Identification and activation of autocrine renin-angiotensin system in adult ventricular myocytes

Zhang, X.; Dostal, David E.; Reiss, Krzysztof; Cheng, Wei; Kajstura, Jan; Li, P.; Huang, Harer; Sonnenblick, Edmund H.; Meggs, Leonard G.; Baker, Kenneth M.

doi:10.1152/ajpheart.1995.269.5.h1791

Cited by 51 publications

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“…Myocytes possess the various components of RAS 29,33,34 and generate Ang II. 2,9 -11,29 Conditions of overload in vivo up-regulate this local system 34 and Ang II blockade improves the outcome of ventricular dysfunction and failure of ischemic and nonischemic origin.…”

Section: Adp53m and Myocyte Rasmentioning

confidence: 99%

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Inhibition of p53 Function Prevents Renin-Angiotensin System Activation and Stretch-Mediated Myocyte Apoptosis

Leri

Fiordaliso

Setoguchi

et al. 2000

The American Journal of Pathology

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To determine whether stretch-induced activation of p53 is necessary for the up-regulation of the local renin-angiotensin system and angiotensin II (Ang II)-induced apoptosis, ventricular myocytes were infected with an adenoviral vector carrying mutated p53, Adp53m, before 12 hours of stretch. Noninfected myocytes and myocytes infected with AdLacZ served as controls. Stretching of Adp53m-infected myocytes prevented stimulation of p53 function that conditioned the expression of p53-dependent genes; quantity of angiotensinogen (Aogen), AT 1 , and Bax decreased, whereas Bcl-2 increased. Ang II generation was not enhanced by stretch. Conversely, stretch produced opposite changes in noninfected and AdLacZinfected myocytes: Aogen increased twofold, AT 1 increased 2.1-fold, Bax increased 2.5-fold, and Ang II increased 2.4-fold. These responses were coupled with 4.5-fold up-regulation of wild-type p53. Stretch elicited comparable adaptations in p53-independent genes, in the presence or absence of mutated p53; renin increased threefold, angiotensin-converting enzyme increased ninefold, and AT 2 increased 1.7-fold. Infection with Adp53m inhibited myocyte apoptosis after stretch. Conversely, stretch increased apoptosis by 6.2-fold in myocytes with elevated endogenous wild-type p53. Thus, a competitor of p53 function interfered with both stretch-induced Ang II formation and apoptosis, indicating that p53 is a major modulator of myocyte renin-angiotensin system and cell survival after mechanical deformation. The tumor suppressor gene, p53, has been implicated in the modulation of cardiac myocyte apoptosis in vitro

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Section: Adp53m and Myocyte Rasmentioning

confidence: 99%

“…2,9 -11,29 Conditions of overload in vivo up-regulate this local system 34 and Ang II blockade improves the outcome of ventricular dysfunction and failure of ischemic and nonischemic origin. 31,32,[35][36][37] We have identified previously that Aogen and AT 1 belong to the group of p53-inducible genes.…”

Section: Adp53m and Myocyte Rasmentioning

confidence: 99%

Inhibition of p53 Function Prevents Renin-Angiotensin System Activation and Stretch-Mediated Myocyte Apoptosis

Leri

Fiordaliso

Setoguchi

et al. 2000

The American Journal of Pathology

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“…The gradient of I to inversely correlates with the gradient of angiotensinogen across the ventricular wall whose expression is more prominent in the subendocardial than in either midmyocardium or epicardium regions (20). Evidence exists that cardiomyocytes, Purkinje fibers, and cardiac fibroblasts produce angiotensin II (21)(22)(23). Therefore, locally produced angiotensin II could act in a paracrine and/or autocrine manner to regulate I to .…”

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confidence: 99%

Angiotensin Receptor Type 1 Forms a Complex with the Transient Outward Potassium Channel Kv4.3 and Regulates Its Gating Properties and Intracellular Localization

Doronin

Potapova

et al. 2004

Journal of Biological Chemistry

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We report a novel signal transduction complex of the angiotensin receptor type 1. In this complex the angiotensin receptor type 1 associates with the potassium channel ␣-subunit Kv4.3 and regulates its intracellular distribution and gating properties. Electrophysiological remodeling in hypertrophy and heart failure predisposes the heart to lethal arrhythmias, which account for half of the mortality (1, 2). Experimental evidence derived from large scale clinical trials shows that inhibition of angiotensin II synthesis by inhibitors of angiotensin-converting enzyme or direct blockade of angiotensin receptor type 1 (AT1 1 receptor) with the antagonist losartan protects the heart from hypertensive complications (3, 4). A substantial reduction in mortality has been attributed to a significant decrease in sudden cardiac deaths possibly because of fewer episodes of complex arrhythmias (5, 6). The positive influence of inhibition of angiotensin-converting enzyme has been linked to bradykinin-mediated effects (7,8). However, the role of direct blockade of the AT1 receptor by losartan in episodes of sudden cardiac arrhythmias is still debated (9 -11). Electrophysiologic remodeling affects the entire spectrum of cardiac ion channels including the transient outward potassium current (I to ) whose density is often decreased in heart failure (2, 12, 13).The mechanism of I to down-regulation in heart failure is not completely understood and is likely to have multiple etiologies. In part it can be explained by the inhibitory effects of angiotensin II. Experiments with spontaneously hypertensive rats suggest that the AT1 receptor might be directly involved in the regulation of I to . In this animal model I to is inhibited and can be recovered by treatment with the AT1 receptor specific antagonist losartan (14). Experiments with isolated cardiomyocytes show that stimulation of the AT1 receptor results in the inhibition of I to in myocytes from rat or canine ventricle (15,16). In large mammals such as dogs or humans with substantial ventricular wall thickness, I to exhibits a transmural gradient that is vital for normal electrical activity (17,18). Distortion of the I to gradient leads to dispersion of repolarization across the ventricular wall, providing a substrate for ventricular arrhythmias (19). In both canine and human ventricle, I to density is higher in epicardial and midmyocardial than in the endocardial cells (17,18). The gradient of I to inversely correlates with the gradient of angiotensinogen across the ventricular wall whose expression is more prominent in the subendocardial than in either midmyocardium or epicardium regions (20). Evidence exists that cardiomyocytes, Purkinje fibers, and cardiac fibroblasts produce angiotensin II (21-23). Therefore, locally produced angiotensin II could act in a paracrine and/or autocrine manner to regulate I to . Experiments in vitro show that losartan stimulates I to in canine cardiomyocytes isolated from endocardium and converts the configuration of the action potential of endocar...

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“…68(3): 227-233, 2006 The renin-angiotensin system (RAS) is an adaptive mechanism of the body that maintains circulatory homeostasis and cardiac function in the presence of excessive hemodynamic overload. Although it has been thought that RAS exists only in the circulatory system (circulating RAS), RAS also has been found to exist in the heart (cardiac RAS) [14,24]. Angiotensin (Ang) II, one of the effector peptides of RAS, is known as a causative agent of cardiac remodeling [15].…”

mentioning

confidence: 99%

“…Although it has been thought that RAS exists only in the circulatory system (circulating RAS), RAS also has been found to exist in the heart (cardiac RAS) [14,24]. Angiotensin (Ang) II, one of the effector peptides of RAS, is known as a causative agent of cardiac remodeling [15].…”

mentioning

confidence: 99%

Effect of Angiotensin II Type 1 Receptor Blocker on Cardiac Angiotensin-Converting Enzyme and Chymase-Like Activities, and Cardiac Fibrosis in Cardiomyopathic Hamsters

Shimizu

Tanaka

Uchida

et al. 2006

The Journal of Veterinary Medical Science

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ABSTRACT. It has been reported that cardiac chymase has an effect on cardiac fibrosis through the Angiotensin (Ang) II formation and an Ang II-independent mechanism. In the present study, Ang II type 1 (AT1) receptor blocker (candesartan cilexetil) was administered to dilated cardiomyopathic (DCM; Bio TO2) hamsters for 4 weeks to study the effect of AT1 receptor blocker on cardiac chymase-like activity and cardiac fibrosis. Echocardiography, histological examination, and assessment of cardiac angiotensin-converting enzyme (ACE)/chymase-like activities were conducted. Hamsters showed cardiac dysfunction due to increased left ventricular dimensions and decreased ventricular wall thickness, significant increase in cardiac chymase-like activity, and fibrosis. This result indicates that the cardiac chymase-like activity is responsible for cardiac fibrosis. When candesartan cilexetil was administered to Bio TO2 hamsters, cardiac chymase-like activity increased significantly, whereas cardiac fibrosis decreased significantly. Cardiac ACE and chymase-like activities were unchanged in non-DCM hamsters with candesartan cilexetil. This suggests that the cardiac Ang II formation mechanism was stimulated by suppressing the effect of cardiac Ang II, and cardiac chymase-like activity could be increased. Moreover, this mechanism may be more highly activated if cardiac Ang II is activated in the heart. In conclusion, we demonstrated that AT1 receptor blocker reduced cardiac fibrosis, although cardiac chymase-like activity increased. Because the Ang II-forming pathway and the effect of chymase in hamsters is similar to that in dogs, the results of the present study may supplement the available information for dogs. KEY WORDS: angiotensin-converting enzyme, chymase, heart failure, remodeling, renin-angiotensin system. J. Vet. Med. Sci. 68(3): 227-233, 2006 The renin-angiotensin system (RAS) is an adaptive mechanism of the body that maintains circulatory homeostasis and cardiac function in the presence of excessive hemodynamic overload. Although it has been thought that RAS exists only in the circulatory system (circulating RAS), RAS also has been found to exist in the heart (cardiac RAS) [14,24]. Angiotensin (Ang) II, one of the effector peptides of RAS, is known as a causative agent of cardiac remodeling [15]. The Ang II-forming mechanism in the dog's heart is the same as that in humans. In both dogs and humans, cardiac Ang II is produced not only by the cardiac angiotensinconverting enzyme (ACE)-dependent pathway, but also by the cardiac chymase-dependent pathway [1,2,23]. The presence of this alternative pathway indicates that ACE inhibitors cannot completely inhibit the cardiac Ang II. A study in rats revealed that Ang II type 1 (AT1) receptor blockers reduced the hemodynamic load and cardiac remodeling by inhibiting the effect of Ang II at the receptor level, and consequently improved cardiac function [20]. Due to this difference in the effector site, AT1 receptor blockers are expected to be more superior to ACE inhibitors....

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Identification and activation of autocrine renin-angiotensin system in adult ventricular myocytes

Cited by 51 publications

References 0 publications

Inhibition of p53 Function Prevents Renin-Angiotensin System Activation and Stretch-Mediated Myocyte Apoptosis

Inhibition of p53 Function Prevents Renin-Angiotensin System Activation and Stretch-Mediated Myocyte Apoptosis

Angiotensin Receptor Type 1 Forms a Complex with the Transient Outward Potassium Channel Kv4.3 and Regulates Its Gating Properties and Intracellular Localization

Effect of Angiotensin II Type 1 Receptor Blocker on Cardiac Angiotensin-Converting Enzyme and Chymase-Like Activities, and Cardiac Fibrosis in Cardiomyopathic Hamsters

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