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J. Biol. Chem., Vol. 281, Issue 10, 6760-6767, March 10, 2006

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Estrogen Prevents Cardiomyocyte Apoptosis through Inhibition of Reactive Oxygen Species and Differential Regulation of p38 Kinase Isoforms^*

Jin Kyung Kim, Ali Pedram, Mahnaz Razandi, and Ellis R. Levin^¶1

From the Divisions of Cardiology and ^¶Endocrinology, University of California, Irvine, California 92717 and the Division of Endocrinology, Long Beach Veterans Affairs Medical Center, Long Beach, California 90822

From human and animal studies, estrogen is known to protect the myocardium from an ischemic insult. However, there is limited knowledge regarding mechanisms by which estrogen directly protects cardiomyocytes. In this report, we employed an in vitro model, in which cultured rat cardiomyocytes underwent prolonged hypoxia followed by reoxygenation (H/R), to study the cardioprotective mechanism of estrogen. 17--estradiol (E2) acting via estrogen receptors inhibited H/R-induced apoptosis of cardiomyocytes. Mitochondrial reactive oxygen species (ROS) generated from H/R activated p38 MAPK, and inhibition of p38 with SB203580 significantly prevented H/R-induced cell death. E2 suppressed ROS formation and p38 activation by H/R and concomitantly augmented the activity of p38. Unlike p38, p38 was little affected by H/R. Dominant negative p38 protein expression decreased E2-mediated cardiomyocyte survival and ROS suppression during H/R stress. The prosurvival signaling molecule, phosphoinositol-3 kinase (PI3K), has previously been linked to cell survival following ischemia-reperfusion injury. Here, E2-activated PI3K was found to inhibit ROS generated from H/R injury, leading to inhibition of downstream p38. We further linked these signaling pathways in that p38 was activated by E2 stimulation of PI3K. Thus, E2 differentially modulated two major isoforms of p38, leading to cardiomyocyte survival. This was achieved by signaling through PI3K, integrating cell survival mediators.

Received for publication, October 11, 2005 , and in revised form, December 5, 2005.

^* This work was supported by grants from the National Institutes of Health (to E. R. L.), American Heart Association (to J. K. K.), and the Department of Veterans Affairs (to E. R. L.). 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: Div. of Endocrinology, Long Beach Veterans Affairs Medical Center, Medical Service (111-1), 5901 E. 7th St., Long Beach, CA 90822. Tel.: 562-826-5748; Fax: 562-826-5515; E-mail: ellis.levin{at}med.va.gov.

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