scholarly journals Regulation of L-type inward calcium channel activity by captopril and angiotensin II via the phosphatidyl inositol 3-kinase pathway in cardiomyocytes from volume-overload hypertrophied rat hearts

2011 ◽  
Vol 89 (3) ◽  
pp. 206-215 ◽  
Author(s):  
Zikiar Alvin ◽  
Graham G. Laurence ◽  
Bernell R Coleman ◽  
Aiqiu Zhao ◽  
Majd Hajj-Moussa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Phosphatidyl Inositol ◽  
Volume Overload ◽  
Acute Administration ◽  
Dependent Manner ◽  
Ang Ii ◽  
Patch Clamp Technique ◽  
Humoral Factors

Heart failure can be caused by pro-hypertrophic humoral factors such as angiotensin II (Ang II), which regulates protein kinase activities. The intermingled responses of these kinases lead to the early compensated cardiac hypertrophy, but later to the uncompensated phase of heart failure. We have shown that although beneficial, cardiac hypertrophy is associated with modifications in ion channels that are mainly mediated through mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase (PI3K) activation. This study evaluates the control of L-type Ca2+ current (ICa,L) by the Ang II/PI3K pathway in hypertrophied ventricular myocytes from volume-overload rats using the perforated patch-clamp technique. To assess activation of the ICa,L in cardiomyocytes, voltages of 350 ms in 10 mV increments from a holding potential of –85 mV were applied to cardiocytes, with a pre-pulse to –45 mV for 300 ms. Volume overload-induced hypertrophy reduces ICa,L, whereas addition of Ang II alleviates the hypertrophic-induced decrease in a PI3K-dependent manner. Acute administration of Ang II (10−6 mol/L) to normal adult cardiomyocytes had no effect; however, captopril reduced their basal ICa,L. In parallel, captopril regressed the hypertrophy and inverted the Ang II effect on ICa,L seemingly through a PI3K upstream effector. Thus, it seems that regression of cardiac hypertrophy by captopril improved ICa,L partly through PI3K.

scholarly journals Dapagliflozin: a sodium–glucose cotransporter 2 inhibitor, attenuates angiotensin II-induced cardiac fibrotic remodeling by regulating TGFβ1/Smad signaling

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Yuze Zhang ◽  
Xiaoyan Lin ◽  
Yong Chu ◽  
Xiaoming Chen ◽  
Heng Du ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Remodeling ◽  
Left Ventricular ◽  
Dependent Manner ◽  
Ang Ii ◽  
Smad Signaling ◽  
Sd Rats ◽  
Sodium Glucose Cotransporter ◽  
Tgf Β1

Abstract Background Cardiac remodeling is one of the major risk factors for heart failure. In patients with type 2 diabetes, sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of the first hospitalization for heart failure, possibly through glucose-independent mechanisms in part, but the underlying mechanisms remain largely unknown. This study aimed to shed light on the efficacy of dapagliflozin in reducing cardiac remodeling and potential mechanisms. Methods Sprague–Dawley (SD) rats, induced by chronic infusion of Angiotensin II (Ang II) at a dose of 520 ng/kg per minute for 4 weeks with ALZET® mini-osmotic pumps, were treated with either SGLT2 inhibitor dapagliflozin (DAPA) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with Ang II (1 μM) with or without the indicated concentration (0.5, 1, 10 μM) of DAPA. The protein levels of collagen and TGF-β1/Smad signaling were measured along with body weight, and blood biochemical indexes. Results DAPA pretreatment resulted in the amelioration of left ventricular dysfunction in Ang II-infused SD rats without affecting blood glucose and blood pressure. Myocardial hypertrophy, fibrosis and increased collagen synthesis caused by Ang II infusion were significantly inhibited by DAPA pretreatment. In vitro, DAPA inhibit the Ang II-induced collagen production of CFs. Immunoblot with heart tissue homogenates from chronic Ang II-infused rats revealed that DAPA inhibited the activation of TGF-β1/Smads signaling. Conclusion DAPA ameliorates Ang II-induced cardiac remodeling by regulating the TGF-β1/Smad signaling in a non-glucose-lowering dependent manner.

scholarly journals Altered Renal Vascular Responsiveness to Vasoactive Agents in Rats with Angiotensin II-Dependent Hypertension and Congestive Heart Failure

2019 ◽  
Vol 44 (4) ◽  
pp. 792-809 ◽  
Author(s):  
Šárka Vacková ◽  
Soňa Kikerlová ◽  
Vojtěch Melenovsky ◽  
František Kolář ◽  
John D. Imig ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Angiotensin Ii ◽  
Renal Dysfunction ◽  
Volume Overload ◽  
Epoxyeicosatrienoic Acids ◽  
Ang Ii ◽  
Vasoactive Agents ◽  
Vascular Responsiveness ◽  
Renal Vascular

Objective: We evaluated the hypothesis that the development of renal dysfunction and congestive heart failure (CHF) caused by volume overload in rats with angiotensin II (ANG II)-dependent hypertension is associated with altered renal vascular responsiveness to ANG II and to epoxyeicosatrienoic acids (EETs). Methods: Ren-2 transgenic rats (TGRs) were used as a model of ANG II-dependent hypertension. CHF was induced by volume overload achieved by the creation of the aorto-caval fistula (ACF). Renal blood flow (RBF) responses were determined to renal arterial administration of ANG II, native 11,12-EET, an analog of 14,15-EETs (EET-A), norepinephrine (NE), acetylcholine (Ach) and bradykinin (Bk) in healthy (i.e., sham-operated) TGR and ACF TGR (5 weeks after ACF creation). Results: Selective intrarenal administration of neither vasoactive drug altered mean arterial pressure in any group. Administration of ANG II caused greater decreases in RBF in ACF TGR than in sham-operated TGR, whereas after administration of NE the respective decreases were comparable in the 2 groups. Administration of Ach and Bk elicited significantly higher RBF increases in ACF TGR as compared with sham-operated TGR. In contrast, administration of 11,12-EET and EET-A caused significantly smaller RBF increases in ACF TGR than in sham-operated TGR. Conclusion: The findings show that 5 weeks after creation of ACF, the TGR exhibit exaggerated renal vasoconstrictor responses to ANG II and reduced renal vasodilatory responses to EETs, suggesting that both these alterations might play an important role in the development of renal dysfunction in this model of CHF.

scholarly journals Rap1GAP Mediates Angiotensin II-Induced Cardiomyocyte Hypertrophy by Inhibiting Autophagy and Increasing Oxidative Stress

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Yan Gao ◽  
Di Zhao ◽  
Wen-zhi Xie ◽  
Tingting Meng ◽  
Chunxiao Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiomyocyte Hypertrophy ◽  
Ros Generation ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Neonatal Cardiomyocytes ◽  
And Oxidative Stress

Abnormal autophagy and oxidative stress contribute to angiotensin II- (Ang II-) induced cardiac hypertrophy and heart failure. We previously showed that Ang II increased Rap1GAP gene expression in cardiomyocytes associated with hypertrophy and autophagy disorders. Using real-time PCR and Western blot, we found that Rap1GAP expression was increased in the heart of Sprague Dawley (SD) rats infused by Ang II compared with saline infusion and in Ang II vs. vehicle-treated rat neonatal cardiomyocytes. Overexpression of Rap1GAP in cultured cardiomyocytes exacerbated Ang II-induced cardiomyocyte hypertrophy, reactive oxygen species (ROS) generation, and cell apoptosis and inhibited autophagy. The increased oxidative stress caused by Rap1GAP overexpression was inhibited by the treatment of autophagy agonists. Knockdown of Rap1GAP by siRNA markedly attenuated Ang II-induced cardiomyocyte hypertrophy and oxidative stress and enhanced autophagy. The AMPK/AKT/mTOR signaling pathway was inhibited by overexpression of Rap1GAP and activated by the knockdown of Rap1GAP. These results show that Rap1GAP-mediated pathway might be a new mechanism of Ang II-induced cardiomyocyte hypertrophy, which could be a potential target for the future treatment of cardiac hypertrophy and heart failure.

Involvement of Rho kinase pathway in the mechanism of renal vasoconstriction and cardiac hypertrophy in rats with experimental heart failure

2006 ◽  
Vol 290 (5) ◽  
pp. H2007-H2014 ◽  
Author(s):  
Joseph Winaver ◽  
Elena Ovcharenko ◽  
Irit Rubinstein ◽  
Konstantin Gurbanov ◽  
Piero Pollesello ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Flow ◽  
Cardiac Hypertrophy ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Weight Ratio ◽  
Volume Overload ◽  
Acute Administration ◽  
Renal Vasoconstriction ◽  
Additional Tool

Rho-dependent kinases serve as downstream effectors of several vasoconstrictor systems, the activities of which are upregulated in congestive heart failure (CHF). We evaluated renal and cardiac effects of Y-27632, a highly selective Rho kinase inhibitor, in an experimental model of volume-overload CHF. Effects of acute administration of Y-27632 (0.3 mg/kg) on renal hemodynamic and clearance parameters and effects of chronic treatment (10.0 mg·kg−1·day−1 for 7 days via osmotic minipumps) on cardiac hypertrophy and cumulative Na+ excretion were studied in male Wistar rats with aortocaval fistula and control rats. The Y-27632-induced decrease in renal vascular resistance (from 40.4 ± 4.6 to 26.0 ± 3.1 resistance units, P < 0.01) in CHF rats was associated with a significant increase in total renal blood flow (+34%) and cortical and medullary blood flow (approx +37 and +27%, respectively). These values were significantly higher than those in control rats and occurred despite a decrease in mean arterial pressure (−15 mmHg). Despite the marked renal vasodilatory effect, Y-27632 did not alter glomerular filtration rate and renal Na+ excretion. Chronic administration of Y-27632 did not alter daily or cumulative renal Na+ excretion in CHF rats but was associated with a significant decrease in heart-to-body weight ratio, an index of cardiac hypertrophy: 0.32 ± 0.007, 0.46 ± 0.017, and 0.37 ± 0.006% in control, CHF, and CHF + Y-27632 rats, respectively. The findings suggest that Rho kinase-dependent pathways are involved in the mechanisms of renal vasoconstriction and cardiac hypertrophy in rats with volume-overload heart failure. Selective blockade of these signaling pathways may be considered an additional tool to improve renal perfusion and attenuate cardiac hypertrophy in heart failure.

scholarly journals The nuclear receptor RORα protects against angiotensin II-induced cardiac hypertrophy and heart failure

2019 ◽  
Vol 316 (1) ◽  
pp. H186-H200 ◽  
Author(s):  
Ju Youn Beak ◽  
Hong Soon Kang ◽  
Wei Huang ◽  
Page H. Myers ◽  
Dawn E. Bowles ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Myocardial Hypertrophy ◽  
Orphan Receptor ◽  
Ang Ii ◽  
Pathological Hypertrophy

The nuclear receptor retinoic acid-related orphan receptor-α (RORα) regulates numerous critical biological processes, including central nervous system development, lymphocyte differentiation, and lipid metabolism. RORα has been recently identified in the heart, but very little is known about its role in cardiac physiology. We sought to determine whether RORα regulates myocardial hypertrophy and cardiomyocyte survival in the context of angiotensin II (ANG II) stimulation. For in vivo characterization of the function of RORα in the context of pathological cardiac hypertrophy and heart failure, we used the “staggerer” (RORαsg/sg) mouse, which harbors a germline mutation encoding a truncated and globally nonfunctional RORα. RORαsg/sg and wild-type littermate mice were infused with ANG II or vehicle for 14 days. For in vitro experiments, we overexpressed or silenced RORα in neonatal rat ventricular myocytes (NRVMs) and human cardiac fibroblasts exposed to ANG II. RORαsg/sg mice developed exaggerated myocardial hypertrophy and contractile dysfunction after ANG II treatment. In vitro gain- and loss-of-function experiments were consistent with the discovery that RORα inhibits ANG II-induced pathological hypertrophy and cardiomyocyte death in vivo. RORα directly repressed IL-6 transcription. Loss of RORα function led to enhanced IL-6 expression, proinflammatory STAT3 activation (phopho-STAT3 Tyr705), and decreased mitochondrial number and function, oxidative stress, hypertrophy, and death of cardiomyocytes upon ANG II exposure. RORα was less abundant in failing compared with nonfailing human heart tissue. In conclusion, RORα protects against ANG II-mediated pathological hypertrophy and heart failure by suppressing the IL-6-STAT3 pathway and enhancing mitochondrial function. NEW & NOTEWORTHY Mice lacking retinoic acid-related orphan receptor-α (RORα) develop exaggerated cardiac hypertrophy after angiotensin II infusion. Loss of RORα leads to enhanced IL-6 expression and NF-κB nuclear translocation. RORα maintains mitochondrial function and reduces oxidative stress after angiotensin II. The abundance of RORα is reduced in failing mouse and human hearts.

Angiotensin II maintains, but does not mediate, isoproterenol-induced cardiac hypertrophy in rats

1994 ◽  
Vol 267 (4) ◽  
pp. H1496-H1506 ◽  
Author(s):  
E. Golomb ◽  
Z. A. Abassi ◽  
G. Cuda ◽  
M. Stylianou ◽  
V. R. Panchal ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Left Ventricular ◽  
Heart Weight ◽  
Dependent Manner ◽  
Ang Ii ◽  
Major Function ◽  
Hypertrophic Response ◽  
Dose Dependent

The role of angiotensin II (ANG II) in the development of isoproterenol (Iso)-induced cardiac hypertrophy was examined in rats. Iso increased cardiac mass, left ventricular RNA-to-DNA ratio, and the cardiac content of both myosin heavy chain and hydroxyproline in a dose-dependent manner, indicating that Iso-induced cardiac hypertrophy involves growth of both muscle and connective tissue. Cardiac hypertrophy reverted within 11-14 days after cessation of Iso. Propranolol prevented development of Iso-induced cardiac hypertrophy but did not affect the rate of its reversal. The ANG II receptor blocker losartan (Los) did not significantly decrease the hypertrophic response to Iso. Los injected after cessation of Iso dramatically enhanced the reversal of cardiac hypertrophy, even in rats that received Los with Iso during the induction of Iso-induced cardiac hypertrophy. ANG II, injected continuously at a subpressor dose that did not affect heart weight when given alone, inhibited reversal of cardiac hypertrophy when given after cessation of Iso. Los did not significantly affect the induction of the protooncogene c-fos by Iso. We conclude that endogenous ANG II has a major function in maintaining Iso-induced cardiac hypertrophy but does not mediate its induction. This suggests that different interactive stimuli may be required for development of cardiac hypertrophy, i.e., for initiation and for maintenance.

scholarly journals Role of angiotensin II in the development of subcellular remodeling in heart failure

2021 ◽  
pp. 352-371
Author(s):  
Sukhwinder K. Bhullar ◽  
Anureet K. Shah ◽  
Naranjan S. Dhalla
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Heart Function ◽  
Critical Role ◽  
Pressure Overload ◽  
Renin Angiotensin System ◽  
Volume Overload ◽  
Experimental Models ◽  
Ang Ii ◽  
Beneficial Effects

The development of heart failure under various pathological conditions such as myocardial infarction (MI), hypertension and diabetes are accompanied by adverse cardiac remodeling and cardiac dysfunction. Since heart function is mainly determined by coordinated activities of different subcellular organelles including sarcolemma, sarcoplasmic reticulum, mitochondria and myofibrils for regulating the intracellular concentration of Ca2+, it has been suggested that the occurrence of heart failure is a consequence of subcellular remodeling, metabolic alterations and Ca2+-handling abnormalities in cardiomyocytes. Because of the elevated plasma levels of angiotensin II (ANG II) due to activation of the renin-angiotensin system (RAS) in heart failure, we have evaluated the effectiveness of treatments with angiotensin converting enzyme (ACE) inhibitors and ANG II type 1 receptor (AT1R) antagonists in different experimental models of heart failure. Attenuation of marked alterations in subcellular activities, protein content and gene expression were associated with improvement in cardiac function in MI-induced heart failure by treatment with enalapril (an ACE inhibitor) or losartan (an AT1R antagonist). Similar beneficial effects of ANG II blockade on subcellular remodeling and cardiac performance were also observed in failing hearts due to pressure overload, volume overload or chronic diabetes. Treatments with enalapril and losartan were seen to reduce the degree of RAS activation as well as the level of oxidative stress in failing hearts. These observations provide evidence which further substantiate to support the view that activation of RAS and high level of plasma ANG II play a critical role in inducing subcellular defects and cardiac dys-function during the progression of heart failure.

scholarly journals Oxidative Stress as A Mechanism for Functional Alterations in Cardiac Hypertrophy and Heart Failure

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 931
Author(s):  
Anureet K. Shah ◽  
Sukhwinder K. Bhullar ◽  
Vijayan Elimban ◽  
Naranjan S. Dhalla
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Critical Role ◽  
Pressure Overload ◽  
Hypertrophied Heart ◽  
Vasoactive Hormones

Although heart failure due to a wide variety of pathological stimuli including myocardial infarction, pressure overload and volume overload is associated with cardiac hypertrophy, the exact reasons for the transition of cardiac hypertrophy to heart failure are not well defined. Since circulating levels of several vasoactive hormones including catecholamines, angiotensin II, and endothelins are elevated under pathological conditions, it has been suggested that these vasoactive hormones may be involved in the development of both cardiac hypertrophy and heart failure. At initial stages of pathological stimuli, these hormones induce an increase in ventricular wall tension by acting through their respective receptor-mediated signal transduction systems and result in the development of cardiac hypertrophy. Some oxyradicals formed at initial stages are also involved in the redox-dependent activation of the hypertrophic process but these are rapidly removed by increased content of antioxidants in hypertrophied heart. In fact, cardiac hypertrophy is considered to be an adaptive process as it exhibits either normal or augmented cardiac function for maintaining cardiovascular homeostasis. However, exposure of a hypertrophied heart to elevated levels of circulating hormones due to pathological stimuli over a prolonged period results in cardiac dysfunction and development of heart failure involving a complex set of mechanisms. It has been demonstrated that different cardiovascular abnormalities such as functional hypoxia, metabolic derangements, uncoupling of mitochondrial electron transport, and inflammation produce oxidative stress in the hypertrophied failing hearts. In addition, oxidation of catecholamines by monoamine oxidase as well as NADPH oxidase activation by angiotensin II and endothelin promote the generation of oxidative stress during the prolonged period by these pathological stimuli. It is noteworthy that oxidative stress is known to activate metallomatrix proteases and degrade the extracellular matrix proteins for the induction of cardiac remodeling and heart dysfunction. Furthermore, oxidative stress has been shown to induce subcellular remodeling and Ca2+-handling abnormalities as well as loss of cardiomyocytes due to the development of apoptosis, necrosis, and fibrosis. These observations support the view that a low amount of oxyradical formation for a brief period may activate redox-sensitive mechanisms, which are associated with the development of cardiac hypertrophy. On the other hand, high levels of oxyradicals over a prolonged period may induce oxidative stress and cause Ca2+-handling defects as well as protease activation and thus play a critical role in the development of adverse cardiac remodeling and cardiac dysfunction as well as progression of heart failure.

Modulation of Ca2+ transients in neonatal and adult rat cardiomyocytes by angiotensin II and endothelin-1

1996 ◽  
Vol 270 (3) ◽  
pp. H857-H868 ◽  
Author(s):  
R. M. Touyz ◽  
J. Fareh ◽  
G. Thibault ◽  
B. Tolloczko ◽  
R. Lariviere ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Receptor Agonist ◽  
Dependent Manner ◽  
Induced Responses ◽  
Ang Ii ◽  
Binding Studies ◽  
Vasoactive Peptides ◽  
Adult Cardiomyocytes ◽  
Etb Receptor ◽  
Dose Dependent

Vasoactive peptides may exert inotropic and chronotropic effects in cardiac muscle by modulating intracellular calcium. This study assesses effects of angiotensin II (ANG II) and endothelin-1 (ET-1) on intracellular free calcium concentration ([Ca2+]i) in cultured cardiomyocytes from neonatal and adult rats. [Ca2+]i was measured microphotometrically and by digital imaging using fura 2 methodology. Receptor subtypes through which these agonists induce responses were determined pharmacologically and by radioligand binding studies. ANG II and ET-1 increased neonatal atrial and ventricular cell [Ca2+]i transients in a dose-dependent manner. ANG II (10(-11) to 10(-7) M) failed to elicit [Ca2+]i responses in adult cardiomyocytes, whereas ET-1 increased [Ca2+]i in a dose-dependent manner. The ETA receptor antagonist BQ-123 significantly reduced (P 7< 0.05) ET-1 induced responses, and the ETB receptor agonist IRL-1620 (10(-7) to 10(-5) M) significantly increased (P < 0.05) [Ca2+]i in neonatal and adult cardiomyocytes. ET-1 binding studies demonstrated 85% displacement by BQ-123 and approximately 15% by the ETB receptor agonist sarafotoxin S6c, suggesting a predominance of ETA receptors. Competition binding studies for ANG II failed to demonstrate significant binding on adult ventricular myocytes, indicating the absence or presence of very few ANG II receptors. These data demonstrate that ANG II and ET-1 have stimulatory [Ca2+]i effects on neonatal cardiomyocytes, whereas in adult cardiomyocytes, ANG II-induced effects are insignificant, and only ET-1-induced responses, which are mediated predominantly via ETA receptors, are preserved. Cardiomyocyte responses to vasoactive peptides may thus vary with cardiac development.

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