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Resveratrol Increases Nitric Oxide Synthase, Induces Accumulation of p53 and p21^WAF1/CIP1, and Suppresses Cultured Bovine Pulmonary Artery EndothelialCell Proliferation by Perturbing Progression through S and G₂¹

Department of Biochemistry and Molecular Biology [T-c. H., J. M. W.] and Brander Cancer Research Institute [G. J., Z. D.], New York Medical College, Valhalla, New York 10595

Epidemiological studies have shown that the regular consumption of red wine may in part account for the apparent compatibility of a high fat diet with a low incidence of coronary atherosclerosis. This phenomenon, commonly referred to as the French paradox, may be associated with red wine constituents that exhibit tumor-preventive properties as well as inhibit reactions that increase the risk of coronary heart disease. Here we show that resveratrol, a polyphenol in red wine, induces nitric oxide synthase, the enzyme responsible for the biosynthesis of NO, in cultured pulmonary artery endothelial cells, suggesting that resveratrol could afford cardioprotection by affecting the expression of nitric oxide synthase. We also show that resveratrol inhibits the proliferation of pulmonary artery endothelial cells, which, based on flow cytometric analysis, correlates with the suppression of cell progression through S and G₂ phases of the cell cycle. Western blot analysis and immunocytochemical protein detection combined with multiparameter flow cytometry further demonstrate that the perturbed progression through S and G₂ phases is accompanied by an increase in the expression of tumor suppressor gene protein p53 and elevation of the level of cyclin-dependent kinase inhibitor p21^WAF1/CIP1. All of the observed effects of resveratrol, including induction of apoptosis at its higher concentration, are also compatible with its putative chemopreventive and/or antitumor activity.

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