (clone Mu-p53-2) to disrupt p53 function. In both clones RPR-115135 induced a significant increase in the frequency of micronucleation at concentrations that did not affect cell membrane integrity. RPR-115135 produced a significant increase in the ratio of CREST+ to CREST- micronuclei. MCF-10A cells were stably transfected with either c-Ha-ras or c-erbB-2 or both H-ras + c-erbB-2. No induction of micronuclei was observed. No induction of micronuclei was reported in human lymphocytes and in primary spinal cells obtained from 7-day chick embryos. In conclusion, RPR-115135 acts as an aneugenic agent in a complex manner, dependent upon the complement of mutations in cell regulatory genes in tumour cells and this activity may be independent of ras genotype.

  3. Central effects of some peptide and non-peptide opioids and naloxone on thermoregulation in the rabbit

    Science.gov (United States)

    Kandasamy, S. B.; Williams, B. A.

    1983-01-01

    The effects of several peptide and non-peptide opiods and naloxone on induced hyperthermia is studied in rabbits. The effect of tyical mu, kappa, and sigma receptor antagonists (morphine, ketocyclazcine and SKF 10,0 10, 047) and some opioid peptides (Beta-endorphin /BE/, methionine-enkaphalin /ME/, and D-Ala2-methionine-enkaphalin-amide /DAME/ are determined. The role of prostaglandins (PG), cAMP, and norepinephrine (NE) in morphine, BE, and DAME induced hyperthermia is investigated. In addition, the effect of naloxone on pyrogen, arachidonic acid, PGE2, prostacyclin, dibutyryl cAMP, and NE induced hyperthermia is determined. Among other results, it is found that the three receptor antagonists induced hyperthermia in rabbits. BE, ME, and DAME were also found to cause hyperthermia, and it is suggested that they act on the same type of receptor. It is also determined that neither NE nor cAMP is involved in the hyperthermia due to morphine, BE, and DAME. It is suggested that an action of endogenous peptides on naloxone sensitive receptors plays little role in normal thermoregulation or in hyperthermia.

  4. Discovery and cardioprotective effects of the first non-Peptide agonists of the G protein-coupled prokineticin receptor-1.

    Directory of Open Access Journals (Sweden)

    Adeline Gasser

    Full Text Available Prokineticins are angiogenic hormones that activate two G protein-coupled receptors: PKR1 and PKR2. PKR1 has emerged as a critical mediator of cardiovascular homeostasis and cardioprotection. Identification of non-peptide PKR1 agonists that contribute to myocardial repair and collateral vessel growth hold promises for treatment of heart diseases. Through a combination of in silico studies, medicinal chemistry, and pharmacological profiling approaches, we designed, synthesized, and characterized the first PKR1 agonists, demonstrating their cardioprotective activity against myocardial infarction (MI in mice. Based on high throughput docking protocol, 250,000 compounds were computationally screened for putative PKR1 agonistic activity, using a homology model, and 10 virtual hits were pharmacologically evaluated. One hit internalizes PKR1, increases calcium release and activates ERK and Akt kinases. Among the 30 derivatives of the hit compound, the most potent derivative, IS20, was confirmed for its selectivity and specificity through genetic gain- and loss-of-function of PKR1. Importantly, IS20 prevented cardiac lesion formation and improved cardiac function after MI in mice, promoting proliferation of cardiac progenitor cells and neovasculogenesis. The preclinical investigation of the first PKR1 agonists provides a novel approach to promote cardiac neovasculogenesis after MI.

  5. Ang-(1-7) promotes the migration and invasion of human renal cell carcinoma cells via Mas-mediated AKT signaling pathway.

    Science.gov (United States)

    Zheng, Shuai; Yang, Ying; Song, Ran; Yang, Xiaomei; Liu, Hua; Ma, Qian; Yang, Longyan; Meng, Ran; Tao, Tao; Wang, Songlin; He, Junqi

    2015-05-01

    Ang-(1-7) is an active peptide component of renin-angiotensin system and endogenous ligand for Mas receptor. In the current study, we showed that Ang-(1-7) enhanced migratory and invasive abilities of renal cell carcinoma cells 786-O and Caki-1 by wound-healing, transwell migration and transwell invasion assays. Mas antagonist A779 pretreatment or shRNA-mediated Mas knockdown abolished the stimulatory effect of Ang-(1-7). Furthermore, Ang-(1-7)-stimulated AKT activation was inhibited by either A779 pretreatment or Mas knockdown. Blockage of AKT signaling by AKT inhibitor VIII inhibited Ang-(1-7)-induced migration and invasion in 786-O cells. Taken together, our results provided the first evidence for the pro-metastatic role of Ang-(1-7) in RCC, which may help to better understand the molecular mechanism underlying the progression of this tumor. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. The antifibrotic agent pirfenidone inhibits angiotensin II-induced cardiac hypertrophy in mice.

    Science.gov (United States)

    Yamazaki, Takanori; Yamashita, Naoto; Izumi, Yasukatsu; Nakamura, Yasuhiro; Shiota, Masayuki; Hanatani, Akihisa; Shimada, Kenei; Muro, Takashi; Iwao, Hiroshi; Yoshiyama, Minoru

    2012-01-01

    Pirfenidone (5-methyl-1-phenyl-2-[(1)H]-pyridone) is an effective drug for idiopathic interstitial pneumonia that can prevent and reverse tissue fibrosis in several organs. Therefore, we investigated whether pirfenidone has a potential role in preventing angiotensin II (Ang II)-induced cardiac hypertrophy. A cardiac hypertrophic mouse model was created using an Ang II infusion (200 ng kg(-1) min(-1)) in wild-type mice for 2 weeks. Mice were divided into the following three groups: a saline-infused (control) group, an Ang II infusion (vehicle) group and an Ang II infusion+pirfenidone-treated (PFD) group, which received pirfenidone (300 mg kg(-1) per day) by gastric gavage during the Ang II infusion. At 2 weeks, we assessed hemodynamics and cardiac function and investigated tissue fibrosis of the myocardium histologically and genetically. Blood pressure in the vehicle group was significantly increased compared to the control group. Although blood pressure was not different between the vehicle and PFD groups, heart weight was significantly decreased in the PFD group. Echocardiography revealed that left ventricular hypertrophy was significantly increased in the vehicle group vs. the control group. Interestingly, pirfenidone significantly inhibited this effect. Continuous infusion of Ang II increased the perivascular and interstitial tissue fibrosis, and pirfenidone inhibited these fibrotic changes. Pirfenidone also inhibited Ang II-induced hypertrophy. In the vehicle group, the mRNA expressions of atrial natriuretic peptide, brain natriuretic peptide and transforming growth factor-β1 were increased, which was significantly inhibited by pirfenidone. Furthermore, the expression of mineralocorticoid receptors was attenuated by pirfenidone. These results indicate that pirfenidone might be effective as an antifibrotic drug in the treatment of cardiac hypertrophy induced by hypertension.

  7. Inhibition of central angiotensin II enhances memory function and reduces oxidative stress status in rat hippocampus.

    Science.gov (United States)

    Bild, Walther; Hritcu, Lucian; Stefanescu, Cristinel; Ciobica, Alin

    2013-06-03

    While it is now well established that the independent brain renin-angiotensin system (RAS) has some important central functions besides the vascular ones, the relevance of its main bioactive peptide angiotensin II (Ang II) on the memory processes, as well as on oxidative stress status is not completely understood. The purpose of the present work was to evaluate the effects of central Ang II administration, as well as the effects of Ang II inhibition with either AT1 and AT 2 receptor specific blockers (losartan and PD-123177, respectively) or an angiotensin-converting enzyme (ACE) inhibitor (captopril). These effects were studied on the short-term memory (assessed through Y-maze) or long-term memory (as determined in passive avoidance) and on the oxidative stress status of the hippocampus. Our results demonstrate memory deficits induced by the administration of Ang II, as showed by the significant decrease of the spontaneous alternation in Y-maze (p=0.015) and latency-time in passive avoidance task (p=0.001) when compared to saline. On the other side, the administration of all the aforementioned Ang II blockers significantly improved the spontaneous alternation in Y-maze task, while losartan also increased the latency time as compared to saline in step-through passive avoidance (p=0.042). Also, increased oxidative stress status was induced in the hippocampus by the administration of Ang II, as demonstrated by increased levels of lipid peroxidation markers (malondialdehyde-MDA concentration) (p0.0001) vs. saline. Moreover, significant correlations were found between all of the memory related behavioral parameters and the main oxidative stress markers from the hippocampus, which is known for its implication in the processes of memory and also where RAS components are well expressed. This could be relevant for the complex interactions between Ang II, behavioral processes and neuronal oxidative stress, and could generate important therapeutic approaches. Copyright

  8. Heme oxygenase-1 gene expression modulates angiotensin II-induced increase in blood pressure.

    Science.gov (United States)

    Yang, Liming; Quan, Shuo; Nasjletti, Alberto; Laniado-Schwartzman, Michal; Abraham, Nader G

    2004-06-01

    The heme-heme oxygenase (HO) system has been implicated in the regulation of vascular reactivity and blood pressure. This study examines the notion that overexpression of HO decreases pressor responsiveness to angiotensin II (Ang II). Five-day-old Sprague-Dawley rats received an intraleft ventricular injection of approximately 5x10(9) cfu/mL of retroviruses containing human HO-1 sense (LSN-HHO-1), rat HO-1 antisense (LSN-RHO-1-AS), or control retrovirus (LXSN). Three months later, rats were instrumented with femoral arterial and venous catheters for mean arterial pressure (MAP) determination and Ang II administration, respectively. Rats injected with LSN-HHO-1, but not with LXSN, expressed human HO-1 mRNA and protein in several tissues. BP increased with administration of Ang II in rats expressing and not expressing human HO-1. However, the Ang II-induced pressor response (mm Hg) in LSN-HHO-1 rats (16+/-3, 27+/-3, and 38+/-3 at 0.5, 2, and 10 ng) was surpassed (PHHO-1 rats with the HO inhibitor tin mesoporphyrin (SnMP) enhanced (P<0.05) the Ang II-induced pressor response to a level not different from that observed in LXSN rats. Rats injected with LSN-RHO-1-AS showed a decrease in renal HO-1 protein expression and HO activity relative to control LXSN rats. Administration of Ang II (0.1 to 2 ng) caused small (4 to 5 mm Hg) but significant increases in MAP in rats injected with LSN-RHO-1-AS (P<0.05) compared with rats injected with LXSN. These data demonstrate that overexpression of HO-1 brings about a reduction in pressor responsiveness to Ang II, which is most likely due to increased generation of an HO-1 product, presumably CO, with the ability to inhibit vascular reactivity to constrictor stimuli.

  9. Platelet-derived growth factor receptor-β in myocyte was upregulated by angiotensin II

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    To observe the regulation of platelet-derived growth factor (PDGF) receptor-βin myocyte stimulated by angiotensin II (AngII) at both integrated and cellular levels and reveal the signal transduction mechanism in cell, two kidneys, one clip (2K1C) renal hypertension were performed by placing a sliver clip around the left renal artery. Blood pressure and the ratio of left ventricular weight to body weight were measured at 4 and 8 weeks after operation. The content of AngII in heart was detected by radioimmunology assay; the protein level of PDGF receptor-βin heart was measured by Western blot analysis. The alteration of PDGF receptor-βstimulated by AngII and several inhibitors was observed on cultured neonatal rat ventricular myocyte (NRVM). The content of AngII in heart of 2K1C renal hypertensive rat at 4 and 8 weeks after operation was increased. Compared with sham group, 4 and 8 weeks after operation, PDGF receptor-βin heart of 2K1C group was upregulated by 100.3% and 127.1% (P < 0.05), respectively. This upregulation could be inhibited by captopril. For cultured myocyte, PDGF receptor-βwas increased by 47.1% after being stimulated by AngII and this upregulation could be inhibited by losartan which was an inhibitor of AT1 receptor. PLC inhibitor (U73122) and MEK inhibitor (PD98059) could partly inhibit PDGF receptor-βupregulation induced by AngII. These results suggested that AngII could upregulate PDGF receptor-βin myocyte by its AT1 receptor and this effect was at least partly dependent on PLC and extracellular signal-regulated kinase (ERK).

  10. Dimethylarginine dimethylaminohydrolase-1 mediates inhibitory effect of interleukin-10 on angiotensin II-induced hypertensive effects in vascular smooth muscle cells of spontaneously hypertensive rats.

    Science.gov (United States)

    Kim, Hye Young; Kim, Hee Sun

    2016-01-01

    In hypertension studies, anti-inflammatory cytokine interleukin-10 (IL-10) has been shown to prevent angiotensin II (Ang II)-induced vasoconstriction and regulate vascular function by down-regulating pro-inflammatory cytokine and superoxide production in vascular cells. However, little is known about the mechanism behind the down-regulatory effect of IL-10 on Ang II-induced hypertensive mediators. In this study, we demonstrated the effects of IL-10 on expression of dimethylarginine dimethylaminohydrolase (DDAH)-1, a regulator of NO bioavailability, as well as the down-regulatory mechanism of action of IL-10 in relation to Ang II-induced hypertensive mediator expression and cell proliferation in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR). IL-10 increased DDAH-1 but not DDAH-2 expression and increased DDAH activity. Additionally, IL-10 attenuated Ang II-induced DDAH-1 inhibition in SHR VSMCs. Increased DDAH activity due to IL-10 was mediated mainly through Ang II subtype II receptor (AT2 R) and AMP-activated protein kinase (AMPK) activation. DDAH-1 induced by IL-10 partially mediated the inhibitory action of IL-10 on Ang II-induced 12-lipoxygenase (LO) and endothelin (ET)-1 expression in SHR VSMCs. In addition, the inhibitory effect of IL-10 on proliferation of Ang II-induced VSMCs was mediated partially via DDAH-1 activity. These results suggest that DDAH-1 plays a potentially important role in the anti-hypertensive activity of IL-10 during Ang II-induced hypertension.

  11. Spatial dynamics in a predator-prey model with Beddington-DeAngelis functional response.

    Science.gov (United States)

    Zhang, Xiao-Chong; Sun, Gui-Quan; Jin, Zhen

    2012-02-01

    In this paper spatial dynamics of the Beddington-DeAngelis predator-prey model is investigated. We analyze the linear stability and obtain the condition of Turing instability of this model. Moreover, we deduce the amplitude equations and determine the stability of different patterns. In Turing space, we found that this model has coexistence of H(0) hexagon patterns and stripe patterns, H(π) hexagon patterns, and H(0) hexagon patterns. To better describe the real ecosystem, we consider the ecosystem as an open system and take the environmental noise into account. It is found that noise can decrease the number of the patterns and make the patterns more regular. What is more, noise can induce two kinds of typical pattern transitions. One is from the H(π) hexagon patterns to the regular stripe patterns, and the other is from the coexistence of H(0) hexagon patterns and stripe patterns to the regular stripe patterns. The obtained results enrich the finding in the Beddington-DeAngelis predator-prey model well.

  12. Angiotensin II-induced Akt activation through the epidermal growth factor receptor in vascular smooth muscle cells is mediated by phospholipid metabolites derived by activation of phospholipase D.

    Science.gov (United States)

    Li, Fang; Malik, Kafait U

    2005-03-01

    Angiotensin II (Ang II) activates cytosolic Ca(2+)-dependent phospholipase A(2) (cPLA(2)), phospholipase D (PLD), p38 mitogen-activated protein kinase (MAPK), epidermal growth factor receptor (EGFR) and Akt in vascular smooth muscle cells (VSMC). This study was conducted to investigate the relationship between Akt activation by Ang II and other signaling molecules in rat VSMC. Ang II-induced Akt phosphorylation was significantly reduced by the PLD inhibitor 1-butanol, but not by its inactive analog 2-butanol, and by brefeldin A, an inhibitor of the PLD cofactor ADP-ribosylation factor, and in cells infected with retrovirus containing PLD(2) siRNA or transfected with PLD(2) antisense but not control LacZ or sense oligonucleotide. Diacylglycerol kinase inhibitor II diminished Ang II-induced and diC8-phosphatidic acid (PA)-increased Akt phosphorylation, suggesting that PLD-dependent Akt activation is mediated by PA. Ang II-induced EGFR phosphorylation was inhibited by 1-butanol and PLD(2) siRNA and also by cPLA(2) siRNA. In addition, the inhibitor of arachidonic acid (AA) metabolism 5,8,11,14-eicosatetraynoic acid (ETYA) reduced both Ang II- and AA-induced EGFR transactivation. Furthermore, ETYA, cPLA(2) antisense, and cPLA(2) siRNA attenuated Ang II-elicited PLD activation. p38 MAPK inhibitor SB202190 [4-(4-flurophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole] reduced PLD activity and EGFR and Akt phosphorylation elicited by Ang II. Pyrrolidine-1, a cPLA(2) inhibitor, and cPLA(2) siRNA decreased p38 MAPK activity. These data indicate that Ang II-stimulated Akt activity is mediated by cPLA(2)-dependent, p38 MAPK regulated PLD(2) activation and EGFR transactivation. We propose the following scheme of the sequence of events leading to activation of Akt in VSMC by Ang II: Ang II-->cPLA(2)-->AA-->p38 MAPK-->PLD(2)-->PA-->EGFR-->Akt.

  13. Coexpression of ang1 and tie2 in odontoblasts of mouse developing and mature teeth-a new insight into dentinogenesis.

    Science.gov (United States)

    Nakajima, Kazunori; Shibata, Yasuaki; Hishikawa, Yoshitaka; Suematsu, Takashi; Mori, Masako; Fukuhara, Shigetomo; Koji, Takehiko; Sawase, Takashi; Ikeda, Tohru

    2014-02-27

    Angiopoietin-1 regulates vascular angiogenesis and stabilization, and is reported to promote bone formation by facilitating angiogenesis. To estimate the role of Ang1 in odontogenesis, we explored the distribution of Ang1 and the receptor, Tie2 in the mouse developing and mature first molar of the mandible. At embryonic day 18, when differentiation of odontoblasts begins, immunosignals for Ang1 were intensely detected in the basement membrane and the distal side, which faced the basement membrane of odontoblasts. In situ hybridization revealed that Ang1 was expressed in odontoblasts and ameloblasts facing the basement membrane. Tie2 was localized in the distal side of odontoblasts. After birth, Ang1 was detected in the predentin, whereas both Ang1 and Tie2 were colocalized in odontoblasts and odontoblast processes. These distributions were retained up to 8 weeks. In contrast to odontoblasts, ameloblasts, cementoblasts and osteoblasts expressed Ang1 but did not express Tie2. Colocalization of Ang1 and Tie2 in odontoblasts and selective expression of Tie2 in odontoblasts among cells responsible for calcified tissue formation suggested the involvement of autocrine signals of Ang1-Tie2 in dentinogenesis.

  14. Characterization of a novel form of angiopoietin-2 (Ang-2B) and expression of VEGF and angiopoietin-2 during chicken testicular development and regression.

    Science.gov (United States)

    Mezquita, J; Mezquita, B; Pau, M; Mezquita, C

    1999-07-05

    The complex process of angiogenesis is controlled by the vascular endothelial growth factor (VEGF) and its receptors and by the recently isolated angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) that signal through the transmembrane endothelial receptor tyrosine kinase Tie2. We report here the characterization of a novel form of Ang-2 (Ang-2B) with a truncated amino-terminal domain resulting from an alternative splicing of the gene. While previous reports have found the expression of Ang-2 limited to the embryo, female reproductive organs, and tumor tissues, we have observed striking changes in Ang-2 expression during chicken testicular development and regression. The expression of Ang-2 and VEGF is abundant in prepuberal testis and low in quiescent adult testis. Testicular regression is accompanied by high expression of Ang-2 and very low expression of VEGF. These observations are in accordance with the proposal that Ang-2 induces angiogenesis in the presence of VEGF and vascular regression in its absence. Copyright 1999 Academic Press.

  15. HEMODYNAMIC AND STRUCTURAL MODIFICATIONS IN CONTINUOUS INFUSION WITH ANGIOTENSIN. II. AN EXPERIMENTAL STUDY

    Directory of Open Access Journals (Sweden)

    Minela Aida Maranduca

    2011-09-01

    Full Text Available The renin-angiotensin-aldosterone system (RAAS is a hormonal system which contributes to the regulation of both arterial pressure and extra cellular fluids volume. The increase of RAAS, especially at angiotensin II (Ang II level, affects the target organs and increases the risk of cardio-vascular issues, by increasing arterial pressure and through the direct effect of Ang II upon the vascular endothelium and the renal and cardiac tissue. Ang II reduces the renal capacity of sodium excretion and initiates a set of events which increase arterial pressure. Increase of arterial pressure is necessary for re-establishing sodium excretion, being realized by the pressure-natriuresis relationship. Arterial hypertension affects the target organs (heart, kidneys and leads to a vicious circle which contributes to maintaining a high arterial pressure. Materials and Method: Male Wistar rats subjected on a normal diet, received either a sham operation (n=9 or continuous angiotensin II (Ang II infusion (300ng/kgc/ min subcutaneously, via mini pumps. Water ingestion and systolic blood pressure were measured for 14 days, after which the animals were sacrificed under anesthesia with ketamin, and the xylasin body weight, water ingestion, heart mass, right and left ventricular mass, right and left kidney mass were measured. Results: After 14 days of Ang II infusion, bodily weight decreased, systolic blood pressure increased, heart and left ventricular mass indexed to body weight were significantly enhanced compared with the sham group, and kidneys mass indexed to body weight was similar in the two groups.

  16. Angiotensin II reduces cardiac AdipoR1 expression through AT1 receptor/ROS/ERK1/2/c-Myc pathway.

    Directory of Open Access Journals (Sweden)

    Li Li

    Full Text Available Adiponectin, an abundant adipose tissue-derived protein, exerts protective effect against cardiovascular disease. Adiponectin receptors (AdipoR1 and AdipoR2 mediate the beneficial effects of adiponectin on the cardiovascular system. However, the alteration of AdipoRs in cardiac remodeling is not fully elucidated. Here, we investigated the effect of angiotensin II (AngII on cardiac AdipoRs expression and explored the possible molecular mechanism. AngII infusion into rats induced cardiac hypertrophy, reduced AdipoR1 but not AdipoR2 expression, and attenuated the phosphorylations of adenosine monophosphate-activated protein kinase and acetyl coenzyme A carboxylase, and those effects were all reversed by losartan, an AngII type 1 (AT1 receptor blocker. AngII reduced expression of AdipoR1 mRNA and protein in cultured neonatal rat cardiomyocytes, which was abolished by losartan, but not by PD123319, an AT2 receptor antagonist. The antioxidants including reactive oxygen species (ROS scavenger NAC, NADPH oxidase inhibitor apocynin, Nox2 inhibitor peptide gp91 ds-tat, and mitochondrial electron transport chain complex I inhibitor rotenone attenuated AngII-induced production of ROS and phosphorylation of extracellular signal-regulated kinase (ERK 1/2. AngII-reduced AdipoR1 expression was reversed by pretreatment with NAC, apocynin, gp91 ds-tat, rotenone, and an ERK1/2 inhibitor PD98059. Chromatin immunoprecipitation assay demonstrated that AngII provoked the recruitment of c-Myc onto the promoter region of AdipoR1, which was attenuated by PD98059. Moreover, AngII-induced DNA binding activity of c-Myc was inhibited by losartan, NAC, apocynin, gp91 ds-tat, rotenone, and PD98059. c-Myc small interfering RNA abolished the inhibitory effect of AngII on AdipoR1 expression. Our results suggest that AngII inhibits cardiac AdipoR1 expression in vivo and in vitro and AT1 receptor/ROS/ERK1/2/c-Myc pathway is required for the downregulation of AdipoR1 induced by AngII.

  17. NF-κB-Dependent Upregulation of NCX1 Induced by Angiotensin II Contributes to Calcium Influx in Rat Aortic Smooth Muscle Cells.

    Science.gov (United States)

    Liu, Bei; Yang, Lixia; Zhang, Bin; Kuang, Chenwei; Huang, Shiliang; Guo, Ruiwei

    2016-11-01

    The reverse mode of Na(+)/Ca(2+) exchanger (NCX) 1 can transport Ca(2+) into cells and is involved in the contractile regulation of vascular smooth muscle cells (VSMCs) and the development of hypertension. We hypothesized that upregulation of NCX1 expression induced by angiotensin II (Ang II) could be dependent on activation of nuclear factor-kappa B (NF-κB) and contributes to Ca(2+) influx in VSMCs. An osmotic minipump was implanted for administration of Ang II in Sprague-Dawley rats, and blood pressure, as well as NCX1 expression, in the aorta was measured. VSMCs were cultured to verify that Ang II-upregulated NCX1 expression is dependent on activation of NF-κB and contributes to Ca(2+) influx. Ang II-upregulated NCX1 expression in rat aortas (2.1-fold at day 6) and VSMCs (1.7-fold at 24 hours) and NF-κB knockdown and p38 mitogen-activated protein kinase (MAPK) inhibitor resulted in 2.1- and 2.0-fold decreases in Ang II-upregulated NCX1 expression in VSMCs. KB-R7943 (an inhibitor of NCX1 reversal) and NCX1 knockdown decreased Ang II-induced Ca(2+) influx 1.4- and 1.3- fold, respectively. KB-R7943 and removal of extracellular Na(+) decreased Ang II-initiated store depletion-mediated Ca(2+) entry by 1.5- and 1.3-fold, respectively. Moreover, NF-κB knockdown and use of a p38 MAPK inhibitor resulted in about 1.3-fold decreases in Ang II-induced Ca(2+) influx through activation of reverse-mode NCX1. Ang II upregulates NCX1 expression through p38 MAPK and NF-κB pathways, and reverse-mode NCX1 plays an important part in Ang II-induced Ca(2+) influx in VSMCs, which may be associated with Ang II-initiated store-operated channel entry. Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  18. The effect of serum angiotensin II and angiotensin II type 1 receptor ...

    African Journals Online (AJOL)

    Ehab

    2012-06-18

    Jun 18, 2012 ... frequency of AT1 receptor CC genotype among a group of Egyptian patients with ..... reported in SLE patients.2,3,15 ACE catalyses the formation of Ang II .... Bombardier C, Gladman DD, Urowitz MB, Caron. D, Chang CH.

  19. Adiponectin attenuates angiotensin II-induced vascular smooth muscle cell remodeling through nitric oxide and the RhoA/ROCK pathway.

    Directory of Open Access Journals (Sweden)

    Wared eNour-Eldine

    2016-04-01

    Full Text Available INTRODUCTION: Adiponectin (APN, an adipocytokine, exerts protective effects on cardiac remodeling, while angiotensin II (Ang II induces hypertension and vascular remodeling. The potential protective role of APN on the vasculature during hypertension has not been fully elucidated yet. Here, we evaluate the molecular mechanisms of the protective role of APN in the physiological response of the vascular wall to Ang II.METHODS AND RESULTS: Rat aortic tissues were used to investigate the effect of APN on Ang II-induced vascular remodeling and hypertrophy. We investigated whether nitric oxide (NO, the RhoA/ROCK pathway, actin cytoskeleton remodeling, and reactive oxygen species (ROS mediate the anti-hypertrophic effect of APN. Ang II-induced protein synthesis was attenuated by pre-treatment with APN, NO donor (SNAP, or cGMP. The hypertrophic response to Ang II was associated with a significant increase in RhoA activation and vascular force production, which were prevented by APN and SNAP. NO was also associated with inhibition of Ang II-induced phosphorylation of cofilin. In addition, immunohistochemistry revealed that 24 hr Ang II treatment increased the F- to G-actin ratio, an effect that was inhibited by SNAP. Ang II-induced ROS formation and upregulation of p22phox mRNA expression were inhibited by APN and NO. Both compounds failed to inhibit Nox1 and p47phox expression. CONCLUSIONS: Our results suggest that the anti-hypertrophic effects of APN are due, in part, to NO-dependent inhibition of the RhoA/ROCK pathway and ROS formation.

  20. Metformin inhibits angiotensin II-induced differentiation of cardiac fibroblasts into myofibroblasts.

    Science.gov (United States)

    Bai, Jian; Zhang, Na; Hua, Ying; Wang, Bingjian; Ling, Lin; Ferro, Albert; Xu, Biao

    2013-01-01

    Differentiation of cardiac fibroblasts into myofibroblasts is a critical event in the progression of cardiac fibrosis that leads to pathological cardiac remodeling. Metformin, an antidiabetic agent, exhibits a number of cardioprotective properties. However, much less is known regarding the effect of metformin on cardiac fibroblast differentiation. Thus, in the present study, we examined the effect of metformin on angiotensin (Ang) II-induced differentiation of cardiac fibroblasts into myofibroblasts and its underlying mechanism. Adult rat cardiac fibroblasts were stimulated with Ang II (100 nM) in the presence or absence of metformin (10-200 µM). Ang II stimulation induced the differentiation of cardiac fibroblasts into myofibroblasts, as indicated by increased expression of α-smooth muscle actin (α-SMA) and collagen types I and III, and this effect of Ang II was inhibited by pretreatment of cardiac fibroblasts with metformin. Metformin also decreased Ang II-induced reactive oxygen species (ROS) generation in cardiac fibroblasts via inhibiting the activation of the PKC-NADPH oxidase pathway. Further experiments using PKC inhibitor calphostin C and NADPH oxidase inhibitor apocynin confirmed that inhibition of the PKC-NADPH oxidase pathway markedly attenuated Ang II-induced ROS generation and myofibroblast differentiation. These data indicate that metformin inhibits Ang II-induced myofibroblast differentiation by suppressing ROS generation via the inhibition of the PKC-NADPH oxidase pathway in adult rat cardiac fibroblasts. Our results provide new mechanistic insights regarding the cardioprotective effects of metformin and provide an efficient therapeutic strategy to attenuate cardiac fibrosis.

  1. Metformin inhibits angiotensin II-induced differentiation of cardiac fibroblasts into myofibroblasts.

    Directory of Open Access Journals (Sweden)

    Jian Bai

    Full Text Available Differentiation of cardiac fibroblasts into myofibroblasts is a critical event in the progression of cardiac fibrosis that leads to pathological cardiac remodeling. Metformin, an antidiabetic agent, exhibits a number of cardioprotective properties. However, much less is known regarding the effect of metformin on cardiac fibroblast differentiation. Thus, in the present study, we examined the effect of metformin on angiotensin (Ang II-induced differentiation of cardiac fibroblasts into myofibroblasts and its underlying mechanism. Adult rat cardiac fibroblasts were stimulated with Ang II (100 nM in the presence or absence of metformin (10-200 µM. Ang II stimulation induced the differentiation of cardiac fibroblasts into myofibroblasts, as indicated by increased expression of α-smooth muscle actin (α-SMA and collagen types I and III, and this effect of Ang II was inhibited by pretreatment of cardiac fibroblasts with metformin. Metformin also decreased Ang II-induced reactive oxygen species (ROS generation in cardiac fibroblasts via inhibiting the activation of the PKC-NADPH oxidase pathway. Further experiments using PKC inhibitor calphostin C and NADPH oxidase inhibitor apocynin confirmed that inhibition of the PKC-NADPH oxidase pathway markedly attenuated Ang II-induced ROS generation and myofibroblast differentiation. These data indicate that metformin inhibits Ang II-induced myofibroblast differentiation by suppressing ROS generation via the inhibition of the PKC-NADPH oxidase pathway in adult rat cardiac fibroblasts. Our results provide new mechanistic insights regarding the cardioprotective effects of metformin and provide an efficient therapeutic strategy to attenuate cardiac fibrosis.

  2. Diagnostic Utility of ANG in Coronary Heart Disease Complicating Chronic Heart Failure: A Cross-Sectional Study

    Directory of Open Access Journals (Sweden)

    Peng Yu

    2016-01-01

    Full Text Available Angiogenin (ANG has been shown to be elevated in several cardiovascular diseases. To detect its levels and diagnostic capacity in coronary heart disease (CHD patients complicating chronic heart failure (CHF, we performed this cross-sectional study and enrolled 616 CHD patients and 53 healthy controls. According to complicating CHF or not, the patients were divided into CHF group (n=203 and CHD disease controls (n=413, in which the CHF group was subdivided as heart failure with reduced ejection fraction (HFrEF group or heart failure with preserved ejection fraction (HFpEF group on the basis of left ventricular ejection fraction (LVEF, or as different NYHA class group. Their plasma ANG levels were detected using enzyme-linked immunosorbent assay (ELISA. Plasma ANG was 342.8 (IQR [273.9,432.9], 304.5 (IQR [254.0,370.5], and 279.7 (IQR [214.4,344.0] ng/mL in the CHF group, CHD disease controls, and healthy controls, respectively, significantly higher in the CHF group compared with the others. Furthermore, among CHF group, ANG is dramatically higher in the HFrEF patients compared with the HFpEF patients. As for the diagnostic capacity of ANG, the area under the receiver operating characteristic curve was 0.71 (95% CI 0.63–0.78. We concluded that plasma ANG is elevated in CHD complicating CHF patients and may be a moderate discriminator of CHF from CHD or the healthy.

  3. Diagnostic Utility of ANG in Coronary Heart Disease Complicating Chronic Heart Failure: A Cross-Sectional Study

    Science.gov (United States)

    Liu, Ming; Yang, Xue; Yu, Ying; Zhao, Ji; Zhang, Lei; Tong, Rui; Zou, Yunzeng; Ge, Junbo

    2016-01-01

    Angiogenin (ANG) has been shown to be elevated in several cardiovascular diseases. To detect its levels and diagnostic capacity in coronary heart disease (CHD) patients complicating chronic heart failure (CHF), we performed this cross-sectional study and enrolled 616 CHD patients and 53 healthy controls. According to complicating CHF or not, the patients were divided into CHF group (n = 203) and CHD disease controls (n = 413), in which the CHF group was subdivided as heart failure with reduced ejection fraction (HFrEF) group or heart failure with preserved ejection fraction (HFpEF) group on the basis of left ventricular ejection fraction (LVEF), or as different NYHA class group. Their plasma ANG levels were detected using enzyme-linked immunosorbent assay (ELISA). Plasma ANG was 342.8 (IQR [273.9,432.9]), 304.5 (IQR [254.0,370.5]), and 279.7 (IQR [214.4,344.0]) ng/mL in the CHF group, CHD disease controls, and healthy controls, respectively, significantly higher in the CHF group compared with the others. Furthermore, among CHF group, ANG is dramatically higher in the HFrEF patients compared with the HFpEF patients. As for the diagnostic capacity of ANG, the area under the receiver operating characteristic curve was 0.71 (95% CI 0.63–0.78). We concluded that plasma ANG is elevated in CHD complicating CHF patients and may be a moderate discriminator of CHF from CHD or the healthy. PMID:27872509

  4. Mechanisms of HNO and NO production from Angeli's salt: density functional and CBS-QB3 theory predictions.

    Science.gov (United States)

    Dutton, Andrew S; Fukuto, Jon M; Houk, K N

    2004-03-31

    The mechanism of decomposition of Angeli's salt, Na(2)N(2)O(3), was explored with B3LYP and CBS-QB3 computational methods. Angeli's salt produces both nitroxyl (HNO) and nitric oxide (NO), depending upon the pH of the solution. These calculations show that protonation on N(2), while less favorable than O protonation, leads spontaneously to HNO production, while diprotonation at O(3) leads to NO generation. K(a) values for protonation at different centers and rate constants have been found which reproduce experimental data satisfactorily.

  5. Effect of Taohong Siwu decoction on angiogenesis of medicine-induced incomplete-abortion in early pregnancy rats and expressions of Ang-1, Ang-2 and Tie-2%桃红四物汤对药物致不完全流产早孕大鼠的血管生成及Ang-1,Ang-2,Tie-2表达的影响

    Institute of Scientific and Technical Information of China (English)

    梁杰; 尹登科; 李白坤; 刘竹青; 李珊珊; 陈孟夏; 王晓宇; 彭代银

    2013-01-01

    目的:观察桃红四物汤对药物致早孕大鼠不完全流产模型的大鼠子宫微血管密度,血清中促血管生成素1(Ang-1)和促血管生成素2(Ang-2)含量及子宫组织中酪氨酸激酶受体(Tie-2)表达的影响.方法:SD早孕大鼠采用灌胃米索前列醇(100 μg·kg-1)和米非司酮(8.3mg·kg-1)造成不完全流产大鼠模型,随机分为模型组(等容量蒸馏水)、阳性药物益母草颗粒组(4.3 g· kg-1)、桃红四物汤高、中、低剂量组(18.0,9.0,4.5 g·kg-1),受孕大鼠作为正常对照组(等容量蒸馏水).连续灌胃7d后腹主动脉取血及大鼠子宫组织,采用酶联免疫吸附法(ELISA)检测血清中Ang-1和Ang-2的含量,采用免疫组化检测子宫组织的Tie-2及微血管密度(MVD)CD34的表达情况.结果:桃红四物汤显著增加药物流产后大鼠子宫的血管微密度,显著升高血清中Ang-1,Ang-2的含量,并使子宫组织中Tie-2的表达显著增加.结论:桃红四物汤有明显的促进不完全流产早孕大鼠子宫血管新生作用,作用机制可能与调节血清中Ang-1和Ang-2的浓度及子宫组织中Tie-2的表达相关.

  6. Angiotensin II directly stimulates ENaC activity in the cortical collecting duct via AT(1) receptors.

    Science.gov (United States)

    Peti-Peterdi, János; Warnock, David G; Bell, P Darwin

    2002-05-01

    Angiotensin II (AngII) helps to regulate overall renal tubular reabsorption of salt and water, yet its effects in the distal nephron have not been well studied. The purpose of these studies was to determine whether AngII stimulates luminal Na(+) transport in the cortical collecting duct (CCD). Intracellular Na(+) concentration ([Na(+)](i)), as a reflection of Na(+) transport across the apical membrane, was measured with fluorescence microscopy using sodium-binding benzofuran isophthalate (SBFI) in isolated, perfused CCD segments dissected from rabbit kidneys. Control [Na(+)](i), during perfusion with 25 mM NaCl and a Na(+)-free solution in the bath containing the Na(+)-ionophore monensin (10 microM, to eliminate basolateral membrane Na(+) transport) averaged 19.3 +/- 5.2 mM (n = 16). Increasing luminal [NaCl] to 150 mM elevated [Na(+)](i) by 9.87 +/- 1.5 mM (n = 7; P < 0.05). AngII (10(-9) M) added to the lumen significantly elevated baseline [Na(+)](i) by 6.3 +/- 1.0 mM and increased the magnitude (Delta = 25.2 +/- 3.7 mM) and initial rate ( approximately 5 fold) of change in [Na(+)](i) to increased luminal [NaCl]. AngII when added to the bath had similar stimulatory effects; however, AngII was much more effective from the lumen. Thus, AngII significantly increased the apical entry of Na(+) in the CCD. To determine if this apical entry step occurred via the epithelial Na(+) channel (ENaC), studies were performed using the specific ENaC blocker, benzamil hydrochloride (10(-6) M). When added to the perfusate, benzamil almost completely inhibited the elevations in [Na(+)](i) to increased luminal [NaCl] in both the presence and absence of AngII. These results suggest that AngII directly stimulates Na(+) channel activity in the CCD. AT(1) receptor blockade with candesartan or losartan (10(-6) M) prevented the stimulatory effects of AngII. Regulation of ENaC activity by AngII may play an important role in distal Na(+) reabsorption in health and disease.

  7. 2-Methoxyestradiol Reduces Angiotensin II-Induced Hypertension and Renal Dysfunction in Ovariectomized Female and Intact Male Mice.

    Science.gov (United States)

    Pingili, Ajeeth K; Davidge, Karen N; Thirunavukkarasu, Shyamala; Khan, Nayaab S; Katsurada, Akemi; Majid, Dewan S A; Gonzalez, Frank J; Navar, L Gabriel; Malik, Kafait U

    2017-06-01

    Cytochrome P450 1B1 protects against angiotensin II (Ang II)-induced hypertension and associated cardiovascular changes in female mice, most likely via production of 2-methoxyestradiol. This study was conducted to determine whether 2-methoxyestradiol ameliorates Ang II-induced hypertension, renal dysfunction, and end-organ damage in intact Cyp1b1(-/-), ovariectomized female, and Cyp1b1(+/+) male mice. Ang II or vehicle was infused for 2 weeks and administered concurrently with 2-methoxyestradiol. Mice were placed in metabolic cages on day 12 of Ang II infusion for urine collection for 24 hours. 2-Methoxyestradiol reduced Ang II-induced increases in systolic blood pressure, water consumption, urine output, and proteinuria in intact female Cyp1b1(-/-) and ovariectomized mice. 2-Methoxyestradiol also reduced Ang II-induced increase in blood pressure, water intake, urine output, and proteinuria in Cyp1b1(+/+) male mice. Treatment with 2-methoxyestradiol attenuated Ang II-induced end-organ damage in intact Cyp1b1(-/-) and ovariectomized Cyp1b1(+/+) and Cyp1b1(-/-) female mice and Cyp1b1(+/+) male mice. 2-Methoxyestradiol mitigated Ang II-induced increase in urinary excretion of angiotensinogen in intact Cyp1b1(-/-) and ovariectomized Cyp1b1(+/+) and Cyp1b1(-/-) female mice but not in Cyp1b1(+/+) male mice. The G protein-coupled estrogen receptor 1 antagonist G-15 failed to alter Ang II-induced increases in blood pressure and renal function in Cyp1b1(+/+) female mice. These data suggest that 2-methoxyestradiol reduces Ang II-induced hypertension and associated end-organ damage in intact Cyp1b1(-/-), ovariectomized Cyp1b1(+/+) and Cyp1b1(-/-) female mice, and Cyp1b1(+/+) male mice independent of G protein-coupled estrogen receptor 1. Therefore, 2-methoxyestradiol could serve as a therapeutic agent for treating hypertension and associated pathogenesis in postmenopausal females, and in males. © 2017 American Heart Association, Inc.

  8. c-Src Inhibition Improves Cardiovascular Function but not Remodeling or Fibrosis in Angiotensin II-Induced Hypertension.

    Science.gov (United States)

    Callera, Glaucia E; Antunes, Tayze T; He, Ying; Montezano, Augusto C; Yogi, Alvaro; Savoia, Carmine; Touyz, Rhian M

    2016-11-01

    c-Src plays an important role in angiotensin II (Ang II) signaling. Whether this member of the Src family kinases is involved in the development of Ang II-induced hypertension and associated cardiovascular damage in vivo remains unknown. Here, we studied Ang II-infused (400 ng/kg/min) mice in which c-Src was partially deleted (c-Src(+/-)) and in wild-type (WT, c-Src(+/+)) mice treated with a c-Src inhibitor (CGP077675; 25 mg/kg/d). Ang II increased blood pressure and induced endothelial dysfunction in WT mice, responses that were ameliorated in c-Src(+/-) and CGP077675-treated mice. Vascular wall thickness and cross-sectional area were similarly increased by Ang II in WT and c-Src(+/-) mice. CGP077675 further increased cross-sectional area in hypertensive mice. Cardiac dysfunction (ejection fraction and fractional shortening) in Ang II-infused WT mice was normalized in c-Src(+/-) mice. Increased oxidative stress (plasma thiobarbituric acid-reactive substances, hydrogen peroxide, and vascular superoxide generation) in Ang II-infused WT mice was attenuated in c-Src-deficient and CGP077675-treated mice. Hyperactivation of vascular c-Src, ERK1/2 (extracellular signal-regulated kinase 1/2), and JNK (c-Jun N-terminal kinase) in hypertensive mice was normalized in CGP077675-treated and c-Src(+/-) mice. Vascular fibronectin was increased by Ang II in all groups and further augmented by CGP077675. Cardiac fibrosis and inflammation induced by Ang II were amplified in c-Src(+/-) and CGP-treated mice. Our data indicate that although c-Src downregulation attenuates development of hypertension, improves endothelial and cardiac function, reduces oxidative stress, and normalizes vascular signaling, it has little beneficial effect on fibrosis. These findings suggest a divergent role for c-Src in Ang II-dependent hypertension, where c-Src may be more important in regulating redox-sensitive cardiac and vascular function than fibrosis and remodeling. © 2016 American Heart Association

  9. Exogenous L-Arginine Attenuates the Effects of Angiotensin II on Renal Hemodynamics and the Pressure Natriuresis-Diuresis Relationship

    Science.gov (United States)

    Das, Satarupa; Mattson, David L.

    2014-01-01

    SUMMARY Administration of exogenous L-Arginine (L-Arg) attenuates Angiotensin II (AngII)-mediated hypertension and kidney disease in rats. The present study assessed renal hemodynamics and pressure-diuresis-natriuresis in anesthetized rats infused with vehicle, AngII (20 ng/kg/min, iv) or AngII + L-Arg (300 µg/kg/min, iv). Increasing renal perfusion pressure (RPP) from approximately 100 to 140 mmHg resulted in a 9–10 fold increase in urine flow and sodium excretion rate in control animals. In comparison, AngII infusion significantly reduced renal blood flow (RBF) and glomerular filtration rate (GFR) by 40–42% and blunted the pressure-dependent increase in urine flow and sodium excretion rate by 54–58% at elevated RPP. Supplementation of L-Arg reversed the vasoconstrictor effects of AngII and restored pressure-dependent diuresis to levels not significantly different from control rats. Experiments in isolated aortic rings were performed to assess L-Arg effects on the vasculature. Dose-dependent contraction to AngII (10−10M to 10−7M) was observed with a maximal force equal to 27±3% of the response to 10−5M phenylephrine. Contraction to 10−7M AngII was blunted by 75±3% with 10−4M L-Arg. The influence of L-Arg to blunt AngII mediated contraction was eliminated by endothelial denudation or incubation with nitric oxide synthase inhibitors. Moreover, the addition of 10−3M cationic or neutral amino acids, which compete with L-Arg for cellular uptake, blocked the effect of L-Arg. Anionic amino acids did not influence the effects of L-Arg on AngII-mediated contraction. These studies indicate that L-Arg blunts AngII-mediated vascular contraction by an endothelial- and NOS-dependent mechanism involving cellular uptake of L-Arg. PMID:24472006

  10. Exogenous L-arginine attenuates the effects of angiotensin II on renal hemodynamics and the pressure natriuresis-diuresis relationship.

    Science.gov (United States)

    Das, Satarupa; Mattson, David L

    2014-04-01

    Administration of exogenous L-arginine (L-Arg) attenuates angiotensin-II (AngII)-mediated hypertension and kidney disease in rats. The present study assessed renal hemodynamics and pressure diuresis-natriuresis in anaesthetized rats infused with vehicle, AngII (20 ng/kg per min i.v.) or AngII + L-Arg (300 μg/kg per min i.v.). Experiments in isolated aortic rings were carried out to assess L-Arg effects on the vasculature. Increasing renal perfusion pressure (RPP) from ~100 to 140 mmHg resulted in a nine- to tenfold increase in urine flow and sodium excretion rate in control animals. In comparison, AngII infusion significantly reduced renal blood flow (RBF) and glomerular filtration rate (GFR) by 40-42%, and blunted the pressure-dependent increase in urine flow and sodium excretion rate by 54-58% at elevated RPP. Supplementation of L-Arg reversed the vasoconstrictor effects of AngII and restored pressure-dependent diuresis to levels not significantly different from control rats. Dose-dependent contraction to AngII (10(-10) mol/L to 10(-7) mol/L) was observed with a maximal force equal to 27 ± 3% of the response to 10(-5) mol/L phenylephrine. Contraction to 10(-7) mol/L AngII was blunted by 75 ± 3% with 10(-4) mol/L L-Arg. The influence of L-Arg to blunt AngII-mediated contraction was eliminated by endothelial denudation or incubation with nitric oxide synthase inhibitors. Furthermore, the addition of 10(-3) mol/L cationic or neutral amino acids, which compete with L-Arg for cellular uptake, blocked the effect of L-Arg. Anionic amino acids did not influence the effects of L-Arg on AngII-mediated contraction. These studies show that L-Arg blunts AngII-mediated vascular contraction by an endothelial- and nitric oxide synthase-dependent mechanism involving cellular uptake of L-Arg.

  11. Estrogen receptor-alpha mediates estrogen protection from angiotensin II-induced hypertension in conscious female mice.

    Science.gov (United States)

    Xue, Baojian; Pamidimukkala, Jaya; Lubahn, Dennis B; Hay, Meredith

    2007-04-01

    It has been shown that the female sex hormones have a protective role in the development of angiotensin II (ANG II)-induced hypertension. The present study tested the hypotheses that 1) the estrogen receptor-alpha (ERalpha) is involved in the protective effects of estrogen against ANG II-induced hypertension and 2) central ERs are involved. Blood pressure (BP) was measured in female mice with the use of telemetry implants. ANG II (800 ng.kg(-1).min(-1)) was administered subcutaneously via an osmotic pump. Baseline BP in the intact, ovariectomized (OVX) wild-type (WT) and ERalpha knockout (ERalphaKO) mice was similar; however, the increase in BP induced by ANG II was greater in OVX WT (23.0 +/- 1.0 mmHg) and ERalphaKO mice (23.8 +/- 2.5 mmHg) than in intact WT mice (10.1 +/- 4.5 mmHg). In OVX WT mice, central infusion of 17beta-estradiol (E(2); 30 microg.kg(-1).day(-1)) attenuated the pressor effect of ANG II (7.0 +/- 0.4 mmHg), and this protective effect of E(2) was prevented by coadministration of ICI-182,780 (ICI; 1.5 microg.kg(-1).day(-1), 18.8 +/- 1.5 mmHg), a nonselective ER antagonist. Furthermore, central, but not peripheral, infusions of ICI augmented the pressor effects of ANG II in intact WT mice (17.8 +/- 4.2 mmHg). In contrast, the pressor effect of ANG II was unchanged in either central E(2)-treated OVX ERalphaKO mice (19.0 +/- 1.1 mmHg) or central ICI-treated intact ERalphaKO mice (19.6 +/- 1.6 mmHg). Lastly, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction in BP in OVX WT, central ER antagonist-treated intact WT, central E(2) + ICI-treated OVX WT, ERalphaKO, and central E(2)- or ICI-treated ERalphaKO mice compared with that in intact WT mice given just ANG II. Together, these data indicate that ERalpha, especially central expression of the ER, mediates the protective effects of estrogen against ANG II-induced hypertension.

  12. The Sirt1 activator SRT1720 attenuates angiotensin II-induced atherosclerosis in apoE{sup −/−} mice through inhibiting vascular inflammatory response

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Yi xi; Zhang, Man; Cai, Yuehua; Zhao, Qihui; Dai, Wenjian, E-mail: wjdai@126.com

    2015-10-02

    Activation of the silent mating type information regulation 2 homolog 1 (SIRT1) has been shown consistent antiinflammatory function. However, little information is available on the function of SIRT1 during Angiotensin II (AngII)-induced atherosclerosis. Here we report atheroprotective effects of sirt1 activation in a model of AngII-accelerated atherosclerosis, characterized by suppression pro-inflammatory transcription factors Nuclear transcription factor (NF)-κB and Signal Transducers and Activators of Transcription. (STAT) signaling pathway, and atherosclerotic lesion macrophage content. In this model, administration of the SIRT1 agonist SRT1720 substantially attenuated AngII-accelerated atherosclerosis with decreasing blood pressure and inhibited NF-κB and STAT3 activation, which was associated with suppression of inflammatory factor and atherogenic gene expression in the artery. In vitro studies demonstrated similar changes in AngII-treated VSMCs and macrophages: SIRT1 activation inhibited the expression levels of proinflammatory factor. These studies uncover crucial proinflammatory mechanisms of AngII and highlight actions of SIRT1 activation to inhibit AngII signaling, which is atheroprotective. - Highlights: • SRT1720 reduced atherosclerotic lesion size in aortic arches and atherosclerotic lesion macrophage content. • SRT1720 could inhibit the phosphorylation of STAT3 and p65 phosphorylation and translocation. • SRT1720 could inhibit the expression of proinflammatory factor.

  13. Nonpeptide and peptide growth hormone secretagogues act both as ghrelin receptor agonist and as positive or negative allosteric modulators of ghrelin signaling

    DEFF Research Database (Denmark)

    Holst, Birgitte; Brandt, Erik; Bach, Anders

    2005-01-01

    Two nonpeptide (L692,429 and MK-677) and two peptide [GH-releasing peptide (GHRP)-6 and ghrelin] agonists were compared in binding and in signal transduction assays: calcium mobilization, inositol phosphate turnover, cAMP-responsive element (CRE), and serum-responsive element (SRE) controlled...... agonist properties and in their ability to modulate ghrelin signaling. A receptor model is presented wherein ghrelin normally only activates one receptor subunit in a dimer and where the smaller nonendogenous agonists bind in the other subunit to act both as coagonists and as either neutral (MK-677...

  14. Regulation of glomerular heparanase expression by aldosterone, angiotensin II and reactive oxygen species.

    Science.gov (United States)

    van den Hoven, Mabel J; Waanders, Femke; Rops, Angelique L; Kramer, Andrea B; van Goor, Harry; Berden, Jo H; Navis, Gerjan; van der Vlag, Johan

    2009-09-01

    Inhibition of the renin-angiotensin-aldosterone system (RAAS) provides renoprotection in adriamycin nephropathy (AN), along with a decrease in overexpression of glomerular heparanase. Angiotensin II (AngII) and reactive oxygen species (ROS) are known to regulate heparanase expression in vivo. However, it is unknown whether this is also the case for aldosterone. Therefore, we further assessed the role of aldosterone, AngII and ROS in the regulation of glomerular heparanase expression. Six weeks after the induction of AN, rats were treated with vehicle (n = 8), lisinopril (75 mg/L, n = 10), spironolactone (3.3 mg/day, n = 12) or the combination of lisinopril and spironolactone (n = 14) for 12 weeks. Age-matched healthy rats served as controls (n = 6). After 18 weeks, renal heparanase and heparan sulfate (HS) expression were examined by immunofluorescence staining. In addition, the effect of aldosterone, AngII and ROS on heparanase expression in cultured podocytes was determined. Treatment with lisinopril, spironolactone or their combination significantly blunted the increased glomerular heparanase expression and restored the decreased HS expression in the GBM. Addition of aldosterone to cultured podocytes resulted in a significantly increased heparanase mRNA and protein expression, which could be inhibited by spironolactone. Heparanase mRNA and protein expression in podocytes were also significantly increased after stimulation with AngII or ROS. Our in vivo and in vitro results show that not only AngII and ROS, but also aldosterone is involved in the regulation of glomerular heparanase expression.

  15. Reactive oxygen species and angiotensin II signaling in vascular cells: implications in cardiovascular disease

    Directory of Open Access Journals (Sweden)

    Touyz R.M.

    2004-01-01

    Full Text Available Diseases such as hypertension, atherosclerosis, hyperlipidemia, and diabetes are associated with vascular functional and structural changes including endothelial dysfunction, altered contractility and vascular remodeling. Cellular events underlying these processes involve changes in vascular smooth muscle cell (VSMC growth, apoptosis/anoikis, cell migration, inflammation, and fibrosis. Many factors influence cellular changes, of which angiotensin II (Ang II appears to be amongst the most important. The physiological and pathophysiological actions of Ang II are mediated primarily via the Ang II type 1 receptor. Growing evidence indicates that Ang II induces its pleiotropic vascular effects through NADPH-driven generation of reactive oxygen species (ROS. ROS function as important intracellular and intercellular second messengers to modulate many downstream signaling molecules, such as protein tyrosine phosphatases, protein tyrosine kinases, transcription factors, mitogen-activated protein kinases, and ion channels. Induction of these signaling cascades leads to VSMC growth and migration, regulation of endothelial function, expression of pro-inflammatory mediators, and modification of extracellular matrix. In addition, ROS increase intracellular free Ca2+ concentration ([Ca2+]i, a major determinant of vascular reactivity. ROS influence signaling molecules by altering the intracellular redox state and by oxidative modification of proteins. In physiological conditions, these events play an important role in maintaining vascular function and integrity. Under pathological conditions ROS contribute to vascular dysfunction and remodeling through oxidative damage. The present review focuses on the biology of ROS in Ang II signaling in vascular cells and discusses how oxidative stress contributes to vascular damage in cardiovascular disease.

  16. Reduced angiotensin II levels cause generalized vascular dysfunction via oxidant stress in hamster cheek pouch arterioles.

    Science.gov (United States)

    Priestley, Jessica R C; Buelow, Matthew W; McEwen, Scott T; Weinberg, Brian D; Delaney, Melanie; Balus, Sarah F; Hoeppner, Carlyn; Dondlinger, Lynn; Lombard, Julian H

    2013-09-01

    We investigated the effect of suppressing plasma angiotensin II (ANG II) levels on arteriolar relaxation in the hamster cheek pouch. Arteriolar diameters were measured via television microscopy during short-term (3-6days) high salt (HS; 4% NaCl) diet and angiotensin converting enzyme (ACE) inhibition with captopril (100mg/kg/day). ACE inhibition and/or HS diet eliminated endothelium-dependent arteriolar dilation to acetylcholine, endothelium-independent dilation to the NO donor sodium nitroprusside, the prostacyclin analogs carbacyclin and iloprost, and the KATP channel opener cromakalim; and eliminated arteriolar constriction during KATP channel blockade with glibenclamide. Scavenging of superoxide radicals and low dose ANG II infusion (25ng/kg/min, subcutaneous) reduced oxidant stress and restored arteriolar dilation in arterioles of HS-fed hamsters. Vasoconstriction to topically-applied ANG II was unaffected by HS diet while arteriolar responses to elevation of superfusion solution PO2 were unaffected (5% O2, 10% O2) or reduced (21% O2) by HS diet. These findings indicate that sustained exposure to low levels of circulating ANG II leads to widespread dysfunction in endothelium-dependent and independent vascular relaxation mechanisms in cheek pouch arterioles by increasing vascular oxidant stress, but does not potentiate O2- or ANG II-induced constriction of arterioles in the distal microcirculation of normotensive hamsters. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Na cela: considerações sobre sentidos inscritos em cartuns de Angeli

    Directory of Open Access Journals (Sweden)

    Francis Lampoglia

    2010-07-01

    Full Text Available Ao contrário de outros textos opinativos marcados, no discurso midiático, pelo efeito de persuasão do leitor com base em argumentos fidedignos, os cartuns e as charges adotam a estratégia do riso como modo de fazer falar a caricatura, a crítica, a denúncia. Tomando tal afirmativa, esse artigo pretende, à luz da Análise do Discurso de matriz francesa e do conceito de dialogismo em Bakhtin, estudar o funcionamento discursivo de alguns cartuns de Angeli. Nosso corpus de análise é composto por trabalhos publicados no jornal Folha de S. Paulo em 2003 e 2007; interessa aqui flagrar o diálogo que eles estabelecem entre si, o modo como remetem um ao outro e a forma como entretecem um modo de falar da justiça em nosso país.

  18. Angélica y Marcela, Leandra y Fiammetta. Mujeres ariostescas en el Quijote

    Directory of Open Access Journals (Sweden)

    Karina García -Zamorategui

    2015-01-01

    Full Text Available Este análisis muestra diversas semejanzas entre los personajes feme - ninos del poema épico Orlando furioso , de Ludovico Ariosto, y el Quijote , de Miguel de Cervantes. Además, se observan coincidencias en las estructuras lite - rarias en las que actúan esos personajes. Por un lado, el discurso de la ‘víctima bella’, en ambas obras con la forma de soliloquio —de Angélica en la del italiano y de Marcela en la del español—. Por otro, hay una especie de colección de mani - fiestos sobre las mujeres puestos en una de las narraciones enmarcadas que cada autor analizado escribió en medio de su respectiva obra maestra.

  19. Stability of a Beddington-DeAngelis type predator-prey model with trichotomous noises

    Science.gov (United States)

    Jin, Yanfei; Niu, Siyong

    2016-06-01

    The stability analysis of a Beddington-DeAngelis (B-D) type predator-prey model driven by symmetric trichotomous noises is presented in this paper. Using the Shapiro-Loginov formula, the first-order and second-order solution moments of the system are obtained. The moment stability conditions of the B-D predator-prey model are given by using Routh-Hurwitz criterion. It is found that the stabilities of the first-order and second-order solution moments depend on the noise intensities and correlation time of noise. The first-order and second-order moments are stable when the correlation time of noise is increased. That is, the trichotomous noise plays a constructive role in stabilizing the solution moment with regard to Gaussian white noise. Finally, some numerical results are performed to support the theoretical analyses.

  20. Existence of complex patterns in the Beddington-DeAngelis predator-prey model.

    Science.gov (United States)

    Haque, Mainul

    2012-10-01

    The study of reaction-diffusion system constitutes some of the most fascinating developments of late twentieth century mathematics and biology. This article investigates complexity and chaos in the complex patterns dynamics of the original Beddington-DeAngelis predator-prey model which concerns the influence of intra species competition among predators. We investigate the emergence of complex patterns through reaction-diffusion equations in this system. We derive the conditions for the codimension-2 Turing-Hopf, Turing-Saddle-node, and Turing-Transcritical bifurcation, and the codimension-3 Turing-Takens-Bogdanov bifurcation. These bifurcations give rise to very complex patterns that have not been observed in previous predator-prey models. A large variety of different types of long-term behavior, including homogenous distributions and stationary spatial patterns are observed through extensive numerical simulations with experimentally-based parameter values. Finally, a discussion of the ecological implications of the analytical and numerical results concludes the paper.

  1. Involvement of Spinal Angiotensin II System in Streptozotocin-Induced Diabetic Neuropathic Pain in Mice.

    Science.gov (United States)

    Ogata, Yoshiki; Nemoto, Wataru; Nakagawasai, Osamu; Yamagata, Ryota; Tadano, Takeshi; Tan-No, Koichi

    2016-09-01

    Renin-angiotensin system (RAS) activity increases under hyperglycemic states, and is thought to be involved in diabetic complications. We previously demonstrated that angiotensin (Ang) II, a main bioactive component of the RAS, might act as a neurotransmitter and/or neuromodulator in the transmission of nociceptive information in the spinal cord. Here, we examined whether the spinal Ang II system is responsible for diabetic neuropathic pain induced by streptozotocin (STZ). Tactile allodynia was observed concurrently with an increase in blood glucose levels the day after mice received STZ (200 mg/kg, i.v.) injections. Tactile allodynia on day 14 was dose-dependently inhibited by intrathecal administration of losartan, an Ang II type 1 (AT1) receptor antagonist, but not by PD123319, an AT2 receptor antagonist. In the lumbar dorsal spinal cord, the expression of Ang II, Ang converting enzyme (ACE), and phospho-p38 mitogen-activated protein kinase (MAPK) were all significantly increased on day 14 after STZ injection compared with vehicle-treated controls, whereas no differences were observed among AT1 receptors or angiotensinogen levels. Moreover, the increase in phospho-p38 MAPK was significantly inhibited by intrathecal administration of losartan. These results indicate that the expression of spinal ACE increased in STZ-induced diabetic mice, which in turn led to an increase in Ang II levels and tactile allodynia. This increase in spinal Ang II was accompanied by the phosphorylation of p38 MAPK, which was shown to be mediated by AT1 receptors.

  2. 杜氏盐藻叶绿体表达载体p64C-ANG-AAD的构建%The Construction of Expression Vectorp 64C-ANG-AAD for Dunaliella Salina Chloroplast

    Institute of Scientific and Technical Information of China (English)

    潘卫东; 张贵星; 付庆; 张娟; 苏堤; 薛乐勋

    2005-01-01

    目的构建表达载体在杜氏盐藻叶绿体中表达重组人血管抑素(Angiostatin,ANG).方法利用基因工程技术将构建完整的人ANG基因插入到叶绿体启动子atpA5和终止子rbcL3′间,组成atpA-ANG-rbcL表达盒,将此表达盒与aadA表达盒串接后,插入含叶绿体同源片段的质粒载体p64上,构建成血管抑素盐藻叶绿体表达载体p64C-ANG-AAD.结果酶切鉴定结果表明,2.2kb的ANG表达盒和1.9kb的aadA表达盒已按照预期顺序插入到质粒p64C上叶绿体chlL基因间.结论叶绿体表达载体p64C-ANG-AAD可以应用于杜氏盐藻的叶绿体转化,表达重组人血管抑素.

  3. Role of α1D -adrenoceptors in vascular wall hypertrophy during angiotensin II-induced hypertension.

    Science.gov (United States)

    Gallardo-Ortíz, I A; Rodríguez-Hernández, S N; López-Guerrero, J J; Del Valle-Mondragón, L; López-Sánchez, P; Touyz, R M; Villalobos-Molina, R

    2015-09-01

    The in vivo effect of continuous angiotensin II (Ang II) infusion on arterial blood pressure, vascular hypertrophy and α1 -adrenoceptors (α1 -ARs) expression was explored. Alzet(®) minipumps filled with Ang II (200 ng kg(-1)  min(-1) ) were subcutaneously implanted in male Wistar rats (3 months-old). Groups of rats were also treated with losartan, an AT1 R antagonist, or with BMY 7378, a selective α1D -AR antagonist. Blood pressure was measured by tail-cuff; after 2 or 4 weeks of treatment, vessels were isolated for functional and structural analyses. Angiotensin II increased systolic blood pressure. Phenylephrine-induced contraction in aorta was greater (40% higher) in Ang II-treated rats than in the controls, and similar effect occurred with KCl 80 mm. Responses in tail arteries were not significantly different among the different groups. Angiotensin II decreased α1D -ARs without modifying the other α1 -ARs and induced an increase in media thickness (hypertrophy) in aorta, while no structural change occurred in tail artery. Losartan prevented and reversed hypertension and hypertrophy, while BMY 7378 prevented and reversed the aorta's hypertrophic response, without preventing or reversing hypertension. Findings indicate that Ang II-induced aortic hypertrophic response involves Ang II-AT1 Rs and α1D -ARs. Angiotensin II-induced α1D -AR-mediated vascular remodeling occurs independently of hypertension. Findings identify a α1D -AR-mediated process whereby Ang II influences aortic hypertrophy independently of blood pressure elevation. © 2016 John Wiley & Sons Ltd.

  4. Adventitial gene transfer of catalase attenuates angiotensin II-induced vascular remodeling.

    Science.gov (United States)

    Liu, Cun-Fei; Zhang, Jia; Shen, Kai; Gao, Ping-Jin; Wang, Hai-Ya; Jin, Xin; Meng, Chao; Fang, Ning-Yuan

    2015-04-01

    Vascular adventitia and adventitia‑derived reactive oxygen species (ROS) contribute to vascular remodeling following vascular injury. A previous ex vivo study in adventitial fibroblasts showed that catalase, one of most important anti‑oxide enzymes, was downregulated by angiotensin II (AngII). The aim of the present study was to investigate whether adventitial gene transfer of catalase affects AngII‑induced vascular remodeling in vivo. Adenoviruses co‑expressing catalase and enhanced green fluorescent protein (eGFP) or expressing eGFP only were applied to the adventitial surface of common carotid arteries of Sprague‑Dawley rats. Alzet minipumps administering AngII (0.75 mg/kg/day) were then implanted subcutaneously for 14 days. Systolic blood pressure and biological parameters of vascular remodeling were measured in each group. Adventitial fibroblasts were cultured and p38 mitogen‑activated protein kinase (MAPK) phosphorylation was measured using western blot analysis. The results showed that adventitial gene transfer of catalase had no effect on AngII‑induced systolic blood pressure elevation. However, catalase adenovirus transfection significantly inhibited AngII‑induced media hypertrophy compared with that of the control virus (Pcatalase transfection significantly attenuated AngII‑induced ROS generation, macrophage infiltration, collagen deposition and adventitial α‑smooth muscle actin expression. Furthermore, catalase transfection significantly inhibited the AngII‑induced increase in p38MAPK phosphorylation. In conclusion, the results of the present study demonstrated that adventitial gene transfer of catalase significantly attenuated AngII‑induced vascular remodeling in rats via inhibition of adventitial p38MAPK phosphorylation.

  5. Liberación de endotelina-1 por angiotensina ll en miocitos cardíacos aislados Angiotensin II-induced endothelin-1 release in cardiac myocytes

    Directory of Open Access Journals (Sweden)

    María C. Villa-Abrille

    2006-06-01

    Full Text Available Muchos de los efectos de la angiotensina II (Ang II son mediados en realidad por la acción de endotelina (ET endógena liberada y/o producida en respuesta a la Ang II. En este trabajo evaluamos la interacción Ang II/ET-1, sus consecuencias en la contractilidad cardíaca y el papel de las especies reactivas del oxígeno (EROs. Se usaron cardiomiocitos aislados de gato. La Ang II, 1 nM, produjo un efecto inotrópico positivo (EIP de 31.8±3.8% que fue cancelado por inhibición de los receptores AT1, de los receptores de ET, del intercambiador Na+/H+ (NHE, del modo inverso del intercambiador Na+/Ca2+ (NCX o por el secuestro de EROs. La Ang II, 100 nM, produjo un EIP de 70.5±7.6% que fue cancelado por inhibición de los receptores AT1 y bloqueado en parte por inhibición de los receptores de ET, del NHE, del modo inverso del NCX o por el secuestro de EROs. La Ang II, 1 nM, incrementó el ARNm de la preproET-1 lo cual fue anulado por el bloqueo de los receptores AT1. Los resultados permiten concluir que el EIP de la Ang II es debido a la acción de la ET-1 endógena liberada/formada por la Ang II. La ET-1 produce: estimulación del NHE, activación del modo inverso del NCX y un consecuente EIP. Dentro de esta cascada también participarían los EROs.Many of the effects thought to be due to angiotensin II (Ang II are due to the release/formation of endothelin (ET. We tested whether Ang II elicits its positive inotropic effect (PIE by the action of endogenous ET-1 and the role played by the reactive oxygen species (ROS in this mechanism. Experiments were performed in cat isolated ventricular myocytes in which sarcomere shortening (SS was measured to asses contractility after pharmacological interventions and the effect of Ang II on inotropism were analyzed. Ang II 1 nM increased SS by 31.8±3.8% (p<0.05. This PIE was cancelled by AT1 receptor blockade, by ET-1 receptors blockade, by Na+/H+ exchanger (NHE inhibition, by reverse mode Na+/Ca2

  6. Dynamics of cooperative predator–prey system with impulsive effects and Beddington–DeAngelis functional response

    Directory of Open Access Journals (Sweden)

    Yao Zhijian

    2013-10-01

    Full Text Available In this paper, cooperative predator–prey system with impulsive effects and Beddington–DeAngelis functional response is studied. By using comparison theorem and some analysis techniques as well as the coincidence degree theory, sufficient conditions are obtained for the permanence, extinction and the existence of positive periodic solution.

  7. Neurocysticercosis in a rural population with extensive pig production in Angónia district, Tete Province, Mozambique

    DEFF Research Database (Denmark)

    Assane, Yunus Amade; Trevisan, Chiara; Schutte, Clara Maria

    2017-01-01

    Neurocysticercosis (NCC) is an important neurological disease in countries with high prevalence of Taenia solium infection and is emerging as a serious public health and economic problem. The aim of this study was to estimate the prevalence of NCC in Angónia district, Tete province, Mozambique...

  8. Effect of angiotensin II-induced arterial hypertension on the voltage-dependent contractions of mouse arteries.

    Science.gov (United States)

    Fransen, Paul; Van Hove, Cor E; Leloup, Arthur J A; Schrijvers, Dorien M; De Meyer, Guido R Y; De Keulenaer, Gilles W

    2016-02-01

    Arterial hypertension (AHT) affects the voltage dependency of L-type Ca(2+) channels in cardiomyocytes. We analyzed the effect of angiotensin II (AngII)-induced AHT on L-type Ca(2+) channel-mediated isometric contractions in conduit arteries. AHT was induced in C57Bl6 mice with AngII-filled osmotic mini-pumps (4 weeks). Normotensive mice treated with saline-filled osmotic mini-pumps were used for comparison. Voltage-dependent contractions mediated by L-type Ca(2+) channels were studied in vaso-reactive studies in vitro in isolated aortic and femoral arteries by using extracellular K(+) concentration-response (KDR) experiments. In aortic segments, AngII-induced AHT significantly sensitized isometric contractions induced by elevated extracellular K(+) and depolarization. This sensitization was partly prevented by normalizing blood pressure with hydralazine, suggesting that it was caused by AHT rather than by direct AngII effects on aortic smooth muscle cells. The EC50 for extracellular K(+) obtained in vitro correlated significantly with the rise in arterial blood pressure induced by AngII in vivo. The AHT-induced sensitization persisted when aortic segments were exposed to levcromakalim or to inhibitors of basal nitric oxide release. Consistent with these observations, AngII-treatment also sensitized the vaso-relaxing effects of the L-type Ca(2+) channel blocker diltiazem during K(+)-induced contractions. Unlike aorta, AngII-treatment desensitized the isometric contractions to depolarization in femoral arteries pointing to vascular bed specific responses of arteries to hypertension. AHT affects the voltage-dependent L-type Ca(2+) channel-mediated contraction of conduit arteries. This effect may contribute to the decreased vascular compliance in AHT and explain the efficacy of Ca(2+) channel blockers to reduce vascular stiffness and central blood pressure in AHT.

  9. Chronic Angiotensin-II Treatment Potentiates HR Slowing in Sprague-Dawley Rat during Acute Behavioral Stress5

    Science.gov (United States)

    Hoyt, Richard E.; Speakman, Richard O.; Brown, David R.; Cassis, Lisa A; Silcox, Dennis L.; Anigbogu, Chikodi N.; Randall, David C.

    2013-01-01

    This study examined the effect of two-weeks infusion of angiotensin-II (Ang-II; 175 ng/kg/min) via minipump in rats (n=7) upon the mean arterial blood pressure (mBP) and heart rate (HR) response to an acute stress as compared to rats infused with saline (n=7). The acute stress was produced by a classical aversive conditioning paradigm: a 15 sec. tone (CS+) followed by a half second tail shock. Baseline mBP in Ang-II infused rats (167.7 ± 21.3 mm Hg; mean ± SD) significantly exceeded that of controls (127.6 ± 13.5 mm Hg). Conversely, baseline HR in the Ang-II infused rats (348 ± 33) was significantly lower than controls (384 ± 19 bpm). The magnitude of the mBP increase during CS+ did not differ between groups, but the HR slowing during CS+ in the Ang-II infused rats (−13.2 ± 8.9 bpm) was significantly greater than that seen in controls (−4.2 ± 5.5 bpm). This augmented bradycardia may be inferentially attributed to an accentuated increase in cardiac parasympathetic activity during CS+ in the Ang-II infused rats. The mBP increased above baseline immediately post-shock delivery in controls, but fell in the Ang-II infused rats, perhaps because of a ‘ceiling effect’ in total vascular resistance. This classical conditioning model of ‘acute stress’ differs from most stress paradigms in rats in yielding a HR slowing concomitant with a pressor response, and this slowing is potentiated by Ang-II. PMID:23317537

  10. Angiotensin II limits NO production by upregulating arginase through a p38 MAPK-ATF-2 pathway.

    Science.gov (United States)

    Shatanawi, Alia; Lemtalsi, Tahira; Yao, Lin; Patel, Chintan; Caldwell, Ruth B; Caldwell, R William

    2015-01-05

    Enhanced vascular arginase activity can impair endothelium-dependent vasorelaxation by decreasing l-arginine availability to endothelial nitric oxide (NO) synthase, thereby reducing NO production and uncoupling NOS function. Elevated angiotensin II (Ang II) is a key component of endothelial dysfunction in many cardiovascular diseases and has been linked to elevated arginase activity. In this study we explored the signaling pathway leading to increased arginase expression/activity in response to Ang II in bovine aortic endothelial cells (BAEC). Our previous studies indicate involvement of p38 mitogen activated protein kinase (MAPK) in Ang II-induced arginase upregulation and reduced NO production. In this study, we further investigated the Ang II-transcriptional regulation of arginase 1 in endothelial cells. Our results indicate the involvement of ATF-2 transcription factor of the AP1 family in arginase 1 upregulation and in limiting NO production. Using small interfering RNA (siRNA) targeting ATF-2, we showed that this transcription factor is required for Ang II-induced arginase 1 gene upregulation and increased arginase 1 expression and activity, leading to reduced NO production. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay further confirmed the involvement of ATF-2. Moreover, our data indicate that p38 MAPK phosphorylates ATF-2 in response to Ang II. Collectively, our results indicate that Ang II increases endothelial arginase activity/expression through a p38 MAPK/ATF-2 pathway leading to reduced endothelial NO production. These signaling steps might be therapeutic targets for preventing vascular endothelial dysfunction associated with elevated arginase activity/expression. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Prostanoids counterbalance the synergism between endothelin-1 and angiotensin II in mesenteric veins of trained rats.

    Science.gov (United States)

    Chies, Agnaldo Bruno; de Oliveira, Priscilla Bianca; Rossignoli, Patrícia de Souza; Baptista, Rafaela de Fátima Ferreira; de Lábio, Roger William; Payão, Spencer Luiz Marques

    2017-02-01

    Exercise-induced adaptations of the modulating mechanisms that influence the angiotensin (Ang II) responses assume different features depending on the venous bed. In femoral veins, exercise mobilizes vasodilator prostanoids to cooperate with NO in order to maintain reduced Ang II responses. On the other hand, exercise's influence on the Ang II responses in veins that drain blood from the mesenteric region has been poorly described. Therefore, the present study aimed to identify the effects of a single bout of exercise, as well as exercise training, on the Ang II responses in mesenteric veins. The present study also aimed to investigate the involvement of prostanoids, NO and ET-1 in eventual exercise-induced modifications in these veins. To this end, mesenteric veins taken from resting-sedentary, exercised-sedentary, resting-trained and exercised-trained animals were studied in organ baths. In addition, the mRNA expression of prepro-endothelin-1 (ppET-1), as well as that of the ETA and ETB receptors, were quantified by real-time PCR in these veins. The results show that, either in absence or in presence of L-NAME, the Ang II responses were not different between groups. In the presence of indomethacin, higher Ang II responses were observed in the resting-trained animals than in the resting-sedentary animals. This difference, however, disappeared when L-NAME, BQ-123 or BQ-788 were added during incubation. In addition, no differences in ppET-1, ETA or ETB mRNA expression were observed between groups. Furthermore, in the presence of PD123,319, the Ang II responses in the exercised-sedentary animals were higher than those in the resting-sedentary animals. In conclusion, exercise training mobilizes endothelin-1 (ET-1) to reinforce the Ang II-induced responses mainly through ETA activation. On the other hand, vasodilator prostanoids are mobilized to act in parallel with NO in order to counterbalance the Ang II responses that have been potentiated by ET-1 in these trained

  12. Dietary sodium deprivation evokes activation of brain regional neurons and down-regulation of angiotensin II type 1 receptor and angiotensin-convertion enzyme mRNA expression.

    Science.gov (United States)

    Lu, B; Yang, X J; Chen, K; Yang, D J; Yan, J Q

    2009-12-15

    Previous studies have indicated that the renin-angiotensin-aldosterone system (RAAS) is implicated in the induction of sodium appetite in rats and that different dietary sodium intakes influence the mRNA expression of central and peripheral RAAS components. To determine whether dietary sodium deprivation activates regional brain neurons related to sodium appetite, and changes their gene expression of RAAS components of rats, the present study examined the c-Fos expression after chronic exposure to low sodium diet, and determined the relationship between plasma and brain angiotensin I (ANG I), angiotensin II (ANG II) and aldosterone (ALD) levels and the sodium ingestive behavior variations, as well as the effects of prolonged dietary sodium deprivation on ANG II type 1 (AT1) and ANG II type 2 (AT2) receptors and angiotensin-convertion enzyme (ACE) mRNA levels in the involved brain regions using the method of real-time polymerase chain reaction (PCR). Results showed that the Fos immunoreactivity (Fos-ir) expression in forebrain areas such as subfornical organ (SFO), paraventricular hypothalamic nuclei (PVN), supraoptic nucleus (SON) and organum vasculosum laminae terminalis (OVLT) all increased significantly and that the levels of ANG I, ANG II and ALD also increased in plasma and forebrain in rats fed with low sodium diet. In contrast, AT1, ACE mRNA in PVN, SON and OVLT decreased significantly in dietary sodium depleted rats, while AT2 mRNA expression did not change in the examined areas. These results suggest that many brain areas are activated by increased levels of plasma and/or brain ANG II and ALD, which underlies the elevated preference for hypertonic salt solution after prolonged exposure to low sodium diet, and that the regional AT1 and ACE mRNA are down-regulated after dietary sodium deprivation, which may be mediated by increased ANG II in plasma and/or brain tissue.

  13. The ACE2/Ang-(1-7)/Mas Axis Regulates the Development of Pancreatic Endocrine Cells in Mouse Embryos.

    Science.gov (United States)

    Wang, Lin; Liang, Juan; Leung, Po Sing

    2015-01-01

    Angiotensin-converting enzyme 2 (ACE2), its product Angiotensin-(1-7) [Ang-(1-7)], and Ang-(1-7) receptor Mas, have been shown to regulate organogenesis during embryonic development in various species. However, it is not known whether a local ACE2/Ang-(1-7)/Mas axis is present in the fetal pancreas. It is hypothesized that there is a local ACE2/Ang-(1-7)/Mas axis in the embryonic pancreas in mice that is involved in regulating islet cell development. To address this issue, the endogenous expression profile of axis constituents in embryonic mouse pancreata was examined. Involvement of the ACE2 axis in the regulation of pancreatic development was also examined. The present experiments showed in an in vivo animal model that endogenous expression levels of ACE2 and the Mas receptor were upregulated in mouse pancreata in late embryogenesis, peaking on embryonic day E16.5, when it reached 3 folds compared to that seen at E12.5. Consistently, endogenous expression of Ang-(1-7) also peaked at E16.5. Treatment with the ACE2 inhibitor DX600 did not alter islet development. However, prenatal treatment with A779, a Mas receptor antagonist, reduced the β-cell to α-cell ratio in neonatal islets, impaired islet insulin secretory function, and impaired the pups' glucose tolerance. In ex vivo pancreas explant cultures, A779 again decreased the β-cell to α-cell ratio, apparently through its effects on β-cell proliferation (reduced proliferation shown with Ki67 staining), and also decreased Insulin and Ngn3 mRNA expression. Furthermore, treatment of explant cultures with Ang-(1-7) increased mRNA levels of Insulin and pancreatic progenitor marker Ngn3, as well as Nox4, the ROS generation enzyme; these stimulatory effects were attenuated by co-treatment with A779, suggesting that Ang-(1-7), via Mas receptor signaling, may promote differentiation of pancreatic progenitors into insulin-producing cells via modulation of reactive oxygen species. These data together suggest that a Mas

  14. Computational Studies of Difference in Binding Modes of Peptide and Non-Peptide Inhibitors to MDM2/MDMX Based on Molecular Dynamics Simulations

    Directory of Open Access Journals (Sweden)

    Yuxin Zhang

    2012-02-01

    Full Text Available Inhibition of p53-MDM2/MDMX interaction is considered to be a promising strategy for anticancer drug design to activate wild-type p53 in tumors. We carry out molecular dynamics (MD simulations to study the binding mechanisms of peptide and non-peptide inhibitors to MDM2/MDMX. The rank of binding free energies calculated by molecular mechanics generalized Born surface area (MM-GBSA method agrees with one of the experimental values. The results suggest that van der Waals energy drives two kinds of inhibitors to MDM2/MDMX. We also find that the peptide inhibitors can produce more interaction contacts with MDM2/MDMX than the non-peptide inhibitors. Binding mode predictions based on the inhibitor-residue interactions show that the π–π, CH–π and CH–CH interactions dominated by shape complimentarity, govern the binding of the inhibitors in the hydrophobic cleft of MDM2/MDMX. Our studies confirm the residue Tyr99 in MDMX can generate a steric clash with the inhibitors due to energy and structure. This finding may theoretically provide help to develop potent dual-specific or MDMX inhibitors.

  15. H2S inhibits angiotensin II-induced atrial Kv1.5 upregulation by attenuating Nox4-mediated ROS generation during atrial fibrillation.

    Science.gov (United States)

    Lu, Guihua; Xu, Chenggui; Tang, Kaiyu; Zhang, Juhong; Li, Qinglang; Peng, Longyun; Wang, Yesong; Huang, Zhibin; Gao, Xiuren

    2017-01-29

    Our previous study demonstrated that angiotensin II (Ang II) upregulates the expression of Kv1.5, a promising target for atrial fibrillation (AF) therapy, by activating ROS-dependent P-Smad2/3 and P-ERK 1/2. A recent study showed that hydrogen sulfide (H2S) may modulate the effects of angiotensin II (Ang II) by inhibiting the NADPH oxidase 4 (Nox4)-ROS signaling in the heart. The present study aimed to determine whether H2S is involved in the regulation of atrial Kv1.5 via ROS-related mechanisms in AF. Cultured neonatal rat atrial myocytes and a beagle model of AF were used for this study. In the neonatal rat atrial myocytes, quantitative PCR and enzyme immunoassays revealed that the mRNA expression levels of angiotensinogen, angiotensin-converting enzyme, and Ang II type I receptor (AT1R) and the Ang II supernatant concentration were significantly increased by hydrogen peroxide (H2O2) incubation, and these H2O2-induced alterations were reversed by diphenyleneiodonium, apocynin and H2S supplementation. Flow cytometry and Western blotting revealed that blockade of H2S biosynthesis using dl-propargylglycine increased ROS production and the expression of Ang II and Kv1.5. Sodium hydrosulfide (an exogenous H2S donor) and Nox4 siRNA inhibited Ang II-induced ROS production and Ang II-induced expression of Kv1.5, P-Smad2/3, P-ERK 1/2. Sodium hydrosulfide suppressed the Ang II-induced upregulation of Nox4. In our beagle AF model, 24 h of rapid atrial pacing (RAP) increased the atrial Ang II concentration, ROS production and the protein expression of Nox4, Kv1.5, P-Smad2/3 and P-ERK 1/2. These RAP-induced changes were inhibited by H2S supplementation and losartan (an AT1R blocker) pretreatment. In conclusion, our study indicates that H2S downregulates Ang II-induced atrial Kv1.5 expression by attenuating Nox4-related ROS-triggered P-Smad2/3 and P-ERK 1/2 activation during AF. H2S supplementation would be beneficial for AF treatment via the suppression of atrial Kv1

  16. Minimally invasive colorectal resection for cancer is associated with a short-lived decrease in soluble Tie-2 receptor levels, which may transiently inhibit VEGF-mediated angiogenesis (via altered blood levels of free Ang-1 and Ang-2).

    Science.gov (United States)

    Shantha Kumara, H M C; Grieco, Michael J; Yan, Xiaohong; Kalady, Matthew F; DiMaggio, Vincent; Kim, Donald G; Hyman, Neil; Feingold, Daniel L; Whelan, Richard L

    2010-10-01

    Angiopoetin- (Ang-) 1 inhibits and Ang-2 promotes VEGF-mediated angiogenesis via binding to endothelial cell-bound Tie-2 receptor (Tie-2). After minimally invasive colorectal resection (MICR), Ang-1 levels decrease and Ang-2 levels increase, which may stimulate angiogenesis in wounds and residual tumor foci. Soluble Tie-2 (sTie-2) modulates the effects of free Ang-1 and Ang-2 by binding to them. This study assessed perioperative MICR plasma sTie-2 levels. Blood samples were taken preoperatively (PreOp) and on postoperative days (POD) 1 and 3 from 50 cancer and 53 benign disease MICR patients. In a subgroup, a fourth sample was taken between POD7 and POD13 and bundled as a single time point. sTie-2 levels (ng/ml) were determined via ELISA. The mean and SD were determined at each time point. The t test used for analysis. PreOp plasma sTie-2 levels were significantly higher in the benign group (27.6 ± 10.2) than in the cancer group (22.9 ± 7.9). A significant drop from PreOp occurred in sTie-2 levels in the cancer group on POD1 (20.0 ± 7.4) and POD3 (21.0 ± 6.6) and in the benign group on POD1 (24.8 ± 9.1). The benign group's POD3 and the cancer group's POD7-13 sTie-2 levels were statistically similar to the PreOp levels while the benign group's POD7-13 level was significantly higher. PreOp sTie-2 levels were significantly lower in cancer patients. MICR is associated with a significant short-lived decrease in plasma sTie-2 levels in cancer patients on POD1 and 3, which may briefly inhibit VEGF-mediated angiogenesis. The benign group's early results were similar.

  17. 血管紧张素II及其受体与恶性肿瘤关系的研究进展%Advance in Research of Angiotensin II and Its Receptor and Malignant Tumor

    Institute of Scientific and Technical Information of China (English)

    孙鹿璐; 史健

    2016-01-01

    Angiotensin AngII, a linear small peptide,which is composed of eight amino acids, is the main effectors of renin-angiotensin systen (Renin-angiotensin system, ARS). AngII, a main biopolypeptide of the ARS, has important patho-physiologic in effects participating in cardiac hypertrophy, vascular cell proproliferation, inlfammation and tissue remodeling through G-protein-coupled receptors. In recent years, Ang II can promote tumor cell proliferation, tumor vessel formation and inhibit the differentiation of the tumor cells. hTis suggests that inhibit the production of AngII or block its effect is expected to become a new measure for the treatment of malignant tumors. hTis article reviews the advances in research on the relationship between AngII and its receptor and malignant tumor in recent years.%血管紧张素II(angiotensin II, AngII)是由8个氨基酸组成的线性小肽,是肾素-血管紧张素系统(re-nin-angiotensinsystem, ARS)主要的效应因子。AngII主要的作用受体有两个,血管紧张素II1型(angiotensin II 1 recep-tor, AT1R)和AT2R分别是AngII作用于靶细胞表面的特异性G蛋白偶联1型和2型受体。AngII通过上述两种受体参与调节血管舒缩、水盐平衡、炎性反应、细胞增殖、细胞凋亡等生物学功能。近年来发现AngII具有促进肿瘤细胞增殖、肿瘤血管形成并抑制肿瘤细胞分化的功能。这提示抑制AngII的产生或阻断其作用有望成为治疗恶性肿瘤的一项新措施。本文就近年来关于AngII及其受体与恶性肿瘤关系的研究进展作一综述。

  18. [The calf mortality of the Angeså reindeer herd (author's transl)].

    Science.gov (United States)

    Rehbinder, C

    1975-05-01

    The heavy losses of reindeer calves in the Angeså forest herd and their seasonal occurrence are discussed on basis of the results obtained from the tables. The management, productivity and breeding conditions of this herd are estimated to be, for the most part the same as in other forest herds. The calf losses in the Angeså herd are high, during some years very high, while the reproductivity rate is comparable to that of the caribou. The extensive form of management makes it impossible to clarify most of the causes for the losses and their interrelationships. Preobrazhenskii (1961) emphasizes the importance of an intensive form of management and of counting the herd at least four times annually in order to control and prevent different kinds of losses. Skjenneberg & Slagsvold (1968) point out that the extensive form of management hinders progress in reindeer breeding, especially in the areas of selection and disease control. These statements seem to be highly relevant to Swedish reindeer breeding as well. The results from the tables clearly indicate the high total losses, the high losses during certain summers and the importance of accessible winter fodder for calf production and post-natal survival. It is important to investigate whether supplementary feeding with commercially available fodder, hay, and minerals would result in better economy in reindeer breeding. It is also desirable to investigate improved methods for supplementary feeding. During certain years calf losses are very high during the summer, but the relationships between different causes (such as stress, bloodsucking diphtera, parasites, keratitis etc.) are not clear. Surveillance of the animals during the calving season, marking of the calves before the fly season and summer heat, and developing a higher degree of domestication will probably result in smaller losses during spring and summer. If the practice of marking the calves in summer is to be continued, steps must be taken to protect the

  19. The angiotensin-(1-7/Mas axis counteracts angiotensin II-dependent and –independent pro-inflammatory signaling in human vascular smooth muscle cells

    Directory of Open Access Journals (Sweden)

    Laura A Villalobos

    2016-12-01

    Full Text Available Background and aims: Targeting inflammation is nowadays considered as a challenging pharmacological strategy to prevent or delay the development of vascular diseases. Angiotensin-(1-7 is a member of the renin-angiotensin system (RAS that binds Mas receptors and has gained growing attention in the last years as a regulator of vascular homeostasis. Here, we explored the capacity of Ang-(1-7 to counteract human aortic smooth muscle cell (HASMC inflammation triggered by RAS-dependent and –independent stimuli, such as Ang II or interleukin (IL-1.Methods and Results: In cultured HASMC, the expression of iNOS and the release of nitric oxide were stimulated by both Ang II and IL-1, as determined by Western blot and indirect immunofluorescence or the Griess method, respectively. iNOS induction was inhibited by Ang-(1-7 in a concentration-dependent manner. This effect was equally blocked by two different Mas receptor antagonists, A779 and D-Pro7-Ang-(1-7, suggesting the participation of a unique Mas receptor subtype. Using pharmacological inhibitors, the induction of iNOS was proven to rely on the consecutive upstream activation of NADPH oxidase and NF-B. Indeed, Ang-(1-7 markedly inhibited the activation of the NADPH oxidase and subsequently of NF-B, as determined by lucigenin-derived chemiluminiscence and electromobility shift assay, respectively.Conclusion: Ang-(1-7 can act as a counter-regulator of the inflammation of vascular smooth muscle cells triggered by Ang II, but also by other stimuli beyond the RAS. Activating or mimicking the Ang-(1-7/Mas axis may represent a pharmacological opportunity to attenuate the pro-inflammatory environment that promotes and sustains the development of vascular diseases.

  20. The Angiotensin-(1-7)/Mas Axis Counteracts Angiotensin II-Dependent and -Independent Pro-inflammatory Signaling in Human Vascular Smooth Muscle Cells.

    Science.gov (United States)

    Villalobos, Laura A; San Hipólito-Luengo, Álvaro; Ramos-González, Mariella; Cercas, Elena; Vallejo, Susana; Romero, Alejandra; Romacho, Tania; Carraro, Raffaele; Sánchez-Ferrer, Carlos F; Peiró, Concepción

    2016-01-01

    Background and Aims: Targeting inflammation is nowadays considered as a challenging pharmacological strategy to prevent or delay the development of vascular diseases. Angiotensin-(1-7) is a member of the renin-angiotensin system (RAS) that binds Mas receptors and has gained growing attention in the last years as a regulator of vascular homeostasis. Here, we explored the capacity of Ang-(1-7) to counteract human aortic smooth muscle cell (HASMC) inflammation triggered by RAS-dependent and -independent stimuli, such as Ang II or interleukin (IL)-1β. Methods and Results: In cultured HASMC, the expression of inducible nitric oxide synthase (iNOS) and the release of nitric oxide were stimulated by both Ang II and IL-1β, as determined by Western blot and indirect immunofluorescence or the Griess method, respectively. iNOS induction was inhibited by Ang-(1-7) in a concentration-dependent manner. This effect was equally blocked by two different Mas receptor antagonists, A779 and D-Pro(7)-Ang-(1-7), suggesting the participation of a unique Mas receptor subtype. Using pharmacological inhibitors, the induction of iNOS was proven to rely on the consecutive upstream activation of NADPH oxidase and nuclear factor (NF)-κB. Indeed, Ang-(1-7) markedly inhibited the activation of the NADPH oxidase and subsequently of NF-κB, as determined by lucigenin-derived chemiluminescence and electromobility shift assay, respectively. Conclusion: Ang-(1-7) can act as a counter-regulator of the inflammation of vascular smooth muscle cells triggered by Ang II, but also by other stimuli beyond the RAS. Activating or mimicking the Ang-(1-7)/Mas axis may represent a pharmacological opportunity to attenuate the pro-inflammatory environment that promotes and sustains the development of vascular diseases.

  1. HDAC6 contributes to pathological responses of heart and skeletal muscle to chronic angiotensin-II signaling.

    Science.gov (United States)

    Demos-Davies, Kimberly M; Ferguson, Bradley S; Cavasin, Maria A; Mahaffey, Jennifer H; Williams, Sarah M; Spiltoir, Jessica I; Schuetze, Katherine B; Horn, Todd R; Chen, Bo; Ferrara, Claudia; Scellini, Beatrice; Piroddi, Nicoletta; Tesi, Chiara; Poggesi, Corrado; Jeong, Mark Y; McKinsey, Timothy A

    2014-07-15

    Little is known about the function of the cytoplasmic histone deacetylase HDAC6 in striated muscle. Here, we addressed the role of HDAC6 in cardiac and skeletal muscle remodeling induced by the peptide hormone angiotensin II (ANG II), which plays a central role in blood pressure control, heart failure, and associated skeletal muscle wasting. Comparable with wild-type (WT) mice, HDAC6 null mice developed cardiac hypertrophy and fibrosis in response to ANG II. However, whereas WT mice developed systolic dysfunction upon treatment with ANG II, cardiac function was maintained in HDAC6 null mice treated with ANG II for up to 8 wk. The cardioprotective effect of HDAC6 deletion was mimicked in WT mice treated with the small molecule HDAC6 inhibitor tubastatin A. HDAC6 null mice also exhibited improved left ventricular function in the setting of pressure overload mediated by transverse aortic constriction. HDAC6 inhibition appeared to preserve systolic function, in part, by enhancing cooperativity of myofibrillar force generation. Finally, we show that HDAC6 null mice are resistant to skeletal muscle wasting mediated by chronic ANG-II signaling. These findings define novel roles for HDAC6 in striated muscle and suggest potential for HDAC6-selective inhibitors for the treatment of cardiac dysfunction and muscle wasting in patients with heart failure. Copyright © 2014 the American Physiological Society.

  2. Perinatal 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure sensitizes offspring to angiotensin II-induced hypertension.

    Science.gov (United States)

    Aragon, Andrea C; Goens, M Beth; Carbett, Eleanor; Walker, Mary K

    2008-01-01

    In utero and lactational exposure of mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) leads to cardiac hypertrophy and hydronephrosis in adulthood. We tested the hypothesis that perinatal TCDD exposure increases the susceptibility to cardiovascular disease when offspring are exposed to a common cardiovascular disease risk factor, angiotensin II (Ang II). Pregnant C57BL/6N mice were exposed to corn oil (control) or 6.0 microg/kg TCDD on gestation day 14.5. Male offspring were then exposed to a subpressor (0.1 mg/kg/day) or pressor (0.7 mg/kg/day) dose of Ang II at 3.5 months and cardiac morphology and blood pressure analyzed, respectively. Perinatal TCDD exposure increased left ventricular cavity dilation during diastole, and wall thickness during diastole and systole. While Ang II stimulated an increase in wall thickness, the degree of increase was equivalent between control and TCDD offspring. In contrast, perinatal TCDD exposure did not alter basal blood pressure. However, Ang II increased systolic blood pressure more rapidly and to a greater degree in TCDD offspring. Further, Ang II stimulated renal myofibroblast differentiation and collagen deposition to a greater degree, and tended to increase procollagen I mRNA in TCDD offspring, compared to controls. These data suggest that perinatal TCDD exposure increases the susceptibility of offspring to renal fibrosis and hypertension in adulthood.

  3. Mechanical stress triggers cardiomyocyte autophagy through angiotensin II type 1 receptor-mediated p38MAP kinase independently of angiotensin II.

    Directory of Open Access Journals (Sweden)

    Li Lin

    Full Text Available Angiotensin II (Ang II type 1 (AT1 receptor is known to mediate a variety of physiological actions of Ang II including autophagy. However, the role of AT1 receptor in cardiomyocyte autophagy triggered by mechanical stress still remains elusive. The aim of this study was therefore to examine whether and how AT1 receptor participates in cardiomyocyte autophagy induced by mechanical stresses. A 48-hour mechanical stretch and a 4-week transverse aorta constriction (TAC were imposed to cultured cardiomyocytes of neonatal rats and adult male C57B/L6 mice, respectively, to induce cardiomyocyte hypertrophy prior to the assessment of cardiomyocyte autophagy using LC3b-II. Losartan, an AT1 receptor blocker, but not PD123319, the AT2 inhibitor, was found to significantly reduce mechanical stretch-induced LC3b-II upregulation. Moreover, inhibition of p38MAP kinase attenuated not only mechanical stretch-induced cardiomyocyte hypertrophy but also autophagy. To the contrary, inhibition of ERK and JNK suppressed cardiac hypertrophy but not autophagy. Intriguingly, mechanical stretch-induced autophagy was significantly inhibited by Losartan in the absence of Ang II. Taken together, our results indicate that mechanical stress triggers cardiomyocyte autophagy through AT1 receptor-mediated activation of p38MAP kinase independently of Ang II.

  4. Angiotensin II reactivation and aldosterone escape phenomena in renin-angiotensin-aldosterone system blockade: is oral renin inhibition the solution?

    Science.gov (United States)

    Athyros, Vasilios G; Mikhailidis, Dimitri P; Kakafika, Anna I; Tziomalos, Konstantinos; Karagiannis, Asterios

    2007-04-01

    This editorial considers the use of the first selective oral renin inhibitor, aliskiren, in reducing angiotensin (Ang) II reactivation or aldosterone (ALDO) escape during renin-angiotensin-aldosterone system (RAAS) inhibition. RAAS blockade with angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor AT(1) blockers (ARBs) is very useful for the treatment of arterial hypertension, chronic heart failure (CHF), atherosclerosis and diabetes. 'Ang II reactivation' and 'ALDO escape' or 'breakthrough' have been observed during either ACEI or ARB treatment, and may attenuate the clinical benefit of RAAS blockade. Renin and Ang I accumulate during ACE inhibition, and might overcome the ability of an ACEI to effectively suppress ACE activity. There is also data suggesting that 30 - 40% of Ang II formation in the healthy human during RAAS activation is formed via renin-dependent, but ACE-independent, pathways. Moreover, ACE gene polymorphisms contribute to the modulation and adequacy of the neurohormonal response to long-term ACE inhibition, at least in patients with CHF (up to 45% of CHF patients have elevated Ang II levels despite the long-term use of an ACEI) or diabetes. The reactivated Ang II promotes ALDO secretion and sodium reabsorption. ALDO breakthrough also occurs during long-term ARB therapy, mainly by an AT(2)-dependent mechanism. This was related to target-organ damage in animal models. Oral renin inhibition with aliskiren has showed excellent efficacy and safety in the treatment of hypertension. Aliskiren can be co-administered with ACEIs, ARBs or hydrochlorothiazide. Furthermore, there is evidence suggesting that aliskiren reduces Ang II reactivation in ACE inhibition and ALDO escape during treatment with an ACEI or an ARB, at least to the degree that this is associated with the RAAS. For RAAS-independent ALDO production, the combination of aliskiren with eplerenone might prove useful.

  5. Culture, power and identity The case of Ang Hien Hoo, Malang

    Directory of Open Access Journals (Sweden)

    Melani Budianta

    2017-05-01

    Full Text Available This paper discusses the intricate relations between culture and identity in a web of larger power structures of politics and the market by looking at the ways in which the Indonesian Chinese attach themselves to a local performing arts tradition. The paper focuses on the history of the wayang orang amateur club called Ang Hien Hoo in Malang, East Java, which emerged from a Chinese diaspora burial association, to attract national limelight in the 1950s and 1960s. In this paper, I see this amateur club as a site, not only for cultural assimilation, but also as a meeting space for the diverse migrant Chinese population residing at a host country. The space is used to negotiate their position as citizens responsible to promote and to become patrons of local traditional performing arts. The paper examines how this amateur club was swept by the Cold War politics and national political turmoil of 1965, and how it fought to survive under the pressures of the global capitalist era. What emerges from the findings is the contradictory fact that the identification of the Chinese with the Javanese traditional performing arts is affirmed precisely as it is marked by Chineseness. Thus, despite the cultural blending, the Chinese Indonesian’s patronage of local traditional art continuously reproduces the double bind of making home in the culture not seen as their own.

  6. A detailed study of the Beddington-DeAngelis predator-prey model.

    Science.gov (United States)

    Haque, Mainul

    2011-11-01

    The present investigation accounts for the influence of intra-specific competition among predators in the original Beddington-DeAngelis predator-prey model. We offer a detailed mathematical analysis of the model to describe some of the significant results that may be expected to arise from the interplay of deterministic and stochastic biological phenomena and processes. In particular, stability (local and global) and bifurcation (Saddle-node, Transcritical, Hopf-Andronov, Bogdanov-Takens) analysis of this model are conducted. Corresponding results from previous well known predator-prey models are compared with the current findings. Nevertheless, we also allow this model in stochastic environment with the influences of both, uncorrelated "white" noise and correlated "coloured" noise. This showing that competition among the predator population is beneficial for a number of predator-prey models by keeping them stable around its positive interior equilibrium (i.e. when both populations co-exist), under environmental stochasticity. Comparisons of these findings with the results of some earlier related investigations allow the general conclusion that predator intra-species competition benefits the predator-prey system under both deterministic and stochastic environments. Finally, an extended discussion of the ecological implications of the analytical and numerical results concludes the paper.

  7. Vasoconstricting effect of angiotensin II in human hand veins: influence of aging, diabetes mellitus and hypertension.

    Science.gov (United States)

    Harada, Kazuhiro; Ohmori, Masami; Fujimura, Akio

    2002-09-01

    We examined human hand veins to determine whether venoconstricting response to angiotensin II (Ang II) and noradrenaline (NA) was influenced by aging or such diseases as diabetes mellitus (DM) and hypertension (HT). Twenty healthy male subjects (20-73 years), and 8 male patients with non-insulin-dependent DM and 8 male patients with essential HT were included in this study. A constant dose (50 ng/min) of Ang II or increasing dose (2-256 ng/min) of NA was infused into the dorsal hand vein and its diameter was measured using a linear variable differential transformer. The constant infusion of Ang II caused rapid desensitization or tachyphylaxis. The venoconstriction by Ang II in the 8 elderly subjects (58 to 73 years) was significantly (p<0.05) larger than that in the 8 young subjects (20 to 36 years) from 6 to 18 min after the start of the infusion (after 6 min: 63.6+/-11.6 (mean+/-SD)% vs. 39.9+/-20.8%, 12 min: 34.0+/-11.9% vs. 12.0+/-12.0%). However, the venoconstriction by Ang II in the patients with DM or HT was not significantly different from that in the 9 age-matched control subjects. No significant difference in venoconstrictor response to NA was observed between the young and elderly subjects, nor between the control subjects and the patients with DM or HT. These findings indicated that venoconstrictor response to Ang II might be greater in the elderly but might not be influenced by DM nor HT.

  8. 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.

  9. Expression of angiotensin II receptors in the caprine ovary and improvement of follicular viability in vitro.

    Science.gov (United States)

    Bruno, J B; Lima-Verde, I B; Celestino, J J H; Lima, L F; Matos, M H T; Faustino, L R; Donato, M A M; Peixoto, C A; Campello, C C; Silva, J R V; Figueiredo, J R

    2016-08-01

    This study aimed to evaluate mRNA levels of angiotensin II (ANG II) receptors (AGTR1 and AGTR2) in caprine follicles and to investigate the influence of ANG II on the viability and in vitro growth of preantral follicles. Real-time polymerase chain reaction (PCR) was used to quantify AGTR1 and AGTR2 mRNA levels in the different follicular stages. For culture, caprine ovaries were collected, cut into 13 fragments and then either directly fixed for histological and ultrastructural analysis (fresh control) or placed in culture for 1 or 7 days in α-minumum essential medium plus (α-MEM+) with 0, 1, 5, 10, 50 or 100 ng/ml ANG II. Then, the fragments were destined to morphological, viability and ultrastructural analysis. The results showed that primordial follicles had higher levels of AGTR1 and AGTR2 mRNA than secondary follicles. Granulosa/theca cells from antral follicles had higher levels of AGTR1 mRNA than their respective cumulus-oocyte complex (COCs). After 7 days of culture, ANG II (10 or 50 ng/ml) maintained the percentages of normal follicles compared with α-MEM+. Fluorescence and ultrastructural microscopy confirmed follicular integrity in ANG II (10 ng/ml). In conclusion, a high expression of AGTR1 and AGTR2 is observed in primordial follicles. Granulosa/theca cells from antral follicles had higher levels of AGTR1 mRNA. Finally, 10 ng/ml ANG II maintained the viability of caprine preantral follicles after in vitro culture.

  10. Obligatory Role for B Cells in the Development of Angiotensin II-Dependent Hypertension.

    Science.gov (United States)

    Chan, Christopher T; Sobey, Christopher G; Lieu, Maggie; Ferens, Dorota; Kett, Michelle M; Diep, Henry; Kim, Hyun Ah; Krishnan, Shalini M; Lewis, Caitlin V; Salimova, Ekaterina; Tipping, Peter; Vinh, Antony; Samuel, Chrishan S; Peter, Karlheinz; Guzik, Tomasz J; Kyaw, Tin S; Toh, Ban-Hock; Bobik, Alexander; Drummond, Grant R

    2015-11-01

    Clinical hypertension is associated with raised serum IgG antibodies. However, whether antibodies are causative agents in hypertension remains unknown. We investigated whether hypertension in mice is associated with B-cell activation and IgG production and moreover whether B-cell/IgG deficiency affords protection against hypertension and vascular remodeling. Angiotensin II (Ang II) infusion (0.7 mg/kg per day; 28 days) was associated with (1) a 25% increase in the proportion of splenic B cells expressing the activation marker CD86, (2) an 80% increase in splenic plasma cell numbers, (3) a 500% increase in circulating IgG, and (4) marked IgG accumulation in the aortic adventitia. In B-cell-activating factor receptor-deficient (BAFF-R(-/-)) mice, which lack mature B cells, there was no evidence of Ang II-induced increases in serum IgG. Furthermore, the hypertensive response to Ang II was attenuated in BAFF-R(-/-) (Δ30±4 mm Hg) relative to wild-type (Δ41±5 mm Hg) mice, and this response was rescued by B-cell transfer. BAFF-R(-/-) mice displayed reduced IgG accumulation in the aorta, which was associated with 80% fewer aortic macrophages and a 70% reduction in transforming growth factor-β expression. BAFF-R(-/-) mice were also protected from Ang II-induced collagen deposition and aortic stiffening (assessed by pulse wave velocity analysis). Finally, like BAFF-R deficiency, pharmacological depletion of B cells with an anti-CD20 antibody attenuated Ang II-induced hypertension by ≈35%. Hence, these studies demonstrate that B cells/IgGs are crucial for the development of Ang II-induced hypertension and vessel remodeling in mice. Thus, B-cell-targeted therapies-currently used for autoimmune diseases-may hold promise as future treatments for hypertension.

  11. Use of Antihypertensive Drugs and Ischemic Stroke Severity - Is There a Role for Angiotensin-II?

    NARCIS (Netherlands)

    Hwong, Wen Yea; Bots, Michiel L.; Selvarajah, Sharmini; Aziz, Zariah Abdul; Sidek, Norsima Nazifah; Spiering, Wilko; Kappelle, L. Jaap; Vaartjes, Ilonca

    2016-01-01

    BACKGROUND: The increase in angiotensin II (Ang II) formation by selected antihypertensive drugs is said to exhibit neuroprotective properties, but this translation into improvement in clinical outcomes has been inconclusive. We undertook a study to investigate the relationship between types of

  12. Rosuvastatin attenuates angiotensin II-induced neointimal formation after stent implantation in the rat

    NARCIS (Netherlands)

    van der Harst, Pim; Groenewegen, Hendrik C.; Roks, Anton J. M.; Buikema, Hendrik; Zijlstra, Felix; van Gilst, Wiek H.; de Smet, Bart J. G. L.

    2008-01-01

    Objective We investigated the efficacy of oral rosuvastatin treatment to reduce in-stent neointima formation, both in the absence and presence of high levels of the proproliferative substance angiotensin II (Ang II). Background Drawbacks of current drug-eluting stents include inhibition of reendothe

  13. Use of Antihypertensive Drugs and Ischemic Stroke Severity - Is There a Role for Angiotensin-II?

    NARCIS (Netherlands)

    Hwong, Wen Yea; Bots, Michiel L.|info:eu-repo/dai/nl/110610032; Selvarajah, Sharmini|info:eu-repo/dai/nl/352274786; Aziz, Zariah Abdul; Sidek, Norsima Nazifah; Spiering, Wilko|info:eu-repo/dai/nl/269114173; Kappelle, L. Jaap; Vaartjes, Ilonca|info:eu-repo/dai/nl/304812102

    2016-01-01

    BACKGROUND: The increase in angiotensin II (Ang II) formation by selected antihypertensive drugs is said to exhibit neuroprotective properties, but this translation into improvement in clinical outcomes has been inconclusive. We undertook a study to investigate the relationship between types of anti

  14. Effect of angiotensin II on proliferation and differentiation of mouse induced pluripotent stem cells into mesodermal progenitor cells

    Energy Technology Data Exchange (ETDEWEB)

    Ishizuka, Toshiaki, E-mail: tishizu@ndmc.ac.jp [Department of Pharmacology, National Defense Medical College, Tokorozawa, Saitama 359-8513 (Japan); Goshima, Hazuki; Ozawa, Ayako; Watanabe, Yasuhiro [Department of Pharmacology, National Defense Medical College, Tokorozawa, Saitama 359-8513 (Japan)

    2012-03-30

    Highlights: Black-Right-Pointing-Pointer Treatment with angiotensin II enhanced LIF-induced DNA synthesis of mouse iPS cells. Black-Right-Pointing-Pointer Angiotensin II may enhance the DNA synthesis via induction of superoxide. Black-Right-Pointing-Pointer Treatment with angiotensin II significantly increased JAK/STAT3 phosphorylation. Black-Right-Pointing-Pointer Angiotensin II enhanced differentiation into mesodermal progenitor cells. Black-Right-Pointing-Pointer Angiotensin II may enhance the differentiation via activation of p38 MAPK. -- Abstract: Previous studies suggest that angiotensin receptor stimulation may enhance not only proliferation but also differentiation of undifferentiated stem/progenitor cells. Therefore, in the present study, we determined the involvement of the angiotensin receptor in the proliferation and differentiation of mouse induced pluripotent stem (iPS) cells. Stimulation with angiotensin II (Ang II) significantly increased DNA synthesis in mouse iPS cells cultured in a medium with leukemia inhibitory factor (LIF). Pretreatment of the cells with either candesartan (a selective Ang II type 1 receptor [AT{sub 1}R] antagonist) or Tempol (a cell-permeable superoxide scavenger) significantly inhibited Ang II-induced DNA synthesis. Treatment with Ang II significantly increased JAK/STAT3 phosphorylation. Pretreatment with candesartan significantly inhibited Ang II- induced JAK/STAT3 phosphorylation. In contrast, induction of mouse iPS cell differentiation into Flk-1-positive mesodermal progenitor cells was performed in type IV collagen (Col IV)- coated dishes in a differentiation medium without LIF. When Col IV-exposed iPS cells were treated with Ang II for 5 days, the expression of Flk-1 was significantly increased compared with that in the cells treated with the vehicle alone. Pretreatment of the cells with both candesartan and SB203580 (a p38 MAPK inhibitor) significantly inhibited the Ang II- induced increase in Flk-1 expression

  15. Cooperative Role of Mineralocorticoid Receptor and Caveolin-1 in Regulating the Vascular Response to Low Nitric Oxide-High Angiotensin II-Induced Cardiovascular Injury.

    Science.gov (United States)

    Pojoga, Luminita H; Yao, Tham M; Opsasnick, Lauren A; Siddiqui, Waleed T; Reslan, Ossama M; Adler, Gail K; Williams, Gordon H; Khalil, Raouf A

    2015-10-01

    Aldosterone interacts with mineralocorticoid receptor (MR) to stimulate sodium reabsorption in renal tubules and may also affect the vasculature. Caveolin-1 (cav-1), an anchoring protein in plasmalemmal caveolae, binds steroid receptors and also endothelial nitric oxide synthase, thus limiting its translocation and activation. To test for potential MR/cav-1 interaction in the vasculature, we investigated if MR blockade in cav-1-replete or -deficient states would alter vascular function in a mouse model of low nitric oxide (NO)-high angiotensin II (AngII)-induced cardiovascular injury. Wild-type (WT) and cav-1 knockout mice (cav-1(-/-)) consuming a high salt diet (4% NaCl) received Nω-nitro-l-arginine methyl ester (L-NAME) (0.1-0.2 mg/ml in drinking water at days 1-11) plus AngII (0.7-2.8 mg/kg per day via an osmotic minipump at days 8-11) ± MR antagonist eplerenone (EPL) 100 mg/kg per day in food. In both genotypes, blood pressure increased with L-NAME + AngII. EPL minimally changed blood pressure, although its dose was sufficient to block MR and reverse cardiac expression of the injury markers cluster of differentiation 68 and plasminogen activator inhibitor-1 in L-NAME+AngII treated mice. In aortic rings, phenylephrine and KCl contraction was enhanced with EPL in L-NAME+AngII treated WT mice, but not cav-1(-/-) mice. AngII-induced contraction was not different, and angiotensin type 1 receptor expression was reduced in L-NAME + AngII treated WT and cav-1(-/-) mice. In WT mice, acetylcholine-induced relaxation was enhanced with L-NAME + AngII treatment and reversed with EPL. Acetylcholine relaxation in cav-1(-/-) mice was greater than in WT mice, not modified by L-NAME + AngII or EPL, and blocked by ex vivo L-NAME, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), or endothelium removal, suggesting the role of NO-cGMP. Cardiac endothelial NO synthase was increased in cav-1(-/-) versus WT mice, further increased with L-NAME + AngII, and not affected by EPL

  16. Over-Expression of Copper/Zinc Superoxide Dismutase in the Median Preoptic Nucleus Attenuates Chronic Angiotensin II-Induced Hypertension in the Rat

    Directory of Open Access Journals (Sweden)

    John P. Collister

    2014-12-01

    Full Text Available The brain senses circulating levels of angiotensin II (AngII via circumventricular organs, such as the subfornical organ (SFO, and is thought to adjust sympathetic nervous system output accordingly via this neuro-hormonal communication. However, the cellular signaling mechanisms involved in these communications remain to be fully understood. Previous lesion studies of either the SFO, or the downstream median preoptic nucleus (MnPO have shown a diminution of the hypertensive effects of chronic AngII, without providing a clear explanation as to the intracellular signaling pathway(s involved. Additional studies have reported that over-expressing copper/zinc superoxide dismutase (CuZnSOD, an intracellular superoxide (O2·− scavenging enzyme, in the SFO attenuates chronic AngII-induced hypertension. Herein, we tested the hypothesis that overproduction of O2·− in the MnPO is an underlying mechanism in the long-term hypertensive effects of chronic AngII. Adenoviral vectors encoding human CuZnSOD (AdCuZnSOD or control vector (AdEmpty were injected directly into the MnPO of rats implanted with aortic telemetric transmitters for recording of arterial pressure. After a 3 day control period of saline infusion, rats were intravenously infused with AngII (10 ng/kg/min for ten days. Rats over-expressing CuZnSOD (n = 7 in the MnPO had a blood pressure increase of only 6 ± 2 mmHg after ten days of AngII infusion while blood pressure increased 21 ± 4 mmHg in AdEmpty-infected rats (n = 9. These results support the hypothesis that production of O2·− in the MnPO contributes to the development of chronic AngII-dependent hypertension.

  17. Angiotensin II induces an increase in MMP-2 expression in idiopathic ascending aortic aneurysm via AT1 receptor and JNK pathway.

    Science.gov (United States)

    Wang, Chunmao; Chang, Qian; Qian, Xiangyang; Tian, Chuan; Sun, Xiaogang

    2015-07-01

    The cellular and molecular mechanisms responsible for human idiopathic ascending aortic aneurysm (IAAA) remain unknown. Matrix metalloproteinase-2 (MMP-2) is a key enzyme for the degradation of extracellular matrix in aneurysmal walls. The aim of this study was to elucidate the role of the angiotensin II (Ang II) pathway in MMP-2 induction in IAAA aortic walls. Quantitative polymerase chain reaction and western blot analysis were used to compare the MMP-2 mRNA and protein levels in ascending aortic specimens with those in IAAA patients (n = 10) and heart transplant donors (n = 5) without any aortopathy. It was found that MMP-2 expression was significantly increased, which was associated with elastic lamellae disruption in IAAA walls. Additionally, the expression levels of angiotensinogen (AGT) and Ang II in the ascending aortic tissues from individuals with and without IAAAs were detected by western blot analysis and radioimmunoassay, respectively. The results demonstrated that the expressions of AGT and Ang II protein were significantly increased in the ascending aortic tissues of IAAA patients. Furthermore, whether Ang II induces MMP-2 expression was investigated using human IAAA walls ex vivo culture. It was found that exogenous Ang II increased the MMP-2 expression in a dose-dependent manner, which was completely inhibited by the Ang II type 1 receptor (AT1R) inhibitor candesartan and was mediated by c-Jun N-terminal kinase (JNK) activation. Taken together, these results indicate that Ang II can induce an increase of MMP-2 expression via AT1R and JNK in ex vivo cultured IAAA aortic walls, and suggest that angiotensin receptor blocker (ARB) drugs and JNK inhibitors have the potential in the prevention or treatment of IAAAs.

  18. Impact of losartan and angiotensin II on the expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in rat vascular smooth muscle cells.

    Science.gov (United States)

    Guo, Yan-Song; Wu, Zong-Gui; Yang, Jun-Ke; Chen, Xin-Jing

    2015-03-01

    The present study aimed to investigate the impact of losartan and angiotensin II (AngII) on the expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1), secreted by rat vascular smooth muscle cells (VSMCs). Rat VSMCs were isolated and cultured in different concentrations of AngII and losartan for 24 h and western blot analysis and quantitative polymerase chain reaction were performed to observe the subsequent impact on the gene and protein expression of MMP-9 and TIMP-1. AngII was shown to promote the protein and gene expression of MMP-9 in VSMCs in a concentration-dependent manner. No effect was observed on the expression of TIMP-1, therefore, an increase in the MMP-9/TIMP-1 ratio was observed. Losartan was shown to be able to inhibit MMP-9 protein and gene expression in a concentration-dependent manner, whilst promoting an increase in TIMP-1 expression, thus decreasing the ratio of MMP-9/TIMP-1. The combined action of losartan and AngII resulted in the same directional changes in MMP-9 and TIMP-1 expression as observed for losartan alone. The comparison of AngII, losartan and the combinatory effect on the expression of MMP-9 and TIMP-1 in VSMCs indicated that losartan inhibited the effects of AngII, therefore reducing the MMP-9/TIMP-1 ratio, which may contribute to the molecular mechanism of losartan in preventing atherosclerosis. In atherosclerosis, the development of the extracellular matrix of plaque is closely correlated with the evolution of AS. The balance between MMPs and TIMPs is important in maintaining the dynamic equilibrium between the ECM, and the renin-angiotensin-aldosterone system, which is involved in the pathologenesis of AS, and in which AngII has a central role.

  19. Role of the Na+/H+ exchanger 3 in angiotensin II-induced hypertension in NHE3-deficient mice with transgenic rescue of NHE3 in small intestines.

    Science.gov (United States)

    Li, Xiao C; Shull, Gary E; Miguel-Qin, Elisa; Chen, Fang; Zhuo, Jia L

    2015-11-01

    The role of Na(+/)H(+) exchanger 3 (NHE3) in the kidney in angiotensin II (ANG II)-induced hypertension remains unknown. The present study used global NHE3-deficient mice with transgenic rescue of the Nhe3 gene in small intestines (tgNhe3(-/-)) to test the hypothesis that genetic deletion of NHE3 selectively in the kidney attenuates ANG II-induced hypertension. Six groups of wild-type (tgNhe3(+/+)) and tgNhe3(-/-) mice were infused with either vehicle or ANG II (1.5 mg/kg/day, i.p., 2 weeks, or 10 nmol/min, i.v., 30 min), treated with or without losartan (20 mg/kg/day, p.o.) for 2 weeks. Basal systolic blood pressure (SBP) and mean intra-arterial blood pressure (MAP) were significantly lower in tgNhe3(-/-) mice (P excretion, urinary Na(+) excretion, urinary K(+) excretion, and urinary Cl(-) excretion were significantly lower in tgNhe3(-/-) mice (P < 0.01). These responses were associated with significantly elevated plasma ANG II and aldosterone levels, and marked upregulation in aquaporin 1, the Na(+)/HCO3 cotransporter, the α1 subunit isoform of Na(+)/K(+)-ATPase, protein kinase Cα, MAP kinases ERK1/2, and glycogen synthase kinase 3 α/β in the renal cortex of tgNhe3(-/-) mice (P < 0.01). ANG II infusion markedly increased SBP and MAP and renal cortical transporter and signaling proteins in tgNhe3(+/+), as expected, but all of these responses to ANG II were attenuated in tgNhe3(-/-) mice (P < 0.01). These results suggest that NHE3 in the kidney is necessary for maintaining normal blood pressure and fully developing ANG II-dependent hypertension.

  20. APE1/Ref-1 promotes the effect of angiotensin II on Ca2+ -activated K+ channel in human endothelial cells via suppression of NADPH oxidase.

    Science.gov (United States)

    Park, Won Sun; Ko, Eun A; Jung, In Duk; Son, Youn Kyoung; Kim, Hyoung Kyu; Kim, Nari; Park, So Youn; Hong, Ki Whan; Park, Yeong-Min; Choi, Tae-Hoon; Han, Jin

    2008-10-01

    The effects of angiotensin II (Ang II) on whole-cell large conductance Ca(2+)-activated K(+) (BK(Ca)) currents was investigated in control and Apurinic/apyrimidinic endonuclease1/redox factor 1 (APE1/Ref-1)-overexpressing human umbilical vein endothelial cells (HUVECs). Ang II blocked the BK(Ca) current in a dose-dependent fashion, and this inhibition was greater in APE1/Ref-1-overexpressing HUVECs than in control HUVECs (half-inhibition values of 102.81+/-9.54 nM and 11.34+/-0.39 nM in control and APE1/Ref-1-overexpressing HUVECs, respectively). Pretreatment with the NADPH oxidase inhibitor diphenyleneiodonium (DPI) or knock down of NADPH oxidase (p22 phox) using siRNA increased the inhibitory effect of Ang II on the BK(Ca) currents, similar to the effect of APE1/Ref-1 overexpression. In addition, application of Ang II increased the superoxide and hydrogen peroxide levels in the control HUVECs but not in APE1/Ref-1-overexpressing HUVECs. Furthermore, direct application of hydrogen peroxide increased BK(Ca) channel activity. Finally, the inhibitory effect of Ang II on the BK(Ca) current was blocked by an antagonist of the Ang II type 1 (AT(1)) receptor in both control and APE1/Ref-1-overexpressing HUVECs. From these results, we conclude that the inhibitory effect of Ang II on BK(Ca) channel function is NADPH oxidase-dependent and may be promoted by APE1/Ref-1.

  1. Construction, expression and immunogenicity of a novel anti-hypertension angiotensin II vaccine based on hepatitis A virus-like particle.

    Science.gov (United States)

    Ou, Xia; Guo, Lili; Wu, Jinyuan; Mi, Kai; Yin, Na; Zhang, Guangming; Li, Hongjun; Sun, Maosheng

    2013-06-01

    Hypertension is a serious worldwide public health problem. The aim of this study is to design anti-hypertension angiotensin II (Ang II) vaccine using molecular biology and immunological method. This novel anti-hypertension vaccine, which is a chimeric protein named pHAV-4Ang IIs, presents four successive repeated Ang IIs as the functional epitope on the surface of the hepatitis A virus-like particle(HAVLP). In this study, pHAV-4Ang IIs was expressed using Bac-to-Bac Baculovirus Expression System. With the RT-PCR analysis, SDS-PAGE, western blot, IFA, electron microscope methods for identification of expression products, these results confirmed that stable expression of pHAV-4Ang IIs can be effectively achieved in infected sf9 cells. Spontaneous hypertensive rats (SHRs) were immunized with pHAV-4Ang IIs to test immunogenicity and pharmacodynamic action. The results showed that this anti-hypertension vaccine can induce high titer Ang II -specific IgG antibody for almost 10 weeks. When antibody titer reached the peak at 8th week, the mean systolic blood pressure (SBP) degraded approximately 23 mmHg compared with the PBS control group, and the mean diastolic blood pressure (DBP) degraded approximately 12 mmHg compared with the PBS control group. These results suggest that this anti-hypertension vaccine has good immunogenicity and good effect on reduction of blood pressure in SHRs, which provide reliable base for large-scale preparation of this hypertension vaccine in the future, and a new direction of exploration for the development of anti-hypertension therapeutic vaccine.

  2. Dynamics of a nonautonomous predator-prey dispersion-delay system with Beddington-DeAngelis functional response

    Energy Technology Data Exchange (ETDEWEB)

    Cai Liming [Department of Mathematics, Xinyang Normal University, Xinyang 464000, Henan (China); Beijing Institute of Information Control, Beijing 100037 (China)], E-mail: lmcai06@yahoo.com.cn; Li Xuezhi [Department of Mathematics, Xinyang Normal University, Xinyang 464000, Henan (China); Yu Jingyuan [Beijing Institute of Information Control, Beijing 100037 (China); Zhu Guangtian [Academy of Mathematics and System Science, C.A.S., Beijing 100080 (China)

    2009-05-30

    A nonautonomous predator-prey dispersion-delay model with Beddington-DeAngelis functional response is investigated. It is proved that the general nonautonomous system is permanent and globally asymptotically stable under appropriate conditions. Furthermore, if the system is a(n) (almost) periodic one, a set of easily verifiable sufficient conditions are established, which guarantee the existence, uniqueness and global asymptotic stability of a positive (almost) periodic solution of the system.

  3. Antenatal betamethasone exposure is associated with lower ANG-(1–7) and increased ACE in the CSF of adult sheep

    Science.gov (United States)

    Marshall, Allyson C.; Shaltout, Hossam A.; Pirro, Nancy T.; Rose, James C.; Diz, Debra I.

    2013-01-01

    Antenatal betamethasone (BM) therapy accelerates lung development in preterm infants but may induce early programming events with long-term cardiovascular consequences. To elucidate these events, we developed a model of programming whereby pregnant ewes are administered BM (2 doses of 0.17 mg/kg) or vehicle at the 80th day of gestation and offspring are delivered at term. BM-exposed (BMX) offspring develop elevated blood pressure; decreased baroreflex sensitivity; and alterations in the circulating, renal, and brain renin-angiotensin systems (RAS) by 6 mo of age. We compared components of the choroid plexus fourth ventricle (ChP4) and cerebral spinal fluid (CSF) RAS between control and BMX male offspring at 6 mo of age. In the choroid plexus, high-molecular-weight renin protein and ANG I-intact angiotensinogen were unchanged between BMX and control animals. Angiotensin-converting enzyme 2 (ACE2) activity was threefold higher than either neprilysin (NEP) or angiotensin 1-converting enzyme (ACE) in control and BMX animals. Moreover, all three enzymes were equally enriched by approximately 2.5-fold in ChP4 brush-border membrane preparations. CSF ANG-(1–7) levels were significantly lower in BMX animals (351.8 ± 76.8 vs. 77.5 ± 29.7 fmol/mg; P < 0.05) and ACE activity was significantly higher (6.6 ± 0.5 vs. 8.9 ± 0.5 fmol·min−1·ml−1; P < 0.05), whereas ACE2 and NEP activities were below measurable limits. A thiol-sensitive peptidase contributed to the majority of ANG-(1–7) metabolism in the CSF, with higher activity in BMX animals. We conclude that in utero BM exposure alters CSF but not ChP RAS components, resulting in lower ANG-(1–7) levels in exposed animals. PMID:23948771

  4. Antenatal betamethasone exposure is associated with lower ANG-(1-7) and increased ACE in the CSF of adult sheep.

    Science.gov (United States)

    Marshall, Allyson C; Shaltout, Hossam A; Pirro, Nancy T; Rose, James C; Diz, Debra I; Chappell, Mark C

    2013-10-01

    Antenatal betamethasone (BM) therapy accelerates lung development in preterm infants but may induce early programming events with long-term cardiovascular consequences. To elucidate these events, we developed a model of programming whereby pregnant ewes are administered BM (2 doses of 0.17 mg/kg) or vehicle at the 80th day of gestation and offspring are delivered at term. BM-exposed (BMX) offspring develop elevated blood pressure; decreased baroreflex sensitivity; and alterations in the circulating, renal, and brain renin-angiotensin systems (RAS) by 6 mo of age. We compared components of the choroid plexus fourth ventricle (ChP4) and cerebral spinal fluid (CSF) RAS between control and BMX male offspring at 6 mo of age. In the choroid plexus, high-molecular-weight renin protein and ANG I-intact angiotensinogen were unchanged between BMX and control animals. Angiotensin-converting enzyme 2 (ACE2) activity was threefold higher than either neprilysin (NEP) or angiotensin 1-converting enzyme (ACE) in control and BMX animals. Moreover, all three enzymes were equally enriched by approximately 2.5-fold in ChP4 brush-border membrane preparations. CSF ANG-(1-7) levels were significantly lower in BMX animals (351.8 ± 76.8 vs. 77.5 ± 29.7 fmol/mg; P < 0.05) and ACE activity was significantly higher (6.6 ± 0.5 vs. 8.9 ± 0.5 fmol·min(-1)·ml(-1); P < 0.05), whereas ACE2 and NEP activities were below measurable limits. A thiol-sensitive peptidase contributed to the majority of ANG-(1-7) metabolism in the CSF, with higher activity in BMX animals. We conclude that in utero BM exposure alters CSF but not ChP RAS components, resulting in lower ANG-(1-7) levels in exposed animals.

  5. Effemeridi del transito meridiano 2017-2020 per la basilica di Santa Maria degli Angeli in Roma

    Science.gov (United States)

    Sigismondi, Costantino

    2016-12-01

    The meridian transit time is computed using the ephemerides of IMCCE and the position of the image's center on the 1702 meridian line is corrected for the average atmospheric refraction at the site of Santa Maria degli Angeli, SMA, in Rome. The ephemerides for 2017-2020 are public on http://www.icra.it/gerbertus/2016/effem-SMA.pdf The measurement at SMA of DUT1=-0.34s on Dec 2016 is in agreement with IERS bullettin D132.

  6. Blood Pressure and the Renal Actions of AT2 Receptors.

    Science.gov (United States)

    Carey, Robert M

    2017-03-01

    Angiotensin type-2 receptors (AT2Rs) in the renal proximal tubule inhibit sodium (Na+) reabsorption by inducing renal cyclic GMP formation and internalizing and inhibiting major Na+ transporters Na+-H+ exchanger-3 (NHE-3) and Na+/K+ATPase (NKA). Instead of angiotensin II (Ang II), angiotensin III (Ang III) is the predominant endogenous agonist for this response. Exogenous non-peptide AT2R agonist Compound-21 induces natriuresis and lowers blood pressure (BP) in normal and Ang II-infused hypertensive rodents. Spontaneously hypertensive rats (SHR; both pre-hypertensive and hypertensive) have defective natriuretic responses to Ang III, suggesting a defect in AT2R-mediated natriuresis in SHR that leads to hypertension. The mechanisms of deficient AT2R-mediated natriuresis in SHR are unknown but could involve either pre-receptor or receptor/post-receptor defects.

  7. Discovery of 1-[4-(N-benzylamino)phenyl]-3-phenylurea derivatives as non-peptidic selective SUMO-sentrin specific protease (SENP)1 inhibitors.

    Science.gov (United States)

    Uno, Masaharu; Koma, Yosuke; Ban, Hyun Seung; Nakamura, Hiroyuki

    2012-08-15

    We developed 1-[4-(N-benzylamino)phenyl]-3-phenylurea derivative 4 (GN6958) as a non-peptidic selective SUMO-sentrin specific protease (SENP)1 protease inhibitor based on the hypoxia inducible factor (HIF)-1α inhibitor 1 (GN6767). The direct interaction of compound 1 with SENP1 protein in cells was observed by the pull-down experiments using the biotin-tagged compound 2 coated on the streptavidin affinity column. Among the various 1-[4-(N-benzylamino)phenyl]-3-phenylurea derivatives tested, compounds 3 and 4 suppressed HIF-1α accumulation in a concentration-dependent manner without affecting the expression level of tubulin protein in HeLa cells. Both compounds inhibited SENP1 protease activity in a concentration-dependent manner, and compound 4 exhibited more potent inhibition than compound 3. Compound 4 exhibited selective inhibition against SENP1 protease activity without inhibiting other protease enzyme activities in vitro.

  8. Topical non-peptide antagonists of sensory neurotransmitters substance P and CGRP do not modify patch test and prick test reactions

    DEFF Research Database (Denmark)

    Wallengren, Joanna; Edvinsson, Lars

    2014-01-01

    developed. Their effect on the skin barrier was measured in terms of transepidermal water loss (TEWL) while permeation was calculated using permeation coefficients. Patch tests in patients allergic to nickel and prick test reactions to histamine were used as models. None of the treatments increased TEWL...... vasoconstriction in the skin but did not change the infiltration of nickel reactions. None of the treatments influenced the nickel patch test induced pruritus. The data suggest that the topical application of non-peptide antagonists penetrates the skin but does not inhibit contact dermatitis or pruritus.......Immunologic responses in the skin can be modulated by such neurotransmitters of sensory nerve fibers as substance P (SP) and calcitonin gene-related peptide (CGRP). The first-generation receptor antagonists were peptides with large molecules and had to be injected intracutaneously. The aim...

  9. Site-directed mutagenesis at the human B2 receptor and molecular modelling to define the pharmacophore of non-peptide bradykinin receptor antagonists.

    Science.gov (United States)

    Meini, Stefania; Cucchi, Paola; Bellucci, Francesca; Catalani, Claudio; Faiella, Angela; Rotondaro, Luigi; Quartara, Laura; Giolitti, Alessandro; Maggi, Carlo Alberto

    2004-02-15

    Combining site-directed mutagenesis with information obtained from molecular modelling of the bradykinin (BK) human B2 receptor (hB2R) as derived from the bovine rhodopsin crystal structure [Science 289 (2000) 739], we previously defined a putative binding mode for the non-peptide B2 receptor antagonists, FR173657 and LF16-0687 [Can J Physiol Pharmacol 80 (2002) 303]. The present work is aimed to define the specific role of the quinoline moiety in the pharmacophore of these non-peptide antagonists. The effect of the mutations I110A, L114A (TM, transmembrane 3), W256A (TM6), F292A, Y295A and Y295F (TM7) was evaluated. None of the mutations affected the binding interaction of peptide ligands: the agonist BK and the peptide antagonist MEN 11270. The affinities in competing for [3H]-BK binding and in blocking the BK-induced IP production by the non-peptide antagonists LF16-0687 and FR173657 at the wild type and mutant receptors were analysed. While the affinities of LF16-0687 and FR173657 were crucially decreased at the I110A, Y295A, and Y295F mutants, the W256A mutation affected the affinity of the LF16-0687 only. The important contribution of the quinoline moiety was shown by the inability of an analogue of LF16-0687, lacking this moiety, to affect BK binding at the wild type receptor. On the other hand, the benzamidine group did not interact with mutated residues, since LF16-0687 analogues without this group or with an oxidated benzamidine displayed pairwise loss of affinity on wild type and mutated receptors. Further differences between FR173657 and LF16-0687 were highlighted at the I110 and Y295 mutants when comparing binding (pK(i)) and functional antagonist (pKB) affinity. First, the I110A mutation similarly impaired their binding affinity (250-fold), but at a less extent the antagonist potency of FR173657 only. Second, both the hydroxyl and the phenyl moieties of the Y295 residue had a specific role in the LF16-0687 interaction with the receptor, as

  10. CGRP receptors mediating CGRP-, adrenomedullin- and amylin-induced relaxation in porcine coronary arteries. Characterization with 'Compound 1' (WO98/11128), a non-peptide antagonist

    DEFF Research Database (Denmark)

    Hasbak, P; Sams, A; Schifter, S

    2001-01-01

    1. Calcitonin gene-related peptide (CGRP), amylin and adrenomedullin (AM) belong to the same family of peptides. Accumulating evidence indicate that the calcitonin (CT) receptor, the CT receptor-like receptor (CRLR) and receptor-activity-modifying proteins (RAMPs) form the basis of all the recept......1. Calcitonin gene-related peptide (CGRP), amylin and adrenomedullin (AM) belong to the same family of peptides. Accumulating evidence indicate that the calcitonin (CT) receptor, the CT receptor-like receptor (CRLR) and receptor-activity-modifying proteins (RAMPs) form the basis of all....... The partial porcine mRNA sequences shared 82 - 92% nucleotide identity with human sequences. 3. The human peptides alphaCGRP, betaCGRP, AM and amylin induced relaxation with pEC(50) values of 8.1, 8.1, 6.7 and 6.1 M respectively. 4. The antagonistic properties of a novel non-peptide CGRP antagonist 'Compound...

  11. Neuropeptides and neuropeptide receptors: drug targets, and peptide and non-peptide ligands: a tribute to Prof. Dieter Seebach.

    Science.gov (United States)

    Hoyer, Daniel; Bartfai, Tamas

    2012-11-01

    both central and peripheral nervous system disorders. Both, receptor subtype-selective antagonists and agonists are being developed, as illustrated by the success of somatostatin agonists, angiotensin, and endothelin antagonists, and the expected clinical applications of NK-1/2/3 (substance P) receptor antagonists, CRF, vasopressin, NPY, neurotensin, orexin antagonists, or neuropeptide receptor modulators; such ligands have efficacy in preclinical or clinical models of pain and neuropsychiatric diseases, such as migraine, chronic/neuropathic pain, anxiety, sleep disorders, depression, and schizophrenia. In addition, both positive and negative allosteric modulators have been described with interesting in vivo activities (e.g., at galanin receptors). The field has become more complex now that an increasing number of heteromeric neuropeptide receptors are described, e.g., ghrelin receptors with 5-HT(2C) or dopamine D(1), D(2) receptors. At long last, structure-based drug discovery can now be envisaged with confidence, since crystal or solution structure of GPCRs and GPCR-ligand complexes, including peptide receptors, are published almost on a monthly basis. Finally, although most compounds acting at peptide receptors are still peptidomimetics, the last decade has seen the emergence of low-molecular-weight nonpeptide ligands (e.g., for orexin, ghrelin, or neurokinin receptors), and surprising progress has been made with β- and γ-peptides as very stable and potent mimetics of, e.g., somatostatin (SRIF), where the native SRIF has a half-life limited to 2-3 min. This last point will be illustrated more specifically, as we have had a long-standing collaboration with Prof. D. Seebach to whom this review is dedicated at the occasion of his 75th birthday.

  12. Grape seed proanthocyanidins inhibit colon cancer-induced angiogenesis through suppressing the expression of VEGF and Ang1.

    Science.gov (United States)

    Huang, Shuangsheng; Yang, Ninggang; Liu, Yuanyuan; Gao, Jing; Huang, Tao; Hu, Lamei; Zhao, Jin; Li, Yongquan; Li, Caili; Zhang, Xiaosu

    2012-12-01

    Tumor cells trigger angiogenesis through overexpression of various angiogenic factors including vascular endothelial growth factor (VEGF) and angiopoietin 1 (Ang1). Therefore, inhibition of the expression of both VEGF and Ang1, the initial step of tumor angiogenesis, is a promising strategy for cancer chemoprevention and therapy. Grape seed proanthocyanidins (GSPs) are widely consumed dietary supplements that have antitumor activity. Due to their polymeric structure, GSPs are poorly absorbed along the gastrointestinal tract and can reach the colon at high concentrations, allowing these chemicals to act as chemopreventive agents for colon cancer. In the present study, we found that GSPs inhibited colon tumor-induced angiogenesis and, thus, the growth of colon tumor xenografts on the chick chorioallantoic membranes. The mechanisms of their action were related to inhibiting the expression of both VEGF and Ang1 through scavenging reactive oxygen species. Previous studies have demonstrated that the chemopreventive effects of GSPs on colon cancer are associated with their growth inhibitory and apoptosis-inducing effects. Our results demonstrate another mechanism by which GSPs inhibit colon tumor growth, which will be helpful for developing GSPs as a pharmacologically safe angiopreventive agent against colorectal cancer.

  13. The AngFus3 Mitogen-Activated Protein Kinase Controls Hyphal Differentiation and Secondary Metabolism in Aspergillus niger.

    Science.gov (United States)

    Priegnitz, Bert-Ewald; Brandt, Ulrike; Pahirulzaman, Khomaizon A K; Dickschat, Jeroen S; Fleißner, André

    2015-06-01

    Adaptation to a changing environment is essential for the survival and propagation of sessile organisms, such as plants or fungi. Filamentous fungi commonly respond to a worsening of their growth conditions by differentiation of asexually or sexually produced spores. The formation of these specialized cell types is, however, also triggered as part of the general life cycle by hyphal age or density. Spores typically serve for dispersal and, therefore, translocation but can also act as resting states to endure times of scarcity. Eukaryotic differentiation in response to environmental and self-derived signals is commonly mediated by three-tiered mitogen-activated protein (MAP) kinase signaling cascades. Here, we report that the MAP kinase Fus3 of the black mold Aspergillus niger (AngFus3) and its upstream kinase AngSte7 control vegetative spore formation and secondary metabolism. Mutants lacking these kinases are defective in conidium induction in response to hyphal density but are fully competent in starvation-induced sporulation, indicating that conidiation in A. niger is triggered by various independent signals. In addition, the mutants exhibit an altered profile of volatile metabolites and secrete dark pigments into the growth medium, suggesting a dysregulation of the secondary metabolism. By assigning the AngFus3 MAP kinase pathway to the transduction of a potentially self-derived trigger, this work contributes to the unraveling of the intricate signaling networks controlling fungal differentiation. Moreover, our data further support earlier observations that differentiation and secondary metabolism are tightly linked in filamentous fungi.

  14. Novel Non-Peptide Inhibitors against SmCL1 of Schistosoma mansoni: In Silico Elucidation, Implications and Evaluation via Knowledge Based Drug Discovery.

    Science.gov (United States)

    Zafar, Atif; Ahmad, Sabahuddin; Rizvi, Asim; Ahmad, Masood

    2015-01-01

    Schistosomiasis is a major endemic disease known for excessive mortality and morbidity in developing countries. Because praziquantel is the only drug available for its treatment, the risk of drug resistance emphasizes the need to discover new drugs for this disease. Cathepsin SmCL1 is the critical target for drug design due to its essential role in the digestion of host proteins for growth and development of Schistosoma mansoni. Inhibiting the function of SmCL1 could control the wide spread of infections caused by S. mansoni in humans. With this objective, a homology modeling approach was used to obtain theoretical three-dimensional (3D) structure of SmCL1. In order to find the potential inhibitors of SmCL1, a plethora of in silico techniques were employed to screen non-peptide inhibitors against SmCL1 via structure-based drug discovery protocol. Receiver operating characteristic (ROC) curve analysis and molecular dynamics (MD) simulation were performed on the results of docked protein-ligand complexes to identify top ranking molecules against the modelled 3D structure of SmCL1. MD simulation results suggest the phytochemical Simalikalactone-D as a potential lead against SmCL1, whose pharmacophore model may be useful for future screening of potential drug molecules. To conclude, this is the first report to discuss the virtual screening of non-peptide inhibitors against SmCL1 of S. mansoni, with significant therapeutic potential. Results presented herein provide a valuable contribution to identify the significant leads and further derivatize them to suitable drug candidates for antischistosomal therapy.

  15. Bcl10 mediates angiotensin II-induced cardiac damage and electrical remodeling.

    Science.gov (United States)

    Markó, Lajos; Henke, Norbert; Park, Joon-Keun; Spallek, Bastian; Qadri, Fatimunnisa; Balogh, András; Apel, Ingrid J; Oravecz-Wilson, Katherine I; Choi, Mira; Przybyl, Lukasz; Binger, Katrina J; Haase, Nadine; Wilck, Nicola; Heuser, Arnd; Fokuhl, Verena; Ruland, Jürgen; Lucas, Peter C; McAllister-Lucas, Linda M; Luft, Friedrich C; Dechend, Ralf; Müller, Dominik N

    2014-11-01

    Angiotensin (Ang) II is a potent mediator of both hypertension and cardiac damage; however, the mechanisms by which this occur remain unclear. B-cell lymphoma/leukemia 10 (Bcl10) is a member of the CBM signalosome, which links Ang II and nuclear factor-κB signaling. We hypothesized that Bcl10 is pivotal in the pathogenesis of Ang II-induced cardiac damage. Ang II infusion in mice lacking Bcl10 resulted in reduced cardiac fibrosis, less cellular infiltration, and improved arrhythmogenic electric remodeling, despite a similar degree of hypertension or cardiac hypertrophy. Adoptive transfer of bone marrow (BM), whereby Bcl10 knockout or wildtype BM was transferred to their opposite genotype recipients, revealed the dual importance of Bcl10 within both cardiac and immune cells. Loss of Bcl10 in cardiac cells resulted in reduced expression of genes important for the adhesion and recruitment of immune cells. In vitro experiments demonstrated that adhesion of monocytes to Ang II-treated endothelial cells also required Bcl10. Additionally, Bcl10 deficiency in macrophages reduced their intrinsic migratory ability. To address the role of BM-derived fibroblasts in the formation of cardiac fibrosis, we explored whether Bcl10 is also important for the infiltration of BM-derived (myo)fibroblasts into the heart. The transfer of green fluorescent protein positive wildtype BM into Bcl10 knockout recipient mice revealed a reduced number of noncardiac (myo)fibroblasts compared with those wildtype recipients. Our results demonstrate the significant role of Bcl10 in multiple cell types important for the generation of Ang II-induced cardiac damage and electric remodeling and may provide a new avenue for therapeutic intervention.

  16. Nuclear angiotensin II type 2 (AT2) receptors are functionally linked to nitric oxide production.

    Science.gov (United States)

    Gwathmey, Tanya M; Shaltout, Hossam A; Pendergrass, Karl D; Pirro, Nancy T; Figueroa, Jorge P; Rose, James C; Diz, Debra I; Chappell, Mark C

    2009-06-01

    Expression of nuclear angiotensin II type 1 (AT(1)) receptors in rat kidney provides further support for the concept of an intracellular renin-angiotensin system. Thus we examined the cellular distribution of renal ANG II receptors in sheep to determine the existence and functional roles of intracellular ANG receptors in higher order species. Receptor binding was performed using the nonselective ANG II antagonist (125)I-[Sar(1),Thr(8)]-ANG II ((125)I-sarthran) with the AT(1) antagonist losartan (LOS) or the AT(2) antagonist PD123319 (PD) in isolated nuclei (NUC) and plasma membrane (PM) fractions obtained by differential centrifugation or density gradient separation. In both fetal and adult sheep kidney, PD competed for the majority of cortical NUC (> or =70%) and PM (> or =80%) sites while LOS competition predominated in medullary NUC (> or =75%) and PM (> or =70%). Immunodetection with an AT(2) antibody revealed a single approximately 42-kDa band in both NUC and PM extracts, suggesting a mature molecular form of the NUC receptor. Autoradiography for receptor subtypes localized AT(2) in the tubulointerstitium, AT(1) in the medulla and vasa recta, and both AT(1) and AT(2) in glomeruli. Loading of NUC with the fluorescent nitric oxide (NO) detector DAF showed increased NO production with ANG II (1 nM), which was abolished by PD and N-nitro-l-arginine methyl ester, but not LOS. Our studies demonstrate ANG II receptor subtypes are differentially expressed in ovine kidney, while nuclear AT(2) receptors are functionally linked to NO production. These findings provide further evidence of a functional intracellular renin-angiotensin system within the kidney, which may represent a therapeutic target for the regulation of blood pressure.

  17. Phosphodiesterase 5 inhibition ameliorates angiotensin II-dependent hypertension and renal vascular dysfunction.

    Science.gov (United States)

    Thieme, Manuel; Sivritas, Sema H; Mergia, Evanthia; Potthoff, Sebastian A; Yang, Guang; Hering, Lydia; Grave, Katharina; Hoch, Henning; Rump, Lars C; Stegbauer, Johannes

    2017-03-01

    Changes in renal hemodynamics have a major impact on blood pressure (BP). Angiotensin (Ang) II has been shown to induce vascular dysfunction by interacting with phosphodiesterase (PDE)1 and PDE5. The predominant PDE isoform responsible for renal vascular dysfunction in hypertension is unknown. Here, we measured the effects of PDE5 (sildenafil) or PDE1 (vinpocetine) inhibition on renal blood flow (RBF), BP, and renal vascular function in normotensive and hypertensive mice. During acute short-term Ang II infusion, sildenafil decreased BP and increased RBF in C57BL/6 (WT) mice. In contrast, vinpocetine showed no effect on RBF and BP. Additionally, renal cGMP levels were significantly increased after acute sildenafil but not after vinpocetine infusion, indicating a predominant role of PDE5 in renal vasculature. Furthermore, chronic Ang II infusion (500 ng·kg(-1)·min(-1)) increased BP and led to impaired NO-dependent vasodilation in kidneys of WT mice. Additional treatment with sildenafil (100 mg·kg(-1)·day(-1)) attenuated Ang II-dependent hypertension and improved NO-mediated vasodilation. During chronic Ang II infusion, urinary nitrite excretion, a marker for renal NO generation, was increased in WT mice, whereas renal cGMP generation was decreased and restored after sildenafil treatment, suggesting a preserved cGMP signaling after PDE5 inhibition. To investigate the dependency of PDE5 effects on NO/cGMP signaling, we next analyzed eNOS-KO mice, a mouse model characterized by low vascular NO/cGMP levels. In eNOS-KO mice, chronic Ang II infusion increased BP but did not impair NO-mediated vasodilation. Moreover, sildenafil did not influence BP or vascular function in eNOS-KO mice. These results highlight PDE5 as a key regulator of renal hemodynamics in hypertension. Copyright © 2017 the American Physiological Society.

  18. [Relation of intramyocardial collagen remodeling to the changes of myocardial systolic property and angiotensin II on the overtraining rats].

    Science.gov (United States)

    Tian, Zhen-Jun

    2002-02-01

    To investigate the relation of intramyocardial collagen (IMC) remodeling to the changes of myocardial systolic property (MSP) and angiotensin II (Ang II) on the overtraining rats. Morphologic remodeling of IMC and changes of contents of IMC and Ang II in myocardium local and circulation, and MSP in SD rat overtraining models were observed and determined by RM-6200 polygraph, Beckman-42 automatic biochemistry analyser, and gamma automatic radio-immunity analyzer and S-570 scanning electron microscope under the conditions. IMC forms a spatial three-dimensional network structure, consisting of collagenous fiber connection among myocardial bundles, cardiac muscle cell group, cardiac muscle cells, endocardium and capillary. There are some regularities in its interlacing. Overtraining could lead to over hyperplasia of IMC in myocardial bundles, cardiac muscle cell group, cardiac muscle cell, endocardium and capillary, and serious injury of MLSP. The relation closes to remodeling of IMC and MSP and Ang II on the overtraining.

  19. The paradox of dopamine and angiotensin II-mediated Na(+), K(+)-ATPase regulation in renal proximal tubules.

    Science.gov (United States)

    Zhang, Linan; Guo, Fang; Guo, Huicai; Wang, Haiyan; Zhang, Zhe; Liu, Xu; Shi, Xiaolu; Gou, Xiangbo; Su, Qian; Yin, Jian; Wang, Yongli

    2010-01-01

    Accumulated studies reported that the natruretic dopamine (DA) and the anti-natruretic angiotensin II (Ang II) represent an important mechanism to regulate renal Na(+) and water excretion through intracellular secondary messengers to inhibit or activate renal proximal tubule (PT) Na(+), K(+)-ATPase (NKA). The antagonistic actions were mediated by the phosphorylation of different position of NKA α₁-subunit and different Pals-associated tight junction protein (PATJ) PDZ domains, the different protein kinase C (PKC) isoforms (PKC-β, PKC-ζ), the common adenylyl cyclase (AC) pathway, and the crosstalk and balance between DA and Ang II to NKA regulation. Besides, Ang II-mediated NKA modulation has bi-phasic effects.

  20. Decreased angiotensin II binding affinity and binding capacity in the anterior pituitary gland of adult spontaneously hypertensive rats

    Energy Technology Data Exchange (ETDEWEB)

    Gutkind, J.S.; Castren, E.; Saavedra, J.M.

    1988-01-01

    Angiotensin II (ANG) binding sites were quantified in single pituitary glands from 4-week-old and 14-week-old male spontaneously hypertensive rats (SHR) and age-matched male normotensive Wistar-Kyoto (WKY) control rats after incubation with /sup 125/I-(Sar/sup 1/)-ANG, autoradiography with computerized densitometry, and comparison to /sup 125/I-standards. The maximum binding capacity (B/sub max/) decreased while the dissociation constant (K/sub d/) for ANG increased in 14-week-old SHR when compared to age-matched WKY control rats. Conversely, no difference between rat strains was found in 4-week-old animals. Our results suggest that pituitary ANG binding sites may play a role in the pathophysiology of established genetic hypertension.

  1. Renal graft failure after addition of an angiotensin II receptor antagonist to an angiotensin-converting enzyme inhibitor

    DEFF Research Database (Denmark)

    Kamper, Anne-Lise; Nielsen, Arne Høj; Baekgaard, Niels

    2002-01-01

    Combined treatment with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II (Ang II) receptor blocker (ARB) has been suggested in order to achieve a more complete blockade of the renin-angiotensin-aldosterone system in cardiovascular and renal disease. The present report...... describes a case of acute renal graft dysfunction following the addition of an ARB to existing ACE inhibition. This unmasked an unknown iliac artery stenosis. The case indicates a possible important role of Ang II generated by non-ACE pathways in this situation....

  2. Effects of female sex hormones on expression of the Ang-(1-7)/Mas-R/nNOS pathways in rat brain.

    Science.gov (United States)

    Cheng, Yuan; Li, Qiaoying; Zhang, Yidan; Wen, Quan; Zhao, Jianjun

    2015-11-01

    Female sex hormones are considered to reduce the risk of ischemic stroke. As a part of the renin-angiotensin system, angiotensin-(1-7) [Ang-(1-7)] has recently been reported to play a role in protecting neuronal tissues from ischemic stroke. Thus, we examined the effects of female sex hormones on the levels of Ang-(1-7) and its downstream pathways in the brain. Female rats were ovariectomized and 17β-estradiol (17β-EST), progesterone (PGR), or a combination of 17β-EST plus PGR were administered. Our data demonstrated that lack of female sex hormones significantly decreased the levels of Ang-(1-7) in the cerebral cortex and hippocampal CA1 area. Also, we observed a linear relationship between cortex levels of Ang-(1-7) and plasma brain natriuretic peptide levels (as an indicator for risk of ischemic stroke). We further showed that lack of female sex hormones decreased the expression of Ang-(1-7), Mas-receptor (Mas-R), and neuronal nitric oxide synthase (nNOS). Overall, our findings show for the first time that Ang-(1-7) and Mas-R/nNOS in the cortex are influenced by circulating 17β-EST and (or) PGR, whereas Ang-(1-7) and its pathways in the hippocampal CA1 area are primarily altered by 17β-EST. This suggests that female sex hormones play a role in regulating the expression of Ang-(1-7) and its pathways during ischemic brain injuries.

  3. Angiotensin II does not acutely regulate conduction velocity in rat atrial tissue

    DEFF Research Database (Denmark)

    Olsen, Kristine B; Braunstein, Thomas H; Sørensen, Charlotte M;

    2011-01-01

    . The aim of the current study was to investigate the acute effect of Ang II on conduction velocity (CV) in atrial tissue from normal and chronically infarcted rats. Methods. Contractile force was measured and CV was determined from the conduction time between electrodes placed on the tissue preparation...... and functional in the free wall preparation. The difference between free wall and auricle was probably not caused by differences in receptor expression since equal amounts of AT1 mRNA were present. To test if myocardial infarction (MI) sensitizes the atrium to Ang II, free atrial wall from rats subjected to 4...

  4. (Pro)renin receptor mediates both angiotensin II-dependent and -independent oxidative stress in neuronal cells.

    Science.gov (United States)

    Peng, Hua; Li, Wencheng; Seth, Dale M; Nair, Anand R; Francis, Joseph; Feng, Yumei

    2013-01-01

    The binding of renin or prorenin to the (pro)renin receptor (PRR) promotes angiotensin (Ang) II formation and mediates Ang II-independent signaling pathways. In the central nervous system (CNS), Ang II regulates blood pressure via inducing oxidative stress; however, the role of PRR-mediated Ang II-independent signaling pathways in oxidative stress in the CNS remains undefined. To address this question, Neuro-2A cells were infected with control virus or an adeno-associated virus encoding the human PRR. Human PRR over-expression alone increased ROS levels, NADPH oxidase activity, as well as NADPH oxidase (NOX) isoforms 2 and 4 mRNA expression levels and these effects were not blocked by losartan. Moreover, the increase in NOX 2 and NOX 4 mRNA levels, NADPH oxidase activity, and ROS levels induced by PRR over-expression was prevented by mitogen activated protein kinase/extracellular signal-regulated kinase 1 and 2 (MAPK/ERK1/2) inhibition, and phosphoinositide 3 kinase/Akt (IP3/Akt) inhibition, indicating that PRR regulates NOX activity and ROS formation in neuro-2A cells through Ang II-independent ERK1/2 and IP3/Akt activation. Interestingly, at a concentration of 2 nM or higher, prorenin promoted Ang II formation, and thus further increased the ROS levels in cultured Neuro-2A cells via PRR. In conclusion, human PRR over-expression induced ROS production through both angiotensin II-dependent and -independent mechanisms. We showed that PRR-mediated angiotensin II-independent ROS formation is associated with activation of the MAPK/ERK1/2 and PI3/Akt signaling pathways and up-regulation of mRNA level of NOX 2 and NOX4 isoforms in neuronal cells.

  5. Safflor yellow B suppresses angiotensin II-mediated human umbilical vein cell injury via regulation of Bcl-2/p22{sup phox} expression

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Chaoyun; He, Yanhao [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong 264003 (China); Department of Pharmacology, Xi' an Jiaotong University School of Medicine, Key Laboratory of Environment and Genes Related to Disease, Ministry of Education, Xi' an, Shaanxi 710061 (China); Yang, Ming; Sun, Hongliu; Zhang, Shuping [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong 264003 (China); Wang, Chunhua, E-mail: chunhuawang2012@163.com [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong 264003 (China)

    2013-11-15

    Intracellular reactive oxygen species (ROS) are derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Angiotensin II (Ang II) can cause endothelial dysfunction by promoting intracellular ROS generation. Safflor yellow B (SYB) effectively inhibits ROS generation by upregulating Bcl-2 expression. In this study, we examined the effects of SYB on Ang II-induced injury to human umbilical vein endothelial cells (HUVECs), and elucidated the roles of NADPH oxidase and Bcl-2. We treated cultured HUVECs with Ang II, SYB, and Bcl-2 siRNA, and determined NADPH oxidase activity and ROS levels. Furthermore, cellular and mitochondrial physiological states were evaluated, and the expression levels of target proteins were analyzed. Ang II significantly enhanced intracellular ROS levels, caused mitochondrial membrane dysfunction, and decreased cell viability, leading to apoptosis. This was associated with increased expression of AT1R and p22{sup phox}, increased NADPH oxidase activity, and an increased ratio of Bax/Bcl-2, leading to decreases in antioxidant enzyme activities, which were further strengthened after blocking Bcl-2. Compared to Ang II treatment alone, co-treatment with SYB significantly reversed HUVEC injury. Taken together, these results demonstrate that SYB could significantly protect endothelial cells from Ang II-induced cell damage, and that it does so by upregulating Bcl-2 expression and inhibiting ROS generation. - Highlights: • Angiotensin II depresses mitochondria physiological function. • Angiotensin II activates NADPH oxidase via up-regulating expresion of p22{sup phox}. • Bcl-2 plays a pivotal role in improving mitochondria function and regulates ROS level. • Inhibitor of Bcl-2 promotes angiotensin II mediated HUVEC injury. • SYB attenuates angiotensin II mediated HUVEC injury via up regulating Bcl-2 expression.

  6. Radiography evaluation of enhanced vascularization of COMP-Ang-1 on acellular nerve%COMP-Ang-1促去细胞神经血管化的放射显影法评价

    Institute of Scientific and Technical Information of China (English)

    丘龙海; 何波; 朱昭炜; 胡军; 刘小林; 朱家恺

    2015-01-01

    Objective To observe the way of vascularization of acellular nerves and evaluate the enhanced vascularization of using COMP-Ang-1 into acellular nerve on bridging sciatic nerve gaps by radiography.Methods From March,2013 to June,2014,acellular nerves were harvested by chemical extraction.Thirty-six female rats weighing 200-250 g were randomly divided into 2 groups:18 animals with 1 cm long sciatic nerve lesions were repaired by nerve grafting (control group),18 animals with 1 cm long sciatic nerve lesions were repaired by nerve grafting and COMP-Ang-1 were administrated after surgery.Grafts were harvested after perfusion of lead oxide (carotid artery) on day 7,day 14 and day 21 postoperatively.Radiography was performed to capture the two dimensional image.The rules of vascularization of acellular nerve and the enhanced effects of COMP-Ang-1 on vascularization were evaluated.Results The density of vessels in COMP-Ang-1 group were higher than control group after 7 days (2701.60 ± 318.93 vs.925.40 ± 106.22,P =0.030),14 days (3309.21 ± 381.31 vs.2832.70 ± 189.23,P =0.210) and 21 days (4787.33 ± 251.09 vs.3469.36 ± 232.10,P =0.030) postoperatively; the area of vessels in COMP-Ang-1 group were higher than control group after 7 days (9231.03 ± 581.91 μm2 vs.4839.01 ± 101.01 μm2,P =0.043) and 14 days (15561.13 ± 697.73 vs.6811.07 ± 250.05,P =0.049) postoperatively.Conclusion COMP-Ang-1 can enhance the vascularization of acellular nerves fairly.%目的 用放射显影法观察去细胞神经血管化方式及评价COMP-Ang-l促去细胞神经血管化效果. 方法 2013年3月-2014年6月,用化学试剂萃取法获得去细胞神经,36只雌性大鼠随机分成2组,每组18只,分别用去细胞神经(对照组)或去细胞神经加COMP-Ang-1(实验组)修复1 cm长的坐骨神经缺损大鼠模型:于术后7、14、21 d用氧化铅经颈动脉灌注取材,用放射显影法扫描去细胞神经,获得平面二维图,观察去细胞神经血管化方式及COMP-Ang

  7. [Codon optimization and eukaryotic expression analysis of the analgesic peptide gene BmK AngM1 from Buthus martensii Karsch].

    Science.gov (United States)

    Yang, Jin-ling; Gao, Li-li; Zhu, Ping; Hou, Qi; Wang, Fen; Yu, Wen-bo; Nie, Tao

    2012-10-01

    Codon bias is an important factor which influences heterologous gene expression. Optimizing codon sequence could improve expression level of heterologous gene. In order to improve the expression level of BmK AngM1 gene encoding the analgesic peptide from Buthus martensii Karsch in Pichia pastoris, the codon-optimized BmK AngM1 gene according to its cDNA sequence and the preference codon usage of P. pastoris were cloned into expression vector pPIC9K and then transformed into P. pastoris. The expersion of recombinant BmK AngM1 (rBmK AngM1) was inducced by methanol in the medium, and the expression level of the optimized BmK AngM1 gene was 3.7 times of the native one. These results suggested that the expression of BmK AngM1 in P. pastoris could be successfully improved by codon optimization.

  8. Identification of Distinct Conformations of the Angiotensin-II Type 1 Receptor Associated with the Gq/11 Protein Pathway and the β-Arrestin Pathway Using Molecular Dynamics Simulations*

    Science.gov (United States)

    Cabana, Jérôme; Holleran, Brian; Leduc, Richard; Escher, Emanuel; Guillemette, Gaétan; Lavigne, Pierre

    2015-01-01

    Biased signaling represents the ability of G protein-coupled receptors to engage distinct pathways with various efficacies depending on the ligand used or on mutations in the receptor. The angiotensin-II type 1 (AT1) receptor, a prototypical class A G protein-coupled receptor, can activate various effectors upon stimulation with the endogenous ligand angiotensin-II (AngII), including the Gq/11 protein and β-arrestins. It is believed that the activation of those two pathways can be associated with distinct conformations of the AT1 receptor. To verify this hypothesis, microseconds of molecular dynamics simulations were computed to explore the conformational landscape sampled by the WT-AT1 receptor, the N111G-AT1 receptor (constitutively active and biased for the Gq/11 pathway), and the D74N-AT1 receptor (biased for the β-arrestin1 and -2 pathways) in their apo-forms and in complex with AngII. The molecular dynamics simulations of the AngII-WT-AT1, N111G-AT1, and AngII-N111G-AT1 receptors revealed specific structural rearrangements compared with the initial and ground state of the receptor. Simulations of the D74N-AT1 receptor revealed that the mutation stabilizes the receptor in the initial ground state. The presence of AngII further stabilized the ground state of the D74N-AT1 receptor. The biased agonist [Sar1,Ile8]AngII also showed a preference for the ground state of the WT-AT1 receptor compared with AngII. These results suggest that activation of the Gq/11 pathway is associated with a specific conformational transition stabilized by the agonist, whereas the activation of the β-arrestin pathway is linked to the stabilization of the ground state of the receptor. PMID:25934394

  9. Rational design and identification of a non-peptidic aggregation inhibitor of amyloid-β based on a pharmacophore motif obtained from cyclo[-Lys-Leu-Val-Phe-Phe-].

    Science.gov (United States)

    Arai, Tadamasa; Araya, Takushi; Sasaki, Daisuke; Taniguchi, Atsuhiko; Sato, Takeshi; Sohma, Youhei; Kanai, Motomu

    2014-07-28

    Inhibition of pathogenic protein aggregation may be an important and straightforward therapeutic strategy for curing amyloid diseases. Small-molecule aggregation inhibitors of Alzheimer's amyloid-β (Aβ) are extremely scarce, however, and are mainly restricted to dye- and polyphenol-type compounds that lack drug-likeness. Based on the structure-activity relationship of cyclic Aβ16-20 (cyclo-[KLVFF]), we identified unique pharmacophore motifs comprising side-chains of Leu(2), Val(3), Phe(4), and Phe(5) residues without involvement of the backbone amide bonds to inhibit Aβ aggregation. This finding allowed us to design non-peptidic, small-molecule aggregation inhibitors that possess potent activity. These molecules are the first successful non-peptidic, small-molecule aggregation inhibitors of amyloids based on rational molecular design.

  10. [Effect of lycium bararum polysaccharides on angiotensin II-induced senescence of human umbilical vein endothelial cells and expressions of P53 and P16].

    Science.gov (United States)

    Liu, Ling; Wang, Xue-ni; Liu, Ze; Wang, Lu-ni; Wu, Jun; Wang, Wei; Feng, Ju-xiang

    2011-06-01

    To investigate the role of lycium bararum polysaccharides (LBP) on angiotensin II (AngII)-induced senescence of human umbilical vein endothelial cells (HUVECs) and expressions of P53 and P16 and explore the mechanism of LBP against aging. HUVECs cultured in vitro were stimulated with 1×10(-6) mmol/L AngII to induce cell senescence, which was identified using β-gal staining. Flow cytometry was used for analyzing the cell cycle changes, and the cell viability was assessed using CCK-8 method. Western blotting was employed to detect the expression of P53 and P16 in the exposed cells. Compared with the control cells, the cells positive for β-gal staining was significantly increased in AngII group, and showed cell cycle arrest at G(0)/G(1) phase with decreased S-phase cell percentage and cell viability. The expression levels of P53 and P16 were significantly increased in the cells with AngII exposure (PP16 (P<0.05). LBP can delay AngII-induced aging of HUVECs possibly by down-regulating the expression of P53 and P15.

  11. Cardiovascular and single-unit responses to microinjection of angiotensin II into the bed nucleus of the stria terminalis in rat.

    Science.gov (United States)

    Kafami, M; Nasimi, A

    2015-08-06

    The bed nucleus of the stria terminalis (BST) is part of the limbic system located in the rostral forebrain. BST is involved in behavioral, neuroendocrine and autonomic functions, including cardiovascular regulation. The angiotensin II (Ang II) receptor, AT1, was found in the BST, however its effects on the cardiovascular system and on single-unit responses have not been studied yet. In the present study, Ang II was microinjected into the BST of anesthetized rats and cardiovascular and single-unit responses were recorded simultaneously. Furthermore the responses were re-tested after the microinjection of a blocker of the AT1 receptor, losartan, into the BST. We found that microinjection of Ang II into the BST produced a pressor response of 11±1mmHg for a duration of 2-8min. Ang II had no consistent effect on heart rate. It also produced two types of single-unit responses in the BST, short excitatory and long inhibitory. Blockade of AT1 receptors abolished both the cardiovascular and single-unit responses, indicating that the responses were mediated through AT1 receptors. These findings imply that Ang II may be utilized as a neurotransmitter and may play a role in returning blood pressure toward normal during hypotension. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  12. Age determines the magnitudes of angiotensin II-induced contractions, mRNA, and protein expression of angiotensin type 1 receptors in rat carotid arteries.

    Science.gov (United States)

    Vamos, Zoltan; Cseplo, Peter; Ivic, Ivan; Matics, Robert; Hamar, Janos; Koller, Akos

    2014-05-01

    In this study, we hypothesized that aging alters angiotensin II (Ang II)-induced vasomotor responses and expression of vascular mRNA and protein angiotensin type 1 receptor (AT1R). Thus, carotid arteries were isolated from the following age groups of rats: 8 days, 2-9 months, 12-20 months, and 20-30 months, and their vasomotor responses were measured in a myograph after repeated administrations of Ang II. Vascular relative AT1R mRNA level was determined by quantitative reverse-transcriptase polymerase chain reaction and the AT1R protein density was measured by Western blot. Contractions to the first administration of Ang II increased from 8 days to 6 months and then they decreased to 30 months. In general, second administration of Ang II elicited reduced contractions, but they also increased from 8 days until 2 months and then they decreased to 30 months. Similarly the AT1R mRNA level increased from 8 days to 12 months and then decreased to 30 months. Similarly the AT1R protein density increased from 8 days until 16 months and then they decreased to 30 months. The pattern of these changes correlated with functional vasomotor data. We conclude that aging (newborn to senescence) has substantial effects on Ang II-induced vasomotor responses and AT1R signaling suggesting the importance of genetic programs.

  13. High-Dose Estradiol-Replacement Therapy Enhances the Renal Vascular Response to Angiotensin II via an AT2-Receptor Dependent Mechanism

    Directory of Open Access Journals (Sweden)

    Tahereh Safari

    2015-01-01

    Full Text Available Physiological levels of estrogen appear to enhance angiotensin type 2 receptor- (AT2R- mediated vasodilatation. However, the effects of supraphysiological levels of estrogen, analogous to those achieved with high-dose estrogen replacement therapy in postmenopausal women, remain unknown. Therefore, we pretreated ovariectomized rats with a relatively high dose of estrogen (0.5 mg/kg/week for two weeks. Subsequently, renal hemodynamic responses to intravenous angiotensin II (Ang II, 30–300 ng/kg/min were tested under anesthesia, while renal perfusion pressure was held constant. The role of AT2R was examined by pretreating groups of rats with PD123319 or its vehicle. Renal blood flow (RBF decreased in a dose-related manner in response to Ang II. Responses to Ang II were enhanced by pretreatment with estradiol. For example, at 300 ng kg−1 min−1, Ang II reduced RBF by 45.7±1.9% in estradiol-treated rats but only by 27.3±5.1% in vehicle-treated rats. Pretreatment with PD123319 blunted the response of RBF to Ang II in estradiol-treated rats, so that reductions in RBF were similar to those in rats not treated with estradiol. We conclude that supraphysiological levels of estrogen promote AT2R-mediated renal vasoconstriction. This mechanism could potentially contribute to the increased risk of cardiovascular disease associated with hormone replacement therapy using high-dose estrogen.

  14. Quercetin and isorhamnetin prevent endothelial dysfunction, superoxide production, and overexpression of p47phox induced by angiotensin II in rat aorta.

    Science.gov (United States)

    Sanchez, Manuel; Lodi, Federica; Vera, Rocio; Villar, Inmaculada C; Cogolludo, Angel; Jimenez, Rosario; Moreno, Laura; Romero, Miguel; Tamargo, Juan; Perez-Vizcaino, Francisco; Duarte, Juan

    2007-04-01

    The dietary flavonoid quercetin reduces blood pressure and improves endothelial function in several rat models of hypertension. We analyzed the effects of quercetin and its methylated metabolite isorhamnetin on the aortic endothelial dysfunction induced by incubation with angiotensin II (AngII) in vitro for 6 h. AngII diminished the relaxant responses to acetylcholine in phenylephrine-contracted aorta. Coincubation with quercetin or isorhamnetin, or addition of superoxide (O(2)(-)) dismutase or apocynin to the assay medium, prevented these inhibitory effects. At 6 h, AngII induced a marked increase in O(2)(-) production as measured by dihydroethidium fluorescence, which was prevented by quercetin and isorhamnetin. AngII also increased the expression of p47(phox), a regulatory subunit of the membrane NADPH oxidase. Immunohistochemical analysis revealed that overexpression of p47(phox) occurred mainly in the medial layer. p47(phox) overexpression was also prevented by quercetin and isorhamnetin. Taken together, these results show for the first time, to our knowledge, that quercetin and isorhamnetin prevent AngII-induced endothelial dysfunction by inhibiting the overexpression of p47(phox) and the subsequent increased O(2)(-) production, resulting in increased nitric oxide bioavailability.

  15. Tumor necrosis factor-α inhibits angiotensin II receptor type 1 expression in dorsal root ganglion neurons via β-catenin signaling.

    Science.gov (United States)

    Yang, Y; Wu, H; Yan, J-Q; Song, Z-B; Guo, Q-L

    2013-09-17

    Both tumor necrosis factor (TNF)-α and the angiotensin (Ang) II/angiotensin II receptor type 1 (AT1) axis play important roles in neuropathic pain and nociception. In the present study, we explored the interaction between the two systems by examining the mutual effects between TNF-α and the Ang II/AT1 receptor axis in dorsal root ganglion (DRG) neurons. Rat DRG neurons were treated with TNF-α in different concentrations for different lengths of time in the presence or absence of transcription inhibitor actinomycin D, TNF receptor 1 (TNFR1) inhibitor SPD304, β-catenin signaling inhibitor CCT031374, or different kinase inhibitors. TNF-α decreased the AT1 receptor mRNA level as well as the AT1a receptor promoter activity in a dose-dependent manner within 30 h, which led to dose-dependent inhibition of Ang II-binding AT1 receptor level on the cell membrane. Actinomycin D (1 mg/ml), SPD304 (50 μM), p38 mitogen-activated protein kinase (MAPK) inhibitor PD169316 (25 μM), and CCT031374 (50 μM) completely abolished the inhibitory effect of TNF-α on AT1 receptor expression. TNF-α dose-dependently increased soluble β-catenin and phosphorylated GSK-3β levels, which was blocked by SPD304 and PD169316. In DRG neurons treated with AT2 receptor agonist CGP421140, or Ang II with or without AT1 receptor antagonist losartan or AT2 receptor antagonist PD123319 for 30 h, we found that Ang II and Ang II+PD123319 significantly decreased TNF-α expression, whereas CPG421140 and Ang II+losartan increased TNF-α expression. In conclusion, we demonstrate that TNF-α inhibits AT1 receptor expression at the transcription level via TNFR1 in rat DRG neurons by increasing the soluble β-catenin level through the p38 MAPK/GSK-3β pathway. In addition, Ang II appears to inhibit and induce TNF-α expression via the AT1 receptor and the AT2 receptor in DRG neurons, respectively. This is the first evidence of crosstalk between TNF-α and the Ang II/AT receptor axis in DRG neurons.

  16. Angiotensin II induces apoptosis of human pulmonary microvascular endothelial cells in acute aortic dissection complicated with lung injury patients through modulating the expression of monocyte chemoattractant protein-1.

    Science.gov (United States)

    Wu, Zhiyong; Dai, Feifeng; Ren, Wei; Liu, Huagang; Li, Bowen; Chang, Jinxing

    2016-01-01

    Patients with acute aortic dissection (AAD) usually showed acute lung injury (ALI). However, its pathogenesis is still not well defined. Apoptosis of pulmonary microvascular endothelial cells (PMVECs) is closely related to the alveolus-capillary barrier injury and the increased vascular permeability. In this study, we aim to investigate the human PMVECs (hPMVECs) apoptosis induced by angiotensin II (AngII) and monocyte chemoattractant protein-1 (MCP-1) and their potential interaction in the pathogenesis of AAD complicated with ALI. Fifty-eight newly diagnosed AAD, 12 matched healthy individuals were included. Pulmonary tissues of AAD complicated with lung injury were obtained from 2 cadavers to determine the levels of AngII type 1 receptor (AT1-R) and MCP-1. Serum AngII was measured using commercial ELISA kit. H&E staining and immunohistostaining were performed to determine the expression of AT1-R and MCP-1. For the in vitro experiment, hPMVECs were divided into control, AngII group, AngII+Bindarit group and Bindarit group, respectively. Flow cytometry was performed to analyze the apoptosis in each group. Reverse transcription-polymerase chain reaction was performed to determine the mRNA expression of MCP-1. Western blot analysis was performed to evaluate the expression of MCP-1 and apoptosis related protein. Apoptosis of hPMVECs was observed in the lung tissues in the cadavers with AAD complicated with ALI. Besides, the expression of AT1-R and MCP-1 was remarkably elevated. Compared with normal individuals and the non-lung injury AAD patients, the expression of serum AngII was remarkably elevated in AAD patients complicated with ALI. In vitro experiments showed AngII contributed to the apoptosis and elevation of MCP1 in hPMVECs. Besides, it involved in the down-regulation of Bcl-2 protein, and up-regulation of Bax and Caspase-3. Such phenomenon was completely reversed after administration of MCP-1 inhibitor (Bindarit). The production of MCP-1 and cellular

  17. Telmisartan prevents angiotensin II-induced endothelial dysfunction in rabbit aorta via activating HGF/Met system and PPARγ pathway.

    Science.gov (United States)

    Hu, Ze-Ping; Fang, Xiao-Ling; Qian, Hai-Yan; Fang, Nan; Wang, Bang-Ning; Wang, Yuan

    2014-10-01

    Telmisartan with partial activation of peroxisome proliferator-activated receptor γ (PPARγ) powerfully reduces blood pressure, improves endothelial function and lipid metabolism. Hepatocyte growth factor/mesenchymal-epithelial transition factor (HGF/Met) system in the local vasculature plays a pivotal role in maintaining normal endothelial function. This study is aimed to evaluate whether telmisartan directly prevents angiotensin II (Ang II)-induced endothelial dysfunction (ED) via activating HGF/Met system and/or PPARγ pathway. The isolated aortic rings of rabbits were incubated with Ang II (0.01-1 μM), telmisartan (0.1-10 μM), SU11274 (5 μM) as a specific Met inhibitor, GW9662 (10 μM) as a PPARγ antagonist alone or a combination for 6 h. Ang II obviously inhibited the mRNA and protein expression of HGF, Met and PPARγ, and the accumulative concentration-relaxation of the aortic rings to acetylcholine, among which the inhibitory effect of 1 μM Ang II was most significant. By contrast, telmisartan significantly increased the mRNA and protein expression of HGF, Met, and PPARγ, thus preventing Ang II-induced ED in a dose-dependent pattern. However, SU11274, GW9662 or a combination of both partially abolished the protective effects derived from telmisartan, with the effect of SU11274 exceeding that of GW9662. These results demonstrate that Ang II-induced ED in rabbit aortic rings in vitro can be prevented by telmisartan through selective PPARγ-modulating pathway. Moreover, this study indicates for the first time that activating HGF/Met system in the local vasculature is involved in the protective mechanism of telmisartan. © 2013 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.

  18. Glucose and angiotensin II-derived endothelial extracellular vesicles regulate endothelial dysfunction via ERK1/2 activation.

    Science.gov (United States)

    Taguchi, Kumiko; Hida, Mari; Narimatsu, Haruka; Matsumoto, Takayuki; Kobayashi, Tsuneo

    2017-02-01

    In various diseases, including diabetes, extracellular vesicles (EVs) have been detected in circulation and tissues. EVs are small membrane vesicles released from various cell types under varying conditions. Recently, endothelial cell-derived EVs (EEVs) were identified as a marker of endothelial dysfunction in diabetes, but the ensuing mechanisms remain poorly understood. In this study, we dissected the ensuing pathways with respect to nitric oxide (NO) production under the condition of type 2 diabetes. Human umbilical vein endothelial cells (HUVECs) were stimulated with glucose alone and with glucose in combination with angiotensin II (Ang II) for 48 h. In supernatants from glucose + Ang II-stimulated HUVECs, release of EEVs was assessed using Western blotting with an anti-CD144 antibody. EEV release was significantly increased after stimulation of HUVECs, and high glucose + Ang II-derived EEVs impaired ACh-induced vascular relaxation responses and NO production in mice aortic rings. Furthermore, high glucose + Ang II-derived EEVs induced ERK1/2 signalling and decreased endothelial NO synthase (eNOS) protein expression in mice aortas. Furthermore, in the presence of the MEK/ERK1/2 inhibitor PD98059, high glucose plus Ang II treatment stimulated EEVs in HUVECs and those EEVs prevented the impairments of ACh-induced relaxation and NO production in mice aortas. These data strongly indicate that high glucose and Ang II directly affect endothelial cells and the production of EEVs; the resultant EEVs aggravate endothelial dysfunction by regulating eNOS protein levels and ERK1/2 signalling in mice aortas.

  19. Protection zone in a diffusive predator-prey model with Beddington-DeAngelis functional response.

    Science.gov (United States)

    He, Xiao; Zheng, Sining

    2016-12-03

    In any reaction-diffusion system of predator-prey models, the population densities of species are determined by the interactions between them, together with the influences from the spatial environments surrounding them. Generally, the prey species would die out when their birth rate is too low, the habitat size is too small, the predator grows too fast, or the predation pressure is too high. To save the endangered prey species, some human interference is useful, such as creating a protection zone where the prey could cross the boundary freely but the predator is prohibited from entering. This paper studies the existence of positive steady states to a predator-prey model with reaction-diffusion terms, Beddington-DeAngelis type functional response and non-flux boundary conditions. It is shown that there is a threshold value [Formula: see text] which characterizes the refuge ability of prey such that the positivity of prey population can be ensured if either the prey's birth rate satisfies [Formula: see text] (no matter how large the predator's growth rate is) or the predator's growth rate satisfies [Formula: see text], while a protection zone [Formula: see text] is necessary for such positive solutions if [Formula: see text] with [Formula: see text] properly large. The more interesting finding is that there is another threshold value [Formula: see text], such that the positive solutions do exist for all [Formula: see text]. Letting [Formula: see text], we get the third threshold value [Formula: see text] such that if [Formula: see text], prey species could survive no matter how large the predator's growth rate is. In addition, we get the fourth threshold value [Formula: see text] for negative [Formula: see text] such that the system admits positive steady states if and only if [Formula: see text]. All these results match well with the mechanistic derivation for the B-D type functional response recently given by Geritz and Gyllenberg (J Theoret Biol 314:106-108, 2012

  20. High-salt diet combined with elevated angiotensin II accelerates atherosclerosis in apolipoprotein E-deficient mice

    DEFF Research Database (Denmark)

    Johansson, Maria E; Bernberg, Evelina; Andersson, Irene J

    2009-01-01

    to atherosclerosis. METHODS: Apolipoprotein E-deficient (ApoE-/-) mice received standard or high-salt diet (8%) alone or in combination with fixed angiotensin II (Ang II) infusion (0.5 microg/kg per min). BP was measured using telemetry, and plaque burden was assessed in the thoracic aorta and innominate artery. We...

  1. Atrial natriuretic peptide (ANP) as a neuropeptide: Interaction with angiotensin II on volume control and renal sodium handling

    OpenAIRE

    Unger, Th.; Badoer, E.; Gareis, C.; Girchev, R.; Kotrba, M.; Qadri, F; Rettig, R.; Rohmeiss, P

    1990-01-01

    1 Angiotensin II (ANG II) and atrial natriuretic peptide (ANP) are functionally antagonistic circulating hormones involved in blood pressure and body fluid regulation. An inappropriate atrial secretion of ANP has been implicated in the pathogenesis of hypertension, but clinical and experimental results on the role of ANP in hypertension are still conflicting.

  2. Comparative Study of Plasma Ang Ⅱ and ET-1 OSAHS Patients Accompanied Hypertension%OSAHS及合并高血压患者血浆中Ang Ⅱ和ET-1的临床研究

    Institute of Scientific and Technical Information of China (English)

    朱利清; 张厚德; 涂向东; 马伦; 招强光; 成能斌; 徐洪; 吴凡伟

    2011-01-01

    目的 探讨阻塞性睡眠呼吸暂停低通气综合征(obstruotive sleep apnea hypopnea syndrome,OSAHS)及阻塞性睡眠呼吸暂停低通气综合征合并高血压(Hypertension)患者血浆中血管紧张素Ⅱ(Angiotensin Ⅱ,Ang Ⅱ)和内皮素-1(plasma,ET-1)的变化.方法 将符合入选条件的中、重度OSAHS患者分为OSAHS并发高血压组、OSAHS血压正常组,另设正常对照组,每组30例,3组均行PSG监测.采用放射免疫法测定血浆中Ang Ⅱ和ET-1水平,并对比分析3组血浆中Ang Ⅱ和ET-1水平及其相关性,评价血浆中Ang Ⅱ和ET-1变化与检测价值.结果 OSAHS合并高血压与OSAHS血压正常组血清ET-1质量浓度(x±s下同)分别是(58.94±16.37)和(44.75±15.68)ng/L,明显高于正常对照组(33.89±20.12)ng/L(P<0.01);同时OSAHS合并高血压组与OSAHS血压正常组之间比较血清ET-1质量浓度也明显增高(P<0.05).两组患者血清ET-1水平与AHI呈明显的正相关(r=0.334,P<0.01).OSAHS及合并高血压患者血浆Ang Ⅱ和ET-1水平与正常对照组相比差异有统计学意义(P<0.01).结论 OSAHS患者存在着明显的睡眠结构紊乱,但合并高血压者并没有特异性改变.ET-1可能在OSAHS合并高血压的发病中起一定作用.%Objective To study the plasma changes of Angiotensin Ⅱ ( Ang Ⅱ )and Endothelin-1 ( ET-1 ) in patients with obstructive sleep apnea-hypopnea syndrome and obstructive sleep apnea hypopnea syndrome accompanied hypertension. Methods 90 cases that qualified as eligible for moderate and severe OSAHS patients with hypertension were divided into three groups, OSAHS with hypertension group,OSAHS group and the normal control group,each group for 30 cases,three groups underwent PSG monitoring. Radioimmunoassay was used to measure Ang Ⅱ and ET-1 level, and comparative analysis of plasma and relevance, assessment the value of the plasma of Ang Ⅱ and ET-1 detection were performed. Results OSAHS and OSAHS with hypertension and normal

  3. Statin treatment in hypercholesterolemic men does not attenuate angiotensin II-induced venoconstriction.

    Directory of Open Access Journals (Sweden)

    Christoph Schindler

    Full Text Available Experimental studies suggested that statins attenuate vascular AT1 receptor responsiveness. Moreover, the augmented excessive pressor response to systemic angiotensin II infusions in hypercholesterolemic patients was normalized with statin treatment. In 12 hypercholesterolemic patients, we tested the hypothesis that statin treatment attenuates angiotensin II-mediated vasoconstriction in hand veins assessed by a linear variable differential transducer. Subjects ingested daily doses of either atorvastatin (40 mg or positive control irbesartan (150 mg for 30 days in a randomized and cross-over fashion. Ang II-induced venoconstriction at minute 4 averaged 59%±10% before and 28%±9% after irbesartan (mean ± SEM; P<0.05 compared to 65%±11% before and 73%±11% after 30 days of atorvastatin treatment. Plasma angiotensin levels increased significantly after irbesartan treatment (Ang II: 17±22 before vs 52±40 pg/mL after [p = 0.048]; Ang-(1-7: 18±10 before vs 37±14 pg/mL after [p = 0.002] compared to atorvastatin treatment (Ang II: 9±4 vs 11±10 pg/mL [p = 0.40]; Ang-(1-7: 24±9 vs 32±8 pg/mL [p = 0.023]. Our study suggests that statin treatment does not elicit major changes in angiotensin II-mediated venoconstriction or in circulating angiotensin II levels whereas angiotensin-(1-7 levels increased modestly. The discrepancy between local vascular and systemic angiotensin II responses might suggest that statin treatment interferes with blood pressure buffering reflexes.ClinicalTrials.gov NCT00154024.

  4. Neurocysticercosis in a rural population with extensive pig production in Angónia district, Tete Province, Mozambique.

    Science.gov (United States)

    Assane, Yunus Amade; Trevisan, Chiara; Schutte, Clara Maria; Noormahomed, Emilia Virginia; Johansen, Maria Vang; Magnussen, Pascal

    2017-01-01

    Neurocysticercosis (NCC) is an important neurological disease in countries with high prevalence of Taenia solium infection and is emerging as a serious public health and economic problem. The aim of this study was to estimate the prevalence of NCC in Angónia district, Tete province, Mozambique based on: prevalence of human T. solium cysticercosis assessed by antigen Enzyme-linked Immunosorbent Assay (Ag-ELISA) seropositivity, history of epilepsy, and brain computed tomography (CT) scan results. A cross sectional study was conducted between September and November 2007 in Angónia district. Questionnaires and blood samples were collected from 1,723 study subjects. Brain CT-scans were carried out on 151 study subjects with confirmed history of epilepsy. A total of 77 (51.0% (95% CI, 42.7-59.2)) and 38 (25.2% (95% CI, 18.5-32.9)) subjects met the criteria for definitive and probable diagnosis of NCC, respectively. T. solium Ag-ELISA seropositivity was found in 15.5% (95% CI, 12.8-16.2) of the study subjects. The estimated life time prevalence of epilepsy was 8.8% (95% CI, 7.5-10.2). Highly suggestive lesions of NCC were found on CT-scanning in 77 (71.9%, (95% CI, 62.4-80.2)) of the seropositive and 8 (18.1%, (95% CI, 8.2-32.7)) of the seronegative study subjects, respectively. The present findings revealed a high prevalence of NCC among people with epilepsy in Angónia district. Determination of effective strategies for prevention and control of T. solium cysticercosis are necessary to reduce the burden of NCC among the affected populations. Copyright © 2016. Published by Elsevier B.V.

  5. Slow-pressor angiotensin II hypertension and concomitant dendritic NMDA receptor trafficking in estrogen receptor β-containing neurons of the mouse hypothalamic paraventricular nucleus are sex and age dependent.

    Science.gov (United States)

    Marques-Lopes, Jose; Van Kempen, Tracey; Waters, Elizabeth M; Pickel, Virginia M; Iadecola, Costantino; Milner, Teresa A

    2014-09-01

    The incidence of hypertension increases after menopause. Similar to humans, "slow-pressor" doses of angiotensin II (AngII) increase blood pressure in young males, but not in young female mice. However, AngII increases blood pressure in aged female mice, paralleling reproductive hormonal changes. These changes could influence receptor trafficking in central cardiovascular circuits and contribute to hypertension. Increased postsynaptic N-methyl-D-aspartate (NMDA) receptor activity in the hypothalamic paraventricular nucleus (PVN) is crucial for the sympathoexcitation driving AngII hypertension. Estrogen receptors β (ERβs) are present in PVN neurons. We tested the hypothesis that changes in ovarian hormones with age promote susceptibility to AngII hypertension, and influence NMDA receptor NR1 subunit trafficking in ERβ-containing PVN neurons. Transgenic mice expressing enhanced green fluorescent protein (EGFP) in ERβ-containing cells were implanted with osmotic minipumps delivering AngII (600 ng/kg/min) or saline for 2 weeks. AngII increased blood pressure in 2-month-old males and 18-month-old females, but not in 2-month-old females. By electron microscopy, NR1-silver-intensified immunogold (SIG) was mainly in ERβ-EGFP dendrites. At baseline, NR1-SIG density was greater in 2-month-old females than in 2-month-old males or 18-month-old females. After AngII infusion, NR1-SIG density was decreased in 2-month-old females, but increased in 2-month-old males and 18-month-old females. These findings suggest that, in young female mice, NR1 density is decreased in ERβ-PVN dendrites thus reducing NMDA receptor activity and preventing hypertension. Conversely, in young males and aged females, NR1 density is upregulated in ERβ-PVN dendrites and ultimately leads to the neurohumoral dysfunction driving hypertension.

  6. Downregulation of ACE2/Ang-(1-7)/Mas axis promotes breast cancer metastasis by enhancing store-operated calcium entry.

    Science.gov (United States)

    Yu, Changhui; Tang, Wei; Wang, Yuhao; Shen, Qiang; Wang, Bin; Cai, Chunqing; Meng, Xiaojing; Zou, Fei

    2016-07-01

    The renin-angiotensin system (RAS) is an important component of the tumor microenvironment and plays a key role in promoting cancer cell proliferation, angiogenesis, metabolism, migration and invasion. Meanwhile, the arm of angiotensin-converting enzyme (ACE)2/angiotensin-(1-7) [Ang-(1-7)]/Mas axis in connection with RAS is associated with anti-proliferative, vasodilatory and anti-metastatic properties. Previous studies have shown that Ang-(1-7) reduces the proliferation of orthotopic human breast tumor growth by inhibiting cancer-associated fibroblasts. However, the role of ACE/Ang-(1-7)/Mas axis in the metastasis of breast cancer cells is still unknown. In the present study, we found that ACE2 protein level is negatively correlated with the metastatic ability of breast cancer cells and breast tumor grade. Upregulation of ACE2/Ang-(1-7)/Mas axis inhibits breast cancer cell migration and invasion in vivo and in vitro. Mechanistically, ACE2/Ang-(1-7)/Mas axis activation inhibits store-operated calcium entry (SOCE) and PAK1/NF-κB/Snail1 pathways, and induces E-cadherin expression. In summary, our results demonstrate that downregulation of ACE2/Ang-(1-7)/Mas axis stimulates breast cancer metastasis through the activation of SOCE and PAK1/NF-κB/Snail1 pathways. These results provide new mechanisms by which breast cancer develop metastasis and shed light on developing novel anti-metastasis therapeutics for metastatic breast cancer by modulating ACE2/Ang-(1-7)/Mas axis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  7. Role of Mas Receptor Antagonist A799 in Renal Blood Flow Response to Ang 1-7 after Bradykinin Administration in Ovariectomized Estradiol-Treated Rats

    Directory of Open Access Journals (Sweden)

    Aghdas Dehghani

    2015-01-01

    Full Text Available Background. The accompanied role of Mas receptor (MasR, bradykinin (BK, and female sex hormone on renal blood flow (RBF response to angiotensin 1-7 is not well defined. We investigated the role of MasR antagonist (A779 and BK on RBF response to Ang 1-7 infusion in ovariectomized estradiol-treated rats. Methods. Ovariectomized Wistar rats received estradiol (OVE or vehicle (OV for two weeks. Catheterized animals were subjected to BK and A799 infusion and mean arterial pressure (MAP, RBF, and renal vascular resistance (RVR responses to Ang 1-7 (0, 100, and 300 ng kg−1 min−1 were determined. Results. Percentage change of RBF (%RBF in response to Ang1-7 infusion increased in a dose-dependent manner. In the presence of BK, when MasR was not blocked, %RBF response to Ang 1-7 in OVE group was greater than OV group significantly (P<0.05. Infusion of 300 ng kg−1 min−1 Ang 1-7 increased RBF by 6.9±1.9% in OVE group versus 0.9±1.8% in OV group. However when MasR was blocked, %RBF response to Ang 1-7 in OV group was greater than OVE group insignificantly. Conclusion. Coadministration of BK and A779 compared to BK alone increased RBF response to Ang 1-7 in vehicle treated rats. Such observation was not seen in estradiol treated rats.

  8. Phase II Trial of Angiotensin-(1-7 for the Treatment of Patients with Metastatic Sarcoma

    Directory of Open Access Journals (Sweden)

    Paul D. Savage

    2016-01-01

    Full Text Available Background. Angiotensin-(1-7 [Ang-(1-7] is an endogenous antiangiogenic hormone with anticancer activity. In a phase I study of Ang-(1-7, two of three patients with metastatic sarcoma experienced disease stabilization. This phase II study examined clinical and biomarker outcomes for patients with metastatic sarcoma. Methods. Ang-(1-7 was administered by subcutaneous injection at a dose of 20 mg daily. If excessive toxicities occurred in the first cohort, a dose deescalation cohort was allowed. Blood samples were obtained to measure changes in biomarkers. Results. Treatment was well-tolerated and the dose deescalation cohort was not required. Plasma PlGF concentrations following treatment were not statistically significantly changed. A significant increase in plasma Ang-(1-7 was observed at 4 hours after injection. The median progression-free survival was 2.7 months (95% CI; 1.4 to 4.1 months, and the median overall survival was 10.2 months (95% CI; 5.3 to 18.3 months. Two patients with vascular sarcomas demonstrated prolonged disease stabilization of 10 months (hemangiopericytoma and 19 months (epithelioid hemangioendothelioma. Conclusions. Ang-(1-7 at a dose of 20 mg daily was well-tolerated. This prospective phase II study failed to confirm the PlGF biomarker effect identified in the prior phase I study. Prolonged disease stabilization in hemangiopericytoma and epithelioid hemangioendothelioma may warrant further investigation.

  9. El «espíritu de lo grotesco» en el teatro de Angélica Liddell

    OpenAIRE

    Garnier, Emmanuelle

    2012-01-01

    El teatro de la dramaturga, directora y actriz Angélica Liddell, por su estética neobarroca hecha de contrastes, paradojas y fusión de géneros (aproximación de lo grave y lo ligero, lo sagrado y lo profano, del amor y del asco, de lo festivo y lo trágico…), por las figuras grotescas que convoca, específicamente en lo que al tratamiento del espacio, del cuerpo y del lenguaje se refiere, recoge el espíritu de lo grotesco para construir el camino de la necesaria subversión artí...

  10. A angústia, o nada e a morte em Heidegger Anguish, nothingness and death in Heidegger

    Directory of Open Access Journals (Sweden)

    Marco Aurélio Werle

    2003-01-01

    Full Text Available O artigo investiga a relação entre os conceitos de medo, angústia, nada e morte na filosofia da existência de Heidegger. Pretende-se apontar para o papel destes fenômenos existenciais na passagem do ser-aí desde a inautenticidade para a autenticidade de seu ser.This paper investigates the relationship between the concepts of fear, anguish, nothingness and death in Heidegger's philosophy of existence. It points to the role of these existential phenomena in the transformation of "Dasein", from the inauthenticity to the authenticity of its Being.

  11. Angélica velázquez guadarrama. primitivo miranda y la construcción visual del liberalismo

    OpenAIRE

    JOSÉ DAVID CORTÉS GUERRERO

    2014-01-01

    Este no es un libro de historia del arte. Es un libro sobre como el arte se contextualiza en procesos históricos y los puede explicar, interpretar y dar sentido. Angélica Velázquez explora varias de las pinturas del artista mexicano decimonónico Primitivo Miranda para indagar por la visión que tenía aquel sobre el liberalismo. Miranda nació en Tula, hoy Estado de Hidalgo, en 1822. Desde temprano, dio muestras de algún talento artístico que comenzó a perfeccionar en Ciudad de México en la Acad...

  12. Viaggio e incertezza, fatalità e ribellione in Ekomo di María Nsue Angüe

    Directory of Open Access Journals (Sweden)

    Danilo Manera

    2011-12-01

    Full Text Available María Nsue Angüe’s novel Ekomo (1985 is a classic of hispanophone Equatorial Guinea, presenting the world vision and experience of a young woman, an ethnic Fang living in rural area, during the decolonization of Africa. This study examines the spacetime coordinates and the cultural conflicts detectable in the text and proposes a map of the main interacting isotopies: journey (therapeutic, initiatory, through memory and myths and borders (physical, temporal, mental and between life and death, uncertainty and helplessness, destiny and mourning, corporeality and rebellion.

  13. Molecular targeting therapy with angiotensin II receptor blocker for prostatic cancer

    Directory of Open Access Journals (Sweden)

    Hiroji Uemura

    2011-12-01

    Full Text Available Angiotensin II (Ang-II plays a key role as a vasoconstrictor in controlling blood pressure and electrolyte/fluid homeostasis. Recently it has also been shown that this peptide is a cytokine, acting as a growth factor in cardiovascular and stromal cells. In addition, the physiological function of Ang-II seems to be similar in prostate cancer and stromal cells. It is widely assumed that Ang-II facilitates the growth of both cells, and its receptor blockers (ARBs have the potential to inhibit the growth of various cancer cells and tumors through the Ang-II receptor type 1 (AT1 receptor. The mechanism of cell growth inhibition by ARBs has been considered to be that of suppression of the signal transduction systems activated by growth factors or cytokines in prostate cancer cells, and suppression of angiogenesis. This review highlights the possible use of ARBs as novel agents for prostatic diseases including prostate cancer and benign hypertrophy, and covers related literature.

  14. Transient Receptor Potential Melastatin 7 Cation Channel Kinase: New Player in Angiotensin II-Induced Hypertension.

    Science.gov (United States)

    Antunes, Tayze T; Callera, Glaucia E; He, Ying; Yogi, Alvaro; Ryazanov, Alexey G; Ryazanova, Lillia V; Zhai, Alexander; Stewart, Duncan J; Shrier, Alvin; Touyz, Rhian M

    2016-04-01

    Transient receptor potential melastatin 7 (TRPM7) is a bifunctional protein comprising a magnesium (Mg(2+))/cation channel and a kinase domain. We previously demonstrated that vasoactive agents regulate vascular TRPM7. Whether TRPM7 plays a role in the pathophysiology of hypertension and associated cardiovascular dysfunction is unknown. We studied TRPM7 kinase-deficient mice (TRPM7Δkinase; heterozygous for TRPM7 kinase) and wild-type (WT) mice infused with angiotensin II (Ang II; 400 ng/kg per minute, 4 weeks). TRPM7 kinase expression was lower in heart and aorta from TRPM7Δkinase versus WT mice, effects that were further reduced by Ang II infusion. Plasma Mg(2+) was lower in TRPM7Δkinase versus WT mice in basal and stimulated conditions. Ang II increased blood pressure in both strains with exaggerated responses in TRPM7Δkinase versus WT groups (Phypertension is exaggerated, cardiac remodeling and left ventricular dysfunction are amplified, and endothelial function is impaired. These processes are associated with hypomagnesemia, blunted TRPM7 kinase expression/signaling, endothelial nitric oxide synthase downregulation, and proinflammatory vascular responses. Our findings identify TRPM7 kinase as a novel player in Ang II-induced hypertension and associated vascular and target organ damage. © 2016 American Heart Association, Inc.

  15. NLRP3 Deficiency Improves Angiotensin II-Induced Hypertension But Not Fetal Growth Restriction During Pregnancy.

    Science.gov (United States)

    Shirasuna, Koumei; Karasawa, Tadayoshi; Usui, Fumitake; Kobayashi, Motoi; Komada, Tadanori; Kimura, Hiroaki; Kawashima, Akira; Ohkuchi, Akihide; Taniguchi, Shun'ichiro; Takahashi, Masafumi

    2015-11-01

    Preeclampsia is a pregnancy-specific syndrome characterized by elevated blood pressure, proteinuria, and intrauterine growth restriction (IUGR). Although sterile inflammation appears to be involved, its pathogenesis remains unclear. Recent evidence indicates that sterile inflammation is mediated through the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes, composed of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1. Here we investigated the role of the NLRP3 inflammasomes in the pathogenesis of preeclampsia using Nlrp3(-/-) and Asc(-/-) (Nlrp3 and Asc deficient) pregnant mice. During pregnancy in mice, continuous infusion of high-dose angiotensin II (AngII) induced hypertension, proteinuria, and IUGR, whereas infusion of low-dose AngII caused hypertension alone. AngII-induced hypertension was prevented in Nlrp3(-/-) mice but not in Asc(-/-), indicating that NLRP3 contributes to gestational hypertension independently of ASC-mediated inflammasomes. Although NLRP3 deficiency had no effect on IUGR, it restored the IL-6 up-regulation in the placenta and kidney of AngII-infused mice. Furthermore, treatment with hydralazine prevented the development of gestational hypertension but not IUGR or IL-6 expression in the placenta and kidney. These findings demonstrate that NLRP3 contributes to the development of gestational hypertension independently of the inflammasomes and that IUGR and kidney injury can occur independent of blood pressure elevation during pregnancy.

  16. Effect of Cyclosporin A and Angiotensin II on cytosolic calcium levels in primary human gingival fibroblasts

    Directory of Open Access Journals (Sweden)

    Ajitkumar Supraja

    2016-01-01

    Full Text Available Background: To evaluate the effect of Cyclosporin A (CsA and angiotensin II (Ang II on cytosolic calcium levels in cultured human gingival fibroblasts (HGFs. Materials and Methods: Healthy gingival samples from six volunteers were obtained, and primary HGFs were cultured. Cell viability and proliferation assay were performed to identify the ideal concentrations of CsA and Ang II. Cytosolic calcium levels in cultured gingival fibroblasts treated with CsA and Ang II were studied using colorimetric assay, confocal and fluorescence imaging. Statistical analyses were done using SPSS software and GraphPad Prism. Results: Higher levels of cytosolic levels were evident in cells treated with CsA and Ang II when compared to control group and was statistically significant (P < 0.05 in both colorimetric assay and confocal imaging. Fluorescent images of the cultured HGFs revealed the same. Conclusion: Thus calcium being a key player in major cellular functions, plays a major role in the pathogenesis of drug-induced gingival overgrowth.

  17. Molecular targeting therapy with angiotensin II receptor blocker for prostatic cancer

    Directory of Open Access Journals (Sweden)

    Hiroji Uemura

    2011-12-01

    Full Text Available Angiotensin II (Ang-II plays a key role as a vasoconstrictor in controlling blood pressure and electrolyte/fluid homeostasis. Recently it has also been shown that this peptide is a cytokine, acting as a growth factor in cardiovascular and stromal cells. In addition, the physiological function of Ang-II seems to be similar in prostate cancer and stromal cells. It is widely assumed that Ang-II facilitates the growth of both cells, and its receptor blockers (ARBs have the potential to inhibit the growth of various cancer cells and tumors through the Ang-II receptor type 1 (AT1 receptor. The mechanism of cell growth inhibition by ARBs has been considered to be that of suppression of the signal transduction systems activated by growth factors or cytokines in prostate cancer cells, and suppression of angiogenesis. This review highlights the possible use of ARBs as novel agents for prostatic diseases including prostate cancer and benign hypertrophy, and covers related literature.

  18. Cleavage of the angiotensin II type 1 receptor and nuclear accumulation of the cytoplasmic carboxy-terminal fragment.

    Science.gov (United States)

    Cook, Julia L; Mills, Sarah J; Naquin, Ryan T; Alam, Jawed; Re, Richard N

    2007-04-01

    Our published studies show that the distribution of the ANG II type 1 (AT(1)) receptor (AT(1)R), expressed as a enhanced yellow fluorescent fusion (YFP) protein (AT(1)R/EYFP), is altered upon cellular treatment with ANG II or coexpression with intracellular ANG II. AT(1)R accumulates in nuclei of cells only in the presence of ANG II. Several transmembrane receptors are known to accumulate in nuclei, some as holoreceptors and others as cleaved receptor products. The present study was designed to determine whether the AT(1)R is cleaved before nuclear transport. A plasmid encoding a rat AT(1)R labeled at the amino terminus with enhanced cyan fluorescent protein (CFP) and at the carboxy terminus with EYFP was employed. Image analyses of this protein in COS-7 cells, CCF-STTG1 glial cells, and A10 vascular smooth muscle cells show the two fluorescent moieties to be largely spatially colocalized in untreated cells. ANG II treatment, however, leads to a separation of the fluorescent moieties with yellow fluorescence accumulating in more than 30% of cellular nuclei. Immunoblot analyses of extracts and conditioned media from transfected cells indicate that the CFP domain fused to the extracellular amino-terminal AT(1)R domain is cleaved from the membrane and that the YFP domain, together with the intracellular cytoplasmic carboxy terminus of the AT(1)R, is also cleaved from the membrane-bound receptor. The carboxy terminus of the AT(1)R is essential for cleavage; cleavage does not occur in protein deleted with respect to this region. Overexpressed native AT(1)R (nonfusion) is also cleaved; the intracellular 6-kDa cytoplasmic domain product accumulates to a significantly higher level with ANG II treatment.

  19. Salvianolic Acid A Attenuates Cell Apoptosis, Oxidative Stress, Akt and NF-κB Activation in Angiotensin-II Induced Murine Peritoneal Macrophages.

    Science.gov (United States)

    Li, Ling; Xu, Tongda; Du, Yinping; Pan, Defeng; Wu, Wanling; Zhu, Hong; Zhang, Yanbin; Li, Dongye

    2016-01-01

    We discuss the role of Salvianolic acid A(SAA), one of the main effective components in Salvia Miltiorrhiza (known as 'Danshen' in traditional Chinese medicine), in apoptotic factors, the production of oxidative products, and the expression of Akt and NF-κB in angiotensin II (Ang II)-mediated murine macrophages. In the present study, Ang II was added to mice abdominal macrophages with or without addition of SAA. After cell identification, apoptosis was measured by DNA strand break level with TdT-mediated dUTP nick-end labeling (TUNEL) staining, and the expression of Bcl-2 and Bax. Intracellular concentrations of superoxide dismutase (SOD) and malondialdehyde (MDA) were also measured. Western blotting determined the expression of Akt, p-Akt, NF-κB and p-NF-κB. Ly294002 (the inhibitor of PI3K) was used to determine the mechanism of SAA. Ang II (1 µM) significantly increased the number of TUNEL-positive cells and Bax expression, but reduced Bcl-2 expression. These effects were antagonized when the cells were pretreated with SAA. SAA decreased MDA, but increased SOD in the cell lysis solution treated with Ang II. It markedly reduced the level of p-NF-κB, as also p-Akt, which was partly blocked by Ly294002. SAA prevents Ang IIinduced apoptosis, oxidative stress and related protein expression in the macrophages. It also inhibits the activation of Akt.

  20. Reversal of obesity and insulin resistance by a non-peptidic glucagon-like peptide-1 receptor agonist in diet-induced obese mice.

    Directory of Open Access Journals (Sweden)

    Min He

    Full Text Available BACKGROUND: Glucagon-like peptide-1 (GLP-1 is recognized as an important regulator of glucose homeostasis. Efforts to utilize GLP-1 mimetics in the treatment of diabetes have yielded clinical benefits. A major hurdle for an effective oral therapy has been the difficulty of finding a non-peptidic GLP-1 receptor (GLP-1R agonist. While its oral bioavailability still poses significant challenges, Boc5, one of the first such compounds, has demonstrated the attainment of GLP-1R agonism in diabetic mice. The present work was to investigate whether subchronic Boc5 treatment can restore glycemic control and induce sustainable weight loss in diet-induced obese (DIO mice, an animal model of human obesity and insulin resistance. METHODOLOGY/PRINCIPAL FINDINGS: DIO mice were treated three times a week with Boc5 (0.3, 1 and 3 mg for 12 weeks. Body weight, body mass index (BMI, food intake, fasting glucose, intraperitoneal glucose tolerance and insulin induced glucose clearance were monitored regularly throughout the treatment. Glucose-stimulated insulin secretion, β-cell mass, islet size, body composition, serum metabolic profiles, lipogenesis, lipolysis, adipose hypertrophy and lipid deposition in the liver and muscle were also measured after 12 weeks of dosing. Boc5 dose-dependently reduced body weight, BMI and food intake in DIO mice. These changes were associated with significant decreases in fat mass, adipocyte hypertrophy and peripheral tissue lipid accumulation. Boc5 treatment also restored glycemic control through marked improvement of insulin sensitivity and normalization of β-cell mass. Administration of Boc5 (3 mg reduced basal but enhanced insulin-mediated glucose incorporation and noradrenaline-stimulated lipolysis in isolated adipocytes from obese mice. Furthermore, circulating leptin, adiponectin, triglyceride, total cholesterol, nonesterified fatty acid and high-density lipoprotein/low-density lipoprotein ratio were normalized to various

  1. Effect of nonpeptide NK1 receptor antagonist L-703,606 on the edema formation in rats at early stage after deep partial-thickness skin scalding

    Institute of Scientific and Technical Information of China (English)

    Ke Tao; Hong-Tao Wang; Bi Chen; Bo-Tao Wang; Zhi-Yuan Li; Xiong-Xiang Zhu; Chao-Wu Tang; Da-Hai Hu

    2013-01-01

    Objective: To investigate the effect and the relevant potential mechanism of nonpeptide neurokinin 1 (NK1) receptor antagonist L-703,606 in the edema formation after burn injury.Method:L-703,606 treatment was performed in Sprague-Dawley (SD) rats at early stage after deep partial-thickness skin scalding. One hundred and fifty two adult male SD rats were used in the study and randomly divided into sham scald (SS, n=8), scald control (SC, n=48), and L-703,606 treatment (LT, n=48) groups. The rats in SC and LT groups were subjected to 20% total body surface area (TBSA) deep partial-thickness skin scalding. Modified Evans blue extravasation, tracing electron microscopy by lanthanum nitrate and mean water content assay were employed to observe and detect the changes of vascular permeability, ultrastructure and edema formation in adjacent tissue to the wounds and in the jejuna of rats at early stage (72 h) after scald. Results:The pathological increase of vascular permeability in the periwound tissue and jejunum of rats in LT group were significantly lower than that in SC group (P<0.01), and recuperated earlier. Meanwhile, the changes of water contents of corresponding tissues in LT group were lighter than those in SC group (P<0.01). The ultrastructural changes of the microvessels in the peri-wound tissue of LT group showed that the junctions between microvascular endothelium cells were more narrow than those of SC group, moreover, and the number of opening and the engorgement and cavitation of the vascular endothelium cells decreased, the areosis and edema in perivascular tissue lightened, and the precipitation of the high eletron density lanthanum tracing agent in the interspace of the tissue decreased significantly in LT group. Conclusions: It is concluded that nonpeptide NK1-receptor antagonist L-703,606 could lighten the vascular permeability and edema formation in the periwound tissue and jejunum, and accelerate the normalization process of pathological changes in

  2. Regard noir sur la Cité des Anges : James Ellroy

    Directory of Open Access Journals (Sweden)

    Frédéric SOUNAC

    2010-03-01

    Full Text Available Le mythe de Los Angeles, largement associé à l’immensité de la ville et à la présence en son sein d’Hollywood, est en grande partie une création du roman noir : cité sismique, Sodome moderne, la « Cité des anges » est souvent décrite comme un lieu violent, pulsionnel, où toute tentative de rachat individuel est rendue impossible par l’omniprésence de la corruption. La décadence de la ville-monde, telle qu’elle est analysée de manière résolument pessimiste par le géographe Mike Davis dans Au-delà de Blade Runner, trouve dans les romans de Michael Connelly et de James Ellroy une puissante représentation fictionnelle. Le premier, à travers les errances de son détective Harry Bosch, tient un discours de type élégiaque, tandis que le deuxième, en élaborant une sorte de « réalisme tragique », élève la ville au rang d’allégorie de la Faute et du Mal. L’œuvre d’Ellroy, en particulier, repose sur un arpentage minutieux et obsessionnel des quartiers de Los Angeles, une observation cruelle de sa sociologie et de son histoire, un rapport de haine-amour avec son architecture : le schéma d’enquête, chez lui, relève d’une quête souvent fatale de la mémoire dans une cité que sa rage autodestructrice et ses mutations incessantes vouent à l’amnésie.The myth of Los Angeles, tightly linked to the city’s hugeness and its heart of hearts Hollywood, is to a great extent a creation of the « dark » novel, or « noir ». A sismic territory and modern Sodoma, the so-called « City of Angels » is often depicted as a violent and all impulse driven place, in which the individual yearning for redemption is always destroyed by endemic corruption. The decadent city analyzed in a rather pessimistic way by Mike Davis in his essay Beyond Blade Runner finds in Michael Connelly’s and James Ellroy’s crime fiction a powerful representation. Connelly’s world, with its whimsical main character detective

  3. Angiotensin II (de)sensitization: Fluid intake studies with implications for cardiovascular control.

    Science.gov (United States)

    Daniels, Derek

    2016-08-01

    Cardiovascular disease is the leading cause of death worldwide and hypertension is the most common risk factor for death. Although many anti-hypertensive pharmacotherapies are approved for use in the United States, rates of hypertension have increased over the past decade. This review article summarizes a presentation given at the 2015 meeting of the Society for the Study of Ingestive Behavior. The presentation described work performed in our laboratory that uses angiotensin II-induced drinking as a model system to study behavioral and cardiovascular effects of the renin-angiotensin system, a key component of blood pressure regulation, and a common target of anti-hypertensives. Angiotensin II (AngII) is a potent dipsogen, but the drinking response shows a rapid desensitization after repeated injections of AngII. This desensitization appears to be dependent upon the timing of the injections, requires activation of the AngII type 1 (AT1) receptor, requires activation of mitogen-activated protein (MAP) kinase family members, and involves the anteroventral third ventricle (AV3V) region as a critical site of action. Moreover, the response does not appear to be the result of a more general suppression of behavior, a sensitized pressor response to AngII, or an aversive state generated by the treatment. More recent studies suggest that the treatment regimen used to produce desensitization in our laboratory also prevents the sensitization that occurs after daily bolus injections of AngII. Our hope is that these findings can be used to support future basic research on the topic that could lead to new developments in treatments for hypertension.

  4. Angiotensin II type 2 receptor (AT2R) localization and antagonist-mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons

    OpenAIRE

    Anand, U; Facer, P; Yiangou, Y.; Sinisi, M; Fox, M.; McCarthy, T.; Bountra, C; Korchev, YE; Anand, P

    2012-01-01

    Background The angiotensin II (AngII) receptor subtype 2 (AT2R) is expressed in sensory neurons and may play a role in nociception and neuronal regeneration. Methods We used immunostaining with characterized antibodies to study the localization of AT2R in cultured human and rat dorsal root ganglion (DRG) neurons and a range of human tissues. The effects of AngII and AT2R antagonist EMA401 on capsaicin responses in cultured human and rat (DRG) neurons were measured with calcium imaging, on neu...

  5. A model for economic evaluation of the use of Adsorbed Natural Gas (ANG); Modelo de avaliacao economica do uso do Gas Natural Adsorvido (GNA)

    Energy Technology Data Exchange (ETDEWEB)

    Azevedo, Diana C.S.; Cavalcante Junior, Celio L.; Torres, A. Eurico B.; Oliveira Junior, Jose A.; Medeiros, Vanildo M. de [Universidade Federal do Ceara (UFC), Fortaleza, CE (Brazil); Campos, Flavio B.; Moura, Newton R. de [PETROBRAS, Rio de Janeiro, RJ (Brazil). Centro de Pesquisas (CENPES). Gerencia de Gas e Energia; Campos, Michel F. [PETROBRAS, Rio de Janeiro, RJ (Brazil). Gerencia de Tecnologia de Gas e Energia; Alexandre, Francisco de Assis Souza

    2004-07-01

    Natural gas is currently transported by two main ways: through pipelines and stored in reservoirs, under compressed (CNG) or liquefied (LNG) forms. Adsorbed natural gas (ANG) is a third alternative to vessel storage, which has been intensively reported in the scientific and technical literature. Working pressures are considerably lower for ANG (3,5 MPa as compared to 25 MPa for CNG), which results in lower costs with vessel construction and compression and safer handling. The project ADSPOR, sponsored by PETROBRAS and part of the R and D portfolio of RedeGasEnergia, aims to assess the technical and economical feasibility of storing and transporting natural gas confined in carbon adsorbents. The objectives of this project are the production of high-capacity active carbons, the collection of adsorption data for NG storage and the economic evaluation of ANG. The present work presents a model for cost estimation of the ANG business, which comprises from the compression into ANG vessels until the distribution to the final costumer, taking into account several shipping modes. The variables involved in the model were: compression costs, equipment and materials technical data, costs with product handling and shipping costs for motor ways, railways and inland waterways. These variables were linked so as to generate a cost matrix that may be used to assess investment and calculate the final cost for GNA transport. The model may be used to carry out parameter sensitivity analysis, for decision-making and management purposes. (author)