This Article Full Text Full Text (PDF) All Versions of this Article: 96/10/1072    most recent 01.RES.0000168807.63013.56v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Anter, E. Articles by Keaney, J. F. Search for Related Content PubMed PubMed Citation Articles by Anter, E. Articles by Keaney, J. F., Jr Related Collections Endothelium/vascular type/nitric oxide Other Vascular biology

(Circulation Research. 2005;96:1072.)
© 2005 American Heart Association, Inc.

Molecular Medicine

p38 Mitogen-Activated Protein Kinase Activates eNOS in Endothelial Cells by an Estrogen Receptor -Dependent Pathway in Response to Black Tea Polyphenols

Elad Anter, Kai Chen, Oz M. Shapira, Richard H. Karas, John F. Keaney, Jr

From the Evans Memorial Department of Medicine and Whitaker Cardiovascular Institute (E.A., K.C., O.M.S., J.F.K.), Boston University School of Medicine, Boston, Mass; and Molecular Cardiology Research Institute (R.H.K.), Tufts University School of Medicine, Boston, Mass.

Correspondence to John F. Keaney Jr, Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany St, Room W507, Boston, MA 02118. E-mail jkeaney{at}bu.edu

Black tea has been shown to improve endothelial function in patients with coronary artery disease and recent data indicate the polyphenol fraction of black tea enhances endothelial nitric oxide synthase (eNOS) activity through p38 MAP kinase (p38 MAPK) activation. Because the mechanisms for this phenomenon are not yet clear, we sought to elucidate the signaling events in response to black tea polyphenols. Bovine aortic endothelial cells (BAECs) exposed to black tea polyphenols demonstrated eNOS activation that was inhibited by the estrogen receptor (ER) antagonist ICI 182,780, and siRNA-mediated silencing of ER expression. Consistent with this observation, black tea polyphenols induced time-dependent phosphorylation of ER on Ser-118 that was inhibited by ICI 182,780. Phosphorylation of ER on Ser-118 was due to p38 MAP kinase (p38 MAPK) as, it was inhibited by SB203580 and overexpression of dominant-negative p38 MAPK. Conversely, constitutively active MKK6 induced p38 MAPK activation that recapitulated the effects of polyphenols by inducing ER phosphorylation and downstream activation of Akt, and eNOS. The key role of ER Ser-118 phosphorylation was confirmed in eNOS-transfected COS-7 cells, as polyphenol-induced eNOS activation required cotransfection with ER subject to phosphorylation at Ser-118. This residue appeared critical for functional association of ER with p38 MAPK as ER with Ser-118 mutated to alanine could not form a complex with p38 MAPK. These findings suggest p38 MAP kinase-mediated eNOS activation requires ER and these data uncover a new mechanism of ER activation that has broad implications for NO bioactivity and endothelial cell phenotype.

Key Words: antioxidants • p38 • endothelial dysfunction • eNOS • estrogen receptor

This article has been cited by other articles:

				W.-H. Kan, J.-T. Hsu, Z.-F. Ba, M. G. Schwacha, J. Chen, M. A. Choudhry, K. I. Bland, and I. H. Chaudry p38 MAPK-dependent eNOS upregulation is critical for 17{beta}-estradiol-mediated cardioprotection following trauma-hemorrhage Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2627 - H2636. [Abstract] [Full Text] [PDF]

				D. Li, C. Yang, Y. Chen, J. Tian, L. Liu, Q. Dai, X. Wan, and Z. Xie Identification of a PKC{varepsilon}-dependent regulation of myocardial contraction by epicatechin-3-gallate Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H345 - H353. [Abstract] [Full Text] [PDF]

				S. M. Shenouda and J. A. Vita Effects of Flavonoid-Containing Beverages and EGCG on Endothelial Function J. Am. Coll. Nutr., August 1, 2007; 26(4): 366S - 372S. [Abstract] [Full Text] [PDF]

				G. E. Mann, D. J. Rowlands, F. Y.L. Li, P. de Winter, and R. C.M. Siow Activation of endothelial nitric oxide synthase by dietary isoflavones: Role of NO in Nrf2-mediated antioxidant gene expression Cardiovasc Res, July 15, 2007; 75(2): 261 - 274. [Abstract] [Full Text] [PDF]

				L. McCollum, A. C. Howlett, and S. Mukhopadhyay Anandamide-Mediated CB1/CB2 Cannabinoid Receptor-Independent Nitric Oxide Production in Rabbit Aortic Endothelial Cells J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 930 - 937. [Abstract] [Full Text] [PDF]

				J.-a Kim, G. Formoso, Y. Li, M. A. Potenza, F. L. Marasciulo, M. Montagnani, and M. J. Quon Epigallocatechin Gallate, a Green Tea Polyphenol, Mediates NO-dependent Vasodilation Using Signaling Pathways in Vascular Endothelium Requiring Reactive Oxygen Species and Fyn J. Biol. Chem., May 4, 2007; 282(18): 13736 - 13745. [Abstract] [Full Text] [PDF]

				M. A. Potenza, F. L. Marasciulo, M. Tarquinio, E. Tiravanti, G. Colantuono, A. Federici, J.-a Kim, M. J. Quon, and M. Montagnani EGCG, a green tea polyphenol, improves endothelial function and insulin sensitivity, reduces blood pressure, and protects against myocardial I/R injury in SHR Am J Physiol Endocrinol Metab, May 1, 2007; 292(5): E1378 - E1387. [Abstract] [Full Text] [PDF]

				V. Stangl, H. Dreger, K. Stangl, and M. Lorenz Molecular targets of tea polyphenols in the cardiovascular system Cardiovasc Res, January 15, 2007; 73(2): 348 - 358. [Abstract] [Full Text] [PDF]

				B. M Popkin, L. E Armstrong, G. M Bray, B. Caballero, B. Frei, and W. C Willett A new proposed guidance system for beverage consumption in the United States Am. J. Clinical Nutrition, March 1, 2006; 83(3): 529 - 542. [Abstract] [Full Text] [PDF]