SIRT1, a longevity gene, downregulates angiotensin II type 1 receptor expression in vascular smooth muscle cells.
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).


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.


CONCLUSIONS
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.
Miyazaki
Ryohei
R
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashiku, 812-8582 Fukuoka, Japan.
Ichiki
Toshihiro
T
Hashimoto
Toru
T
Inanaga
Keita
K
Imayama
Ikuyo
I
Sadoshima
Junichi
J
Sunagawa
Kenji
K
D000804:Angiotensin II; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology; D009536:Niacinamide / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects*; D000077185:Resveratrol; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D016329:Sp1 Transcription Factor; D013267:Stilbenes; D000804:Angiotensin II; D009536:Niacinamide; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D037761:Sirtuins; D000077185:Resveratrol