Estrogen improves cardiac recovery after ischemia/reperfusion by decreasing tumor necrosis factor-α

Background: Estrogen has cardioprotective effects on ischemia/reperfasion (I/R). Tumor necrosis factor alpha (TNF alpha) is an inflammatory cytokine with depressor effects on myocardial function and has been suggested to mediate I/R injury. Whether cardiac TNF alpha levels are influenced by estrogen status is unknown. We investigated the effect of estrogen on TNF alpha levels and TNFa receptors in the ischernic heart and its role in estrogen modulation of I/R injury. Methods: Hearts were isolated from ovariectomized Sprague-Dawley female rats that were treated with either estrogen or placebo for 4 weeks. Working heart preparations were subjected to global, no-flow ischemia (25 min) followed by reperfusion (40 min). Results: I/R increased TNFalevels in coronary effluent and in the left ventricle (LV) of estrogen-deficient rats, which were decreased by estrogen replacement. Moreover, estrogen improved functional recovery (55.0 +/- 5.0% vs. 22.0 +/- 7.0%, P < 0.05), decreased LV apoptosis, and reduced myocardial necrosis. To further evaluate the role of TNF alpha in I/R injury, a selective TNF(alpha inhibitor (etanercept) was used in vitro before the ischernic insult. TNF alpha inhibition improved functional recovery (39 +/- 4.4% vs. 22.0 7.0%, P < 0.05) and reduced apoptosis and myocardial necrosis in estrogen-deficient animals but did not have a summative protective effect in the hearts of estrogen-replaced animals. Conclusions: These data indicate that estrogen modulates cardiac expression of TNF alpha and TNF alpha receptors. Moreover, the cardioprotective effects of estrogen are in part mediated by regulation of TNFalevels in the isebernic heart. (c) 2005 European Society of Cardiology. Published by Elsevier B.V All rights reserved.