Regulation of angiotensin II receptors on ventricular myocytes after myocardial infarction in rats.

Meggs, Leonard G.; Coupet, Joseph; Huang, Harer; Cheng, Wei; Li, Peng; Capasso, J. M.; Homcy, Charles J.; Anversa, Piero

doi:10.1161/01.res.72.6.1149

Cited by 145 publications

(72 citation statements)

References 50 publications

(22 reference statements)

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“…Thus, the number of AT1 receptors defines the biological efficacy of angiotensin II. The RAS has also been implicated in cardiovascular pathology, and the upregulation of AT1 receptors in the cardiovascular system has been reported in diseases like thyroid dysfunction, hypertension and myocardial infarction [22][23][24]. Our present findings demonstrate increased densities of the AT1 receptor mRNA and protein in human atrial myocardium of patients suffering from type 2 diabetes.…”

Section: Discussionsupporting

confidence: 71%

The increased angiotensin II (type 1) receptor density in myocardium of type 2 diabetic patients is prevented by blockade of the renin–angiotensin system

et al. 2006

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Aims/hypothesis The angiotensin II (type 1) (AT1) receptor mediates many biological effects of the renin-angiotensin system (RAS), leading to remodelling of cardiac tissue. The present study was designed to analyse changes in the function and expression of the AT1 receptor as principal effector of the RAS in myocardium from type 2 diabetic patients compared with non-diabetic myocardium as control. In addition, we determined the effect of treatment with ACE inhibitors or AT1 receptor blockers on expression levels of the receptor in diabetic patients. Methods Gene expression of the AT1 receptor was analysed by quantitative RT-PCR and protein expression was determined by immunoblot analysis in human right atrial myocardium. We investigated functional coupling of the receptors by measuring contractility in isolated trabeculae stimulated with increasing concentrations of angiotensin II. Results Diabetic myocardium showed a significant increase in protein expression (170±16% of control) and median mRNA expression (186% of control) of the AT1 receptor.The additional receptors were functionally coupled, resulting in a stronger inotropic response upon stimulation with angiotensin II (89±5.5% vs 29±1.6% in controls), whereas receptor affinity was similar in both groups. However, myocardium from diabetic patients treated with ACE inhibitors or AT1 receptor blockers showed no increase in AT1 receptor expression. Conclusions/interpretation AT1 receptor expression in myocardium of type 2 diabetic patients is dynamic, depending on the level of glycaemic control and the activity of the RAS. These findings could at least in part explain the strong therapeutic benefit of RAS inhibition in diabetic patients.

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Section: Discussionsupporting

confidence: 71%

The increased angiotensin II (type 1) receptor density in myocardium of type 2 diabetic patients is prevented by blockade of the renin–angiotensin system

et al. 2006

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“…[45][46][47][48] Microscopic analysis revealed that cross-sectional areas of cardiac myocytes were increased both in KO mice and in WT mice (Fig 6A), indicating that each cardiac myocyte was increased in size by pressure overload without AT 1 signaling. Perivascular fibrosis was prominent after pressure overload in KO hearts as well as in WT hearts (Fig 6B).…”

Section: Histological Changes In Hypertrophied Heartsmentioning

confidence: 98%

Pressure Overload Induces Cardiac Hypertrophy in Angiotensin II Type 1A Receptor Knockout Mice

Harada

Komuro²,

Shiojima³

et al. 1998

Circulation

230

152

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Background-Many studies have suggested that the renin-angiotensin system plays an important role in the development of pressure overload-induced cardiac hypertrophy. Moreover, it has been reported that pressure overload-induced cardiac hypertrophy is completely prevented by ACE inhibitors in vivo and that the stored angiotensin II (Ang II) is released from cardiac myocytes in response to mechanical stretch and induces cardiomyocyte hypertrophy through the Ang II type 1 receptor (AT 1 ) in vitro. These results suggest that the AT 1 -mediated signaling is critical for the development of mechanical stress-induced cardiac hypertrophy. Methods and Results-To determine whether AT 1 -mediated signaling is indispensable for the development of pressure overload-induced cardiac hypertrophy, pressure overload was produced by constricting the abdominal aorta of AT 1A knockout (KO) mice. Quantitative reverse transcriptase-polymerase chain reaction revealed that the cardiac AT 1 (probably AT 1B ) mRNA levels in AT 1A KO mice were Ͻ10% of those of wild-type (WT) mice and were not affected by pressure overload. Chronic treatment with subpressor doses of Ang II increased left ventricular mass in WT mice but not in KO mice. Pressure overload, however, fully induced cardiac hypertrophy in KO as well as WT mice. There were no significant differences between WT and KO mice in expression levels of fetal-type cardiac genes, in the left ventricular wall thickness and systolic function as revealed by the transthoracic echocardiogram, or in the histological changes such as myocyte hypertrophy and fibrosis.

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“…AT 2 receptors are numerous in neonatal cardiac myocytes, but their number decreases rapidly postnatally and adult ventricular myocytes have been claimed to possess exclusively AT 1 . 40,41 The possibility was raised that AT 2 is re-expressed in the overloaded heart in both myocytes 42 and fibroblasts, 43 but the myocyte localization remained unclear. In this study, AT 2 was detected in nonstretched myocytes and its expression increased with the mechanical stimulus.…”

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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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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Regulation of angiotensin II receptors on ventricular myocytes after myocardial infarction in rats.

Cited by 145 publications

References 50 publications

The increased angiotensin II (type 1) receptor density in myocardium of type 2 diabetic patients is prevented by blockade of the renin–angiotensin system

The increased angiotensin II (type 1) receptor density in myocardium of type 2 diabetic patients is prevented by blockade of the renin–angiotensin system

Pressure Overload Induces Cardiac Hypertrophy in Angiotensin II Type 1A Receptor Knockout Mice

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

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