Running Exercise and Angiotensin II Type I Receptor Blocker Telmisartan Are Equally Effective in Preventing Angiotensin II-Mediated Vulnerable Atherosclerotic Lesions

2016 ◽  
Vol 22 (2) ◽  
pp. 159-168 ◽  
Author(s):  
Maxime Pellegrin ◽  
Justyna Szostak ◽  
Karima Bouzourène ◽  
Jean-François Aubert ◽  
Alain Berthelot ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Receptor Expression ◽  
Treadmill Running ◽  
Receptor Blocker ◽  
Atherosclerotic Cardiovascular Disease ◽  
Type I ◽  
Ang Ii ◽  
T Helper ◽  
Plaque Vulnerability ◽  
Running Exercise

Introduction: The present study was conducted to directly compare the efficacy of running exercise and telmisartan treatment on angiotensin (Ang) II-mediated atherosclerosis and plaque vulnerability. Materials and Methods: Apolipoprotein E-deficient (ApoE−/−) mice with Ang II-mediated atherosclerosis (2-kidney, 1-clip [2K1C] renovascular hypertension model) were randomized into 3 groups: treadmill running exercise (RUN), telmisartan treatment (TEL), and sedentary untreated controls (SED) for 5 weeks. Atherosclerosis was assessed using histological and immunohistochemical analyses. Gene expression was determined by real-time reverse transcription polymerase chain reaction. Results: TEL but not RUN mice significantly decreased (50%) atherosclerotic lesion size compared to SED. RUN and TEL promoted plaque stabilization to a similar degree in ApoE−/− 2K1C mice. However, plaque composition and vascular inflammatory markers were differently affected: RUN decreased plaque macrophage infiltration (35%), whereas TEL reduced lipid core size (88%); RUN significantly increased aortic peroxisome proliferator-activated receptor (PPAR)-α, -δ, and -γ expression, whereas TEL significantly modulated T-helper 1/T-helper 2 (Th1/Th2) aortic response toward an anti-inflammatory state (decreased aortic interleukin [IL] 2 to IL-10 and IL-2 to IL-13 expression ratios). Plaque smooth muscle cell content was similarly increased (128% and 141%, respectively). Aortic AT1 and AT2 receptor expression as well as aortic CD11c/CD206 and IL-1β/IL-1ra expression ratios were not significantly modulated by either RUN or TEL. Conclusion: Running exercise and telmisartan treatment are equally effective in preventing Ang II-mediated plaque vulnerability but through distinct cellular and molecular mechanisms. Our findings further support the use of exercise training and selective AT1 receptor blocker therapies for atherosclerotic cardiovascular disease prevention.

Mechanisms of angiotensin II-induced ERK1/2 activation in fetal cardiomyocytes

2010 ◽  
Vol 2 (3) ◽  
Author(s):  
Xing Yin ◽  
Lian Hu ◽  
Hao Feng ◽  
Lazar Z. Krsmanovic ◽  
Kevin J. Catt
Keyword(s):  
Angiotensin Ii ◽  
Protein Kinase ◽  
Feedback Inhibition ◽  
Receptor Expression ◽  
Type I ◽  
Ang Ii ◽  
Myocardial Repair ◽  
Cell Based Therapy ◽  
Fetal Cardiomyocytes ◽  
At2 Receptors

AbstractFetal cardiomyocytes have been utilized in studies on myocardial repair in the damaged hearts of rodents and other species. Changes in angiotensin II (Ang II) receptor expression, especially decline of its type II receptor (AT2), are known to occur during the growth of cardiomyocytes from fetus to adult. However, the extent to which changes in the signaling pathways of Ang II type I (AT1) and AT2 receptors via p42/44 mitogen-activated protein kinase (ERK1/2) activation affect the physiological and pathophysiological functions in cardiomyocytes has not been defined. The roles of these receptors were analyzed by confocal fluorescence microscopy, immunoblot analysis, reverse transcription PCR, measurement of intracellular 3′,5′-cyclic AMP levels and siRNA technology in cultured rat fetal cardiomyocytes. These studies revealed that Gq is required for Ang II-induced ERK1/2 activation via the synergy of AT1 and AT2 receptors. It has also been shown that phospholipase Cβ1, protein kinase Cα and protein kinase A mediate the feedback inhibition of ERK1/2 activation via c-Raf and/or other intermediate signaling molecules. The observed mechanism of Ang II-induced ERK1/2 activation in fetal cardiomyocytes could be relevant to the understanding of cardiomyocyte development and turnover, as well as clinical approaches using protein- and cell-based therapy for diseases such as heart failure.

A role for angiotensin II AT1 receptors in ureteric bud cell branching

2003 ◽  
Vol 285 (2) ◽  
pp. F199-F207 ◽  
Author(s):  
Igor V. Iosipiv ◽  
Mercedes Schroeder
Keyword(s):  
Angiotensin Ii ◽  
Type I Collagen ◽  
Branching Morphogenesis ◽  
Receptor Expression ◽  
Receptor Protein ◽  
Type I ◽  
Ang Ii ◽  
Collagen Gels ◽  
Ureteric Bud

Gene-targeting studies in mice demonstrate that the renin-angiotensin system is required for the proper development of the renal medulla. In the absence of angiotensin II (ANG II) or the ANG II type 1 (AT1) receptor, mice exhibit poor papillary development and a severe urinary-concentrating defect. These findings imply that the ureteric bud (UB) and its branches are targets for ANG II actions during renal development. However, direct evidence linking ANG II with UB-branching morphogenesis does not exist. Using immunohistochemistry, we demonstrated that UB-derived epithelia express angiotensinogen (Ao) and the AT1 receptor during murine metanephrogenesis. Ao and AT1 receptors are expressed in the UB branches and to a lesser extent in the stromal mesenchyme. AT1 receptor expression in UB-derived epithelia increased from embryo day 12 to day 16 and was observed on both luminal and basolateral membranes. In accord with these findings, cultured murine UB cells express AT1 receptor protein and mRNA. Treatment of UB cells cultured in three-dimensional type I collagen gels with ANG II (10–7 to 10–5 M) elicits a dose-related increase in the number of cells that have primary and secondary branches. These effects of ANG II on UB branching are abrogated by pretreatment with the AT1 receptor antagonist candesartan. These data demonstrate a direct and independent role for ANG II acting via AT1 receptors on UB cell branching in vitro. The presence of Ao in the stroma and AT1 on UB cells supports the notion that cross talk between stroma and epithelial cells is crucial to epithelial branching morphogenesis in the developing kidney.

scholarly journals Salvianolic Acid B Attenuates Rat Hepatic Fibrosis via Downregulating Angiotensin II Signaling

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Shu Li ◽  
Lina Wang ◽  
Xiuchuan Yan ◽  
Qinglan Wang ◽  
Yanyan Tao ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Hepatic Fibrosis ◽  
Water Soluble ◽  
Salvianolic Acid B ◽  
Type I ◽  
Ang Ii ◽  
Radix Salviae Miltiorrhizae ◽  
Fibrotic Liver ◽  
Salvianolic Acid

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 modelin vivoand 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) andα-smooth muscle actin (α-SMA) productionin 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.

Abstract 1476: Angiotensin II Induced Hypertrophic Response And Oxidative Stress Is Attenuated In Mice Lacking The Gene For Tnf-α

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Srinivas Sriramula ◽  
Nithya Mariappan ◽  
Elizabeth McILwain ◽  
Joseph Francis
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Collagen Type ◽  
Resonance Spectroscopy ◽  
Type I ◽  
Ang Ii ◽  
Hypertrophic Response ◽  
Tnf Α ◽  
And Oxidative Stress

Tumor necrosis factor-alpha (TNF-α) and angiotensin II (Ang II) play an important role in the pathophysiology of cardiovascular disease in part by inducing the cardiac hypertrophic response and oxidative stress. Recently we demonstrated that angiotensin induced hypertensive response is attenuated in mice lacking the gene for TNF-α. In this study, we examined whether Ang II induced cardiac hypertrophy and increased oxidative stress is mediated through TNF-α. Methods and results: Male TNF-α (−/−) and age matched control (WT) mice were subcutaneously implanted with osmotic minipumps containing Ang II (1 μg/kg/min) or saline for 14 days. Human recombinant TNF-α was injected in one group of TNF-α (−/−) mice (10 μg/kg/day) for 14 days. In WT+Ang mice, a temporal increase in blood pressure was observed during the study as measured by radio telemetry transmitters. At the end of the study, echocardiography revealed an increase in thickness and dimensions of left ventricle (LV) and decreased fractional shortening (%FS) in WT+Ang mice. Real time RT-PCR showed that Ang II- infusion resulted in an increase in heart/bodyweight ratio and of cardiac hypertrophy markers ANP and BNP, and profibrotic genes Collagen Type I, Collagen Type II, and TGF-β in WT mice. Electron Spin resonance spectroscopy revealed an increase in total ROS, superoxide and peroxynitrite in the WT+ANG mice when compared to control WT mice. However, these changes were all attenuated in TNF-α (−/−)+Ang mice. Ang II infusion also increased significantly the mRNA expression of gp91Phox, NOX-1, NOX-4 and AT1R in the LV of WT mice, but not in TNF-α (−/−) mice. Interestingly, injection of TNF-α in the TNF-α (−/−) mice, treated with Ang II resulted in increased cardiac hypertrophy and oxidative stress. Conclusions: Findings from the present study suggest that TNF-α plays an important role in the development of cardiac hypertrophy and oxidative stress in Ang II-induced hypertension.

K depletion alters angiotensin II receptor expression in vascular smooth muscle cells

1990 ◽  
Vol 258 (5) ◽  
pp. C849-C854 ◽  
Author(s):  
S. L. Linas ◽  
R. Marzec-Calvert ◽  
M. E. Ullian
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Receptor Expression ◽  
Ang Ii ◽  
Surface Receptors ◽  
K Depletion

Dietary K depletion (KD) results in increases in the number of angiotensin II (ANG II) receptors and prevents ANG II-induced downregulation of ANG II receptors in membrane preparations of vessels from KD animals. Because dietary KD results in changes in factors other than K, we K depleted vascular smooth muscle cells (VSMC) in culture to determine the specific effects of KD on ANG II receptor expression and processing. Scatchard analysis of ANG II uptake at 4 degrees C revealed that the number of surface receptors was increased by 37% in cells in which K had been reduced by 45%. This increase also occurred in the presence of cycloheximide. To determine the effect of KD on receptor processing, we measured the number of surface receptors after exposure to ANG II in concentrations sufficient to cause down-regulation. After 30-min exposure to ANG II, the number of surface receptors was reduced by 63% in control cells but only 33% in KD cells. Thirty minutes after withdrawing ANG II, surface binding returned to basal levels in control cells but was still reduced by 20% in KD cells. To determine the functional significance of impaired receptor processing, we measured ANG II uptake at 21 degrees C. Uptake at 21 degrees C depends on the functional number of receptors, i.e., the absolute number of surface receptors and the rate at which receptors are recycled to the surface after ANG II binding. ANG II uptake at 21 degrees C was reduced by 50% in KD cells.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Carvedilol Inhibits Angiotensin II-Induced Proliferation and Contraction in Hepatic Stellate Cells through the RhoA/Rho-Kinase Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Ying Wu ◽  
Zhen Li ◽  
Sining Wang ◽  
Aiyuan Xiu ◽  
Chunqing Zhang
Keyword(s):  
Cell Cycle ◽  
Angiotensin Ii ◽  
Liver Fibrosis ◽  
Cell Cycle Progression ◽  
Rho Kinase ◽  
Cell Counting ◽  
Type I ◽  
Dependent Manner ◽  
Ang Ii ◽  
Cycle Progression

Aim. Carvedilol is a nonselective beta-blocker used to reduce portal hypertension. This study investigated the effects and potential mechanisms of carvedilol in angiotensin II- (Ang II-) induced hepatic stellate cell (HSC) proliferation and contraction. Methods. The effect of carvedilol on HSC proliferation was measured by Cell Counting Kit-8 (CCK-8). Cell cycle progression and apoptosis in HSCs were determined by flow cytometry. A collagen gel assay was used to confirm HSC contraction. The extent of liver fibrosis in mice was evaluated by hematoxylin-eosin (H&E) and Sirius Red staining. Western blot analyses were performed to detect the expression of collagen I, collagen III, α-smooth muscle actin (α-SMA), Ang II type I receptor (AT1R), RhoA, Rho-kinase 2 (ROCK2), and others. Results. The results showed that carvedilol inhibited HSC proliferation and arrested the cell cycle at the G0/G1 phase in a dose-dependent manner. Carvedilol also modulated Bcl-2 family proteins and increased apoptosis in Ang II-treated HSCs. Furthermore, carvedilol inhibited HSC contraction induced by Ang II, an effect that was associated with AT1R-mediated RhoA/ROCK2 pathway interference. In addition, carvedilol reduced α-SMA expression and collagen deposition and attenuated liver fibrosis in carbon tetrachloride (CCl4)-treated mice. The in vivo data further confirmed that carvedilol inhibited the expression of angiotensin-converting enzyme (ACE), AT1R, RhoA, and ROCK2. Conclusions. The results indicated that carvedilol dose-dependently inhibited Ang II-induced HSC proliferation by impeding cell cycle progression, thus alleviating hepatic fibrosis. Furthermore, carvedilol could inhibit Ang II-induced HSC contraction by interfering with the AT1R-mediated RhoA/ROCK2 pathway.

scholarly journals Deficiency of T-type Ca2+ channels Cav3.1 and Cav3.2 has no effect on angiotensin II-induced hypertension but differential effect on plasma aldosterone in mice

2019 ◽  
Vol 317 (2) ◽  
pp. F254-F263
Author(s):  
Anne D. Thuesen ◽  
Stine H. Finsen ◽  
Louise L. Rasmussen ◽  
Ditte C. Andersen ◽  
Boye L. Jensen ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Mineralocorticoid Receptor ◽  
Plasma Aldosterone ◽  
Receptor Blocker ◽  
Ang Ii ◽  
Induced Hypertension

T-type Ca2+ channel Cav3.1 promotes microvessel contraction ex vivo. It was hypothesized that in vivo, functional deletion of Cav3.1, but not Cav3.2, protects mice against angiotensin II (ANG II)-induced hypertension. Mean arterial blood pressure (MAP) and heart rate were measured continuously with chronically indwelling catheters during infusion of ANG II (30 ng·kg−1·min−1, 7 days) in wild-type (WT), Cav3.1−/−, and Cav3.2−/− mice. Plasma aldosterone and renin concentrations were measured by radioimmunoassays. In a separate series, WT mice were infused with ANG II (100 ng·kg−1·min−1) with and without the mineralocorticoid receptor blocker canrenoate. Cav3.1−/− and Cav3.2−/− mice exhibited no baseline difference in MAP compared with WT mice, but day-night variation was blunted in both Cav3.1 and Cav3.2−/− mice. ANG II increased significantly MAP in WT, Cav3.1−/−, and Cav3.2−/− mice with no differences between genotypes. Heart rate was significantly lower in Cav3.1−/− and Cav3.2−/− mice compared with control mice. After ANG II infusion, plasma aldosterone concentration was significantly lower in Cav3.1−/− compared with Cav3.2−/− mice. In response to ANG II, fibrosis was observed in heart sections from both WT and Cav3.1−/− mice and while cardiac atrial natriuretic peptide mRNA was similar, the brain natriuretic peptide mRNA increase was mitigated in Cav3.1−/− mice ANG II at 100 ng/kg yielded elevated pressure and an increased heart weight-to-body weight ratio in WT mice. Cardiac hypertrophy, but not hypertension, was prevented by the mineralocorticoid receptor blocker canrenoate. In conclusion, T-type channels Cav3.1and Cav3.2 do not contribute to baseline blood pressure levels and ANG II-induced hypertension. Cav3.1, but not Cav3.2, contributes to aldosterone secretion. Aldosterone promotes cardiac hypertrophy during hypertension.

scholarly journals Angiotensin II increases GABAB receptor expression in nucleus tractus solitarii of rats

2008 ◽  
Vol 294 (6) ◽  
pp. H2712-H2720 ◽  
Author(s):  
Fanrong Yao ◽  
Colin Sumners ◽  
Stephen T. O'Rourke ◽  
Chengwen Sun
Keyword(s):  
Angiotensin Ii ◽  
Gabab Receptor ◽  
Neuronal Response ◽  
Neuronal Firing ◽  
Receptor Expression ◽  
Nucleus Tractus Solitarii ◽  
Neuronal Cultures ◽  
Ang Ii ◽  
Western Blots ◽  
Intracerebroventricular Infusion

Increasing evidence indicates that both the angiotensin II (ANG II) and γ-aminobutyric acid (GABA) systems play a very important role in the regulation of blood pressure (BP). However, there is little information concerning the interactions between these two systems in the nucleus tractus solitarii (NTS). In the present study, we examined the effects of ANG II on GABAA and GABAB receptor (GAR and GBR) expression in the NTS of Sprague-Dawley rats. The direct effect of ANG II on GBR expression was determined in neurons cultured from NTS. Treatment of neuronal cultures with ANG II (100 nM, 5 h) induced a twofold increase in GBR1 expression, as detected with real-time RT-PCR and Western blots, but had no effect on GBR2 or GAR expression. In electrophysiological experiments, perfusion of neuronal cultures with the GBR agonist baclofen decreased neuronal firing rate by 39% and 63% in neurons treated with either PBS (control) or ANG II, respectively, indicating that chronic ANG II treatment significantly enhanced the neuronal response to GBR activation. In contrast, ANG II had no significant effect on the inhibitory action of the GAR agonist muscimol. In whole animal studies, intracerebroventricular infusion of ANG II induced a sustained increase in mean BP and an elevation of GBR1 mRNA and protein levels in the NTS. These results indicate that ANG II stimulates GBR expression in NTS neurons, and this could contribute to the central nervous system actions of ANG II that result in dampening of baroreflexes and elevated BP in the central actions of ANG II.

scholarly journals Angiotensin II enhances GABAB receptor-mediated responses and expression in nucleus tractus solitarii of rats

2009 ◽  
Vol 297 (5) ◽  
pp. H1837-H1844 ◽  
Author(s):  
Qi Zhang ◽  
Fanrong Yao ◽  
Stephen T. O'Rourke ◽  
Steven Y. Qian ◽  
Chengwen Sun
Keyword(s):  
Angiotensin Ii ◽  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Gabab Receptor ◽  
Receptor Expression ◽  
Nucleus Tractus Solitarii ◽  
Neuronal Cultures ◽  
Ang Ii ◽  
Intracerebroventricular Infusion ◽  
Cgp 35348

Angiotensin II (ANG II) increases GABAB receptor expression in neuronal cultures from the nucleus tractus solitarii (NTS). In the present study, the chronic effects of ANG II on GABAB receptor expression and activity were examined in the NTS of Sprague-Dawley rats. Intracerebroventricular infusion of ANG II caused a significant elevation in blood pressure (BP) and an increase in GABAB receptor expression in the NTS. Conversely, chronic NG-nitro-l-arginine methyl ester (l-NAME) treatment also increased BP, but had no effect on GABAB receptor expression in the NTS. Next, we examined the BP response to the GABAB receptor agonist baclofen microinjected into the NTS of ANG II- or artificial cerebrospinal fluid (aCSF)-infused rats. NTS microinjection of baclofen increased BP in both groups of rats. However, the pressor response to baclofen was enhanced in ANG II-infused rats compared with aCSF-infused rats. In addition, bilateral microinjection of the GABAB receptor antagonist CGP-35348 into the NTS evoked a decrease in BP in both group of rats, and the depressor responses to CGP-35348 were enhanced in the ANG II-infused rats. In contrast, the pressor responses to the GABAA receptor agonist muscimol and the depressor responses to the GABAA receptor antagonist bicuculline were comparable between aCSF- and ANG II-infused rats. These results indicate that chronic ANG II infusion stimulates GABAB receptor expression and augments GABAB receptor-mediated responses in the NTS. This effect could contribute to the central nervous system actions of ANG II that result in dampening of baroreflexes and elevation in arterial BP.

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