Resveratrol protects human endothelium from H(2)O(2)-induced oxidative stress and senescence via SirT1 activation.
OBJECTIVE
Silencing information regulator (SirT1), a NAD-dependent histone deacetylase, is an essential mediator of longevity in normal cells by calorie restriction. SirT1 has many biological functions, including transcription regulation, cell differentiation inhibition, cell cycle regulation, and anti-apoptosis. Resveratrol (RV)-induced SirT1 activation also improves endothelial dysfunction and suppresses vascular inflammation. In this study, we investigated the roles of RV-induced SirT1 activation in endothelial cells under oxidative stress.


METHODS
SirT1 mRNA expression levels were examined in the endothelium layer (endothelial cells) of cardiac coronary vessels from patients receiving coronary artery bypass graft surgery (CABG) surgery and aged rats using reverse transcriptase polymerase chain reaction (RT-PCR). To further explore the effect of SirT1 activation on oxidative stress-induced aging, senescence-associated β-galactosidase (SA-β-gal) expression in RV-treated human umbilical vein endothelial cells (HUVECs) with or without H(2)O(2) treatment was evaluated.


RESULTS
SirT1 expression was decreased in aged and atherosclerotic vessels in vivo, and significantly reduced in endothelial cells purified from vessel tissues. Furthermore, SirT1 levels were dose-dependently increased in RV-treated HUVECs. The SA-β gal assay showed that RV inhibited the senescent phenotype of H(2)O(2)-treated HUVECs. Reactive oxygen species (ROS) production and the percentage of cells positive for SA-β gal were significantly increased in siRNA-SirT1 (knockdown of SirT1 expression)-treated HUVEC cells. Importantly, the treatment effect of RV was significantly abolished in the oxidative effects of H(2)O(2)-treated HUVECs by siRNA-SirT1.


CONCLUSIONS
Our data suggested that SirT1 could be a crucial factor involved in the endothelial cells of atherosclerotic CAGB patients and aging rats. RV is a potential candidate for preventing oxidative stress-induced aging in endothelial cells. RV may also prevent ROS-induced damage via increased endothelial SirT1 expression.
Kao
Chung-Lan
CL
Department of Physical Medicine and Rehabilitation, Taipei Veterans General Hospital, Taipei, Taiwan. clkao@vghtpe.gov.tw
Chen
Liang-Kung
LK
Chang
Yuh-Lih
YL
Yung
Ming-Chih
MC
Hsu
Chuan-Chih
CC
Chen
Yu-Chih
YC
Lo
Wen-Liang
WL
Chen
Shih-Jen
SJ
Ku
Hung-Hai
HH
Hwang
Shin-Jang
SJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001483:Base Sequence; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D003324:Coronary Artery Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017931:DNA Primers / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*
D000975:Antioxidants; D017931:DNA Primers; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013267:Stilbenes; D006861:Hydrogen Peroxide; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077185:Resveratrol