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J. Biol. Chem., Vol. 282, Issue 18, 13736-13745, May 4, 2007

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Epigallocatechin Gallate, a Green Tea Polyphenol, Mediates NO-dependent Vasodilation Using Signaling Pathways in Vascular Endothelium Requiring Reactive Oxygen Species and Fyn^*

Jeong-a Kim, Gloria Formoso, Yunhua Li, Maria A. Potenza, Flora L. Marasciulo, Monica Montagnani, and Michael J. Quon¹

From the Diabetes Unit, NCCAM, National Institutes of Health, Bethesda, Maryland 20892 and the Department of Pharmacology and Human Physiology, University of Bari, 70124 Bari, Italy

Green tea consumption is associated with reduced cardiovascular mortality in some epidemiological studies. Epigallocatechin gallate (EGCG), a bioactive polyphenol in green tea, mimics metabolic actions of insulin to inhibit gluconeogenesis in hepatocytes. Because signaling pathways regulating metabolic and vasodilator actions of insulin are shared in common, we hypothesized that EGCG may also have vasodilator actions to stimulate production of nitric oxide (NO) from endothelial cells. Acute intra-arterial administration of EGCG to mesenteric vascular beds isolated ex vivo from WKY rats caused dose-dependent vasorelaxation. This was inhibitable by L-NAME (NO synthase inhibitor), wortmannin (phosphatidylinositol 3-kinase inhibitor), or PP2 (Src family kinase inhibitor). Treatment of bovine aortic endothelial cells (BAEC) with EGCG (50 µM) acutely stimulated production of NO (assessed with NO-specific fluorescent dye DAF-2) that was inhibitable by L-NAME, wortmannin, or PP2. Stimulation of BAEC with EGCG also resulted in dose- and time-dependent phosphorylation of eNOS that was inhibitable by wortmannin or PP2 (but not by MEK inhibitor PD98059). Specific knockdown of Fyn (but not Src) with small interfering RNA inhibited both EGCG-stimulated phosphorylation of Akt and eNOS as well as production of NO in BAEC. Treatment of BAEC with EGCG generated intracellular H₂O₂ (assessed with H₂O₂-specific fluorescent dye CM-H₂DCF-DA), whereas treatment with N-acetylcysteine inhibited EGCG-stimulated phosphorylation of Fyn, Akt, and eNOS. We conclude that EGCG has endothelial-dependent vasodilator actions mediated by intracellular signaling pathways requiring reactive oxygen species and Fyn that lead to activation of phosphatidylinositol 3-kinase, Akt, and eNOS. This mechanism may explain, in part, beneficial vascular and metabolic health effects of green tea consumption.

Received for publication, October 16, 2006 , and in revised form, March 5, 2007.

^* This work was supported in part by research grant awards from Ministero Italiano Università e Ricerca (MIUR) and European Foundation for the Study of Diabetes (EFSD) Eli Lilly (to M. M.), by the Intramural Research Program, NCCAM, National Institutes of Health (to M. J. Q.), and by a research award from the American Diabetes Association (to M. J. Q.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 10 Center Dr., Bldg. 10, Rm. 6C-205, Bethesda, MD 20892-1632. Tel.: 301-496-6269; Fax: 301-402-1679; E-mail: quonm{at}nih.gov.

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