Angiotensin Type 2 Receptors Are Reexpressed by Cardiac Fibroblasts From Failing Myopathic Hamster Hearts and Inhibit Cell Growth and Fibrillar Collagen Metabolism

Ohkubo, Naohiko; Matsubara, Hiroaki; Nozawa, Yoshihisa; Mori, Yoshihide; Murasawa, Satoshi; Kijima, Kazuhisa; Maruyama, Katsuya; Masaki, Hiroya; Tsutumi, Yoshiaki; Shibazaki, Yoshinobu; Iwasaka, Toshiji; Inada, Mitsuo

doi:10.1161/01.cir.96.11.3954

Cited by 228 publications

(189 citation statements)

References 42 publications

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“…5,6,7,9 The AT 1 cellular receptor site appears to mediate most of the known actions of angiotensin II, although a second receptor site exists, AT 2 , 10 which appears to play an important role in apoptosis 11 and inhibition of cell growth and fibrillar collagen metabolism. 12 Valsartan is a new orally active angiotensin II antagonist which inhibits the RAS by selectively preventing the interaction of angiotensin II at its AT 1 cellular receptor site 9,13 Previous Phase I trials with valsartan have shown it to be well tolerated in single doses ranging from 10 to 400 mg once daily. 14 Adverse experiences reported in these trials were of mild-to-moderate intensity, generally self-limiting and judged unlikely to be related to valsartan.…”

Section: Introductionmentioning

confidence: 99%

Dose-response efficacy of valsartan, a new angiotensin II receptor blocker

et al. 1999

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Section: Introductionmentioning

confidence: 99%

Dose-response efficacy of valsartan, a new angiotensin II receptor blocker

et al. 1999

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“…1,2 Recent studies, mostly in cellular and adult animal models, mapped the distribution of AT 2 R in certain areas of the brain, 3 kidneys, 4 coronary arteries, cardiomyocytes, ventricular myocardium, 5 and the vasculature. 6,7 Increased AT 2 R expression has been observed under pathological conditions, such as vascular injury, 8 hypertension, 6,7 myocardial infarction, 9,10 congestive heart failure, 11 renal failure, 12 and brain ischemia. 13 Few studies have investigated the functional expression of AT 2 R in humans.…”

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confidence: 99%

Angiotensin Type 2 Receptor in Resistance Arteries of Type 2 Diabetic Hypertensive Patients

et al. 2007

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Abstract-The role of angiotensin type 2 receptor (AT 2 R) on vascular responses to angiotensin II in humans remains unclear. In this study we explored whether AT 2 R is expressed and functionally active on peripheral resistance arteries of hypertensive diabetic patients treated for 1 year with either the angiotensin receptor blocker valsartan or the ␤-blocker atenolol. Twenty-six hypertensive type 2 diabetic patients treated with oral hypoglycemic and antihypertensive agents (not receiving angiotensin receptor blockers or ␤-blockers) were randomly assigned to double-blind treatment for 1 year with valsartan or atenolol once daily added to their previous therapy in a clinical trial that we reported recently and compared with 10 normal subjects. Resistance arteries dissected from gluteal subcutaneous tissues were assessed on a pressurized myograph. Vasomotor response curves to angiotensin II (1 nmol/L to 1 mol/L) were performed on norepinephrine precontracted vessels in the presence of valsartan (10 mol/L) with or without the AT 2 R inhibitor PD123319 (1 mol/L). AT 2 R expression was evaluated by confocal microscopy. After 1 year of treatment, systolic and diastolic blood pressure was controlled and comparable in the valsartan and atenolol groups. Angiotensin II evoked a significant vasodilatory response only on resistance arteries from patients treated with valsartan, effect blocked by PD123319. AT 2 R expression was 4-fold higher in small arteries of valsartan-treated patients. A ngiotensin II (Ang II) is the main biological effector of the renin-angiotensin system, which plays a major role in cardiovascular and renal homeostasis. Most of the physiological and pathophysiological effects of Ang II are mediated by the angiotensin type 1 receptor (AT 1 R), which is widely expressed by most cell types. Expression of the angiotensin type 2 receptor (AT 2 R) is more limited and occurs predominantly in fetal tissues where it may play a role during development. 1,2 Recent studies, mostly in cellular and adult animal models, mapped the distribution of AT 2 R in certain areas of the brain, 3 kidneys, 4 coronary arteries, cardiomyocytes, ventricular myocardium, 5 and the vasculature. 6,7 Increased AT 2 R expression has been observed under pathological conditions, such as vascular injury, 8 hypertension, 6,7 myocardial infarction, 9,10 congestive heart failure, 11 renal failure, 12 and brain ischemia. 13 Few studies have investigated the functional expression of AT 2 R in humans. AT 2 Rs are expressed in the human skin (throughout the epidermal and dermal structures) 14 and are markedly upregulated in incisional cutaneous wounds. 15 AT 2 Rs have been demonstrated in the human coronary microcirculation, where they may contribute to vasodilation. 16 Studies in cellular and animal models suggest that AT 2 R counteracts many AT 1 R actions by inducing vasodilation, antiproliferation, and apoptosis. 2 We showed recently in animal models of hypertension that AT 2 R is upregulated and mediates vasodilation only when AT 1 Rs are bl...

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“…In agreement with this idea, Stoll et al (1995) first reported that AT 2 receptor activation inhibits the proliferation of endothelial cells. The antiproliferative action of the AT 2 receptor was also documented in VSMC (Nakajima et al, 1995), PC12W pheochromocytoma cells (Meffert et al, 1996), renomedullary cells (Maric et al, 1998), and cardiac fibroblasts (Ohkubo et al, 1997). Comparison of embryonic VSMC cultures from wild-type and AT 2 receptor null mice further indicated that AT À 2 cells display an exaggerated proliferative response to serum .…”

Section: Introductionmentioning

confidence: 89%

Expression of angiotensin type II receptor downregulates Cdk4 synthesis and inhibits cell-cycle progression

et al. 2003

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Accumulating evidence suggests that angiotensin II type II (AT 2 ) receptor subtype negatively regulates cell proliferation in pathophysiological conditions associated with tissue remodeling. However, the mechanisms through which AT 2 receptor achieves this effect remain poorly understood. In this study, we demonstrate that expression of AT 2 receptor inhibits the proliferation of rat fibroblasts in a ligand-independent manner. The antiproliferative action of AT 2 is dependent on the density of surface receptors. We show that AT 2 receptor expression negatively regulates G1 phase progression in both cycling cells and G0-arrested cells stimulated to re-enter the cell cycle, but has no detectable effect on apoptosis. The delay in cell-cycle progression of AT 2 -expressing cells is associated with downregulation of cyclin E expression, decreased assembly of cyclin E-Cdk2 complexes, and the resulting attenuation of Cdk2 activation. The induction of Cdk4 expression and activity is also markedly attenuated, which likely contributes to the inhibition of cyclin E expression. Ectopic expression of Cdk4 alleviates the proliferation defect of AT 2 -expressing cells. These findings suggest that the growth-inhibitory effects of the AT 2 receptor are attributable in part to its spontaneous inhibitory action on the cell cycle machinery.

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Angiotensin Type 2 Receptors Are Reexpressed by Cardiac Fibroblasts From Failing Myopathic Hamster Hearts and Inhibit Cell Growth and Fibrillar Collagen Metabolism

Cited by 228 publications

References 42 publications

Dose-response efficacy of valsartan, a new angiotensin II receptor blocker

Dose-response efficacy of valsartan, a new angiotensin II receptor blocker

Angiotensin Type 2 Receptor in Resistance Arteries of Type 2 Diabetic Hypertensive Patients

Expression of angiotensin type II receptor downregulates Cdk4 synthesis and inhibits cell-cycle progression

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