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J. Biol. Chem., Vol. 279, Issue 7, 6190-6195, February 13, 2004

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A Constituent of Green Tea, Epigallocatechin-3-gallate, Activates Endothelial Nitric Oxide Synthase by a Phosphatidylinositol-3-OH-kinase-, cAMP-dependent Protein Kinase-, and Akt-dependent Pathway and Leads to Endothelial-dependent Vasorelaxation^*

Mario Lorenz, Silja Wessler, Elena Follmann, Wanda Michaelis, Thomas Düsterhöft, Gert Baumann, Karl Stangl, and Verena Stangl

From the Medizinische Klinik mit Schwerpunkt Kardiologie, Angiologie, Pneumologie, Charité, Campus Mitte, Humboldt-Universität zu Berlin, Berlin D-10117, Germany

Epidemiological studies suggest that tea catechins may reduce the risk of cardiovascular disease, but the mechanisms of benefit have not been determined. The objective of the present study was to investigate the effects of epigallocatechin-3-gallate (EGCG), the major constituent of green tea, on vasorelaxation and on eNOS expression and activity in endothelial cells. EGCG (1-50 µM) induced dose-dependent vasodilation in rat aortic rings. Vasodilation was abolished by pretreatment with N^G-nitro L-arginine methyl ester. In bovine aortic endothelial cells, EGCG increased endothelial nitric oxide (eNOS) activity dose-dependently after 15 min. Treatment with EGCG induced a sustained activation of Akt, ERK1/2, and eNOS Ser¹¹⁷⁹ phosphorylation. Inhibition of extracellular signal-regulated kinase (ERK)1/2 had no influence on eNOS activity or Ser¹¹⁷⁹ phosphorylation. Simultaneous treatment of cells with selective inhibitors for cAMP-dependent protein kinase (PKA) and Akt completely prevented the increase in eNOS activity by EGCG after 15 min, indicating that both kinases act in concert. Specific phosphatidylinositol-3-OH-kinase inhibitors yielded identical results. Akt inhibition prevented eNOS Ser¹¹⁷⁹ phosphorylation, whereas inhibition of PKA did not influence Akt and eNOS Ser¹¹⁷⁹ phosphorylation. Pretreatment of endothelial cells with EGCG for 4 h markedly enhanced the increase in eNOS activity stimulated by Ca-ionomycin, suggesting that Akt accounts for prolonged eNOS activation. Treatment of cells for 72 h with EGCG did not change eNOS protein levels. Our results indicate that EGCG-induced endothelium-dependent vasodilation is primarily based on rapid activation of eNOS by a phosphatidylinositol 3-kinase-, PKA-, and Akt-dependent increase in eNOS activity, independently of an altered eNOS protein content.

Received for publication, August 18, 2003 , and in revised form, November 16, 2003.

^* 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.

To whom correspondence should be addressed: Medizinische Klinik mit Schwerpunkt Kardiologie, Angiologie, Pneumologie, Humboldt-Universität Berlin, Charité, Campus Mitte, Schumannstrasse 20-21, D-10117 Berlin, Germany. Tel.: 49-30-450-513153; Fax: 49-30-450-513932; E-mail: verena.stangl{at}charite.de.

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