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1 New York Medical College
2 University of Texas
3 U Missouri
4 NIH
5 National Institutes of Health
6 NIA/NIH
* To whom correspondence should be addressed. E-mail: ZOLTAN_UNGVARI{at}NYMC.EDU.
The dietary polyphenolic compound resveratrol, by activating the protein deacetylase enzyme SIR2/SIRT1 prolongs lifespan in evolutionarily distant organisms and may mimic the cytoprotective effects of dietary restriction. The present study was designed to elucidate the effects of resveratrol on cigarette smoke-induced vascular oxidative stress and inflammation, which is a clinically highly relevant model of accelerated vascular aging. Cigarette smoke exposure of rats impaired acetylcholine-induced relaxation of carotid arteries, which could be prevented by resveratrol treatment. Smoking and in vitro treatment with cigarette smoke extract (CSE) increased ROS production in rat arteries and cultured coronary arterial endothelial cells (CAECs), respectively, which was attenuated by resveratrol treatment. Smoking-induced up-regulation of inflammatory markers (ICAM-1, iNOS, IL-6, TNF
) in rat arteries was also abrogated by resveratrol treatment. Resveratrol also inhibited CSE-induced NF-
B activation and inflammatory gene expression in CAECs. In CAECs the aforementioned protective effects of resveratrol were abolished by knockdown of SIRT1, whereas overexpression of SIRT1 mimicked the effects of resveratrol. Resveratrol treatment of rats protected aortic endothelial cells against cigarette smoking-induced apoptotic cell death. Resveratrol also exerted anti-apoptotic effects in CSE-treated CAECs, which could be abrogated by knockdown of SIRT1. Resveratrol treatment also attenuated CSE-induced DNA damage in CAECs (comet assay). Thus, resveratrol and SIRT1 exert anti-oxidant, anti-inflammatory and anti-apoptotic effects, which protect the endothelial cells against the adverse effects of cigarette smoking-induced oxidative stress. The vasoprotective effects of resveratrol will likely contribute to its anti-aging action in mammals and may be especially beneficial in pathophysiological conditions associated with accelerated vascular aging.
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