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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1263.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

SIRT1, a Longevity Gene, Downregulates Angiotensin II Type 1 Receptor Expression in Vascular Smooth Muscle Cells

Ryohei Miyazaki; Toshihiro Ichiki; Toru Hashimoto; Keita Inanaga; Ikuyo Imayama; Junichi Sadoshima; Kenji Sunagawa

From the Departments of Cardiovascular Medicine (R.M., T.I., T.H., K.I., I.I., K.S.) and Advanced Therapeutics for Cardiovascular Diseases (T.I.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; and the Cardiovascular Research Institute (J.S.), University of Medicine and Dentistry of New Jersey, Newark.

Correspondence to Toshihiro Ichiki, MD, Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashiku, 812-8582 Fukuoka, Japan. E-mail ichiki{at}cardiol.med.kyushu-u.ac.jp

Abstract

Objective— Resveratrol (3,5,4'-trihydroxystilbene), a polyphenol found in red wine, is known to activate sirtuin1 (SIRT1), a longevity gene. Previous studies have demonstrated that resveratrol extends the life span of diverse species through activation of SIRT1. It was also reported that inhibition of angiotensin II function by angiotensin II type I receptor (AT1R) antagonist prolonged rat life span. We, therefore, hypothesized that resveratrol may inhibit the renin-angiontein system and examined whether resveratrol affects AT1R expression in vascular smooth muscle cells (VSMCs).

Methods and Results— Northern and Western blot analysis revealed that resveratrol significantly decreased the expression of AT1R at mRNA and protein levels in a dose- and time-dependent manner. Overexpression of SIRT1 reduced AT1R expression whereas nicotinamide, an inhibitor of SIRT1, increased AT1R expression and reversed the resveratrol-induced AT1R downregulation. AT1R gene promoter activity was decreased by resveratrol, but resveratrol did not affect the AT1R mRNA stability. Deletion analysis showed that the most proximal region of AT1R gene promoter containing Sp1 site is responsible for downregulation. Administration of resveratrol suppressed AT1R expression in the mouse aorta and blunted angiotensin II–induced hypertension.

Conclusion— Resveratrol suppressed AT1R expression through SIRT1 activation both in vivo and in vitro. The inhibition of the renin-angiotensin system may contribute, at least in part, to the resveratrol-induced longevity and antiatherogenic effect of resveratrol.

Sirtuin1 (SIRT1) belongs to class III histone/protein deacetylases and are associated with longevity. Resveratrol significantly suppressed AT1R expression at the transcriptional level through SIRT1 activation both in vivo and in vitro. The downregulation of renin-angiotensin system may contribute to the longevity and antiatherogenic effect of resveratrol.

Key Words: resveratrol • SIRT1 • angiotensin II receptor • vascular smooth muscle cell