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Cardiovascular Research 2006 69(4):836-844; doi:10.1016/j.cardiores.2005.11.031
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Copyright © 2005, European Society of Cardiology

Estrogen improves cardiac recovery after ischemia/reperfusion by decreasing tumor necrosis factor-{alpha}

Yi Xu1, Ivan A. Arenas1, Stephen J. Armstrong, Wayne C. Plahta, Han Xu and Sandra T. Davidge*

232 HMRC Departments of Obstetrics/Gynecology and Physiology, Perinatal Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2

* Corresponding author. Tel.: +1 780 492 1864; fax: +1 780 492 1308. Email address: sandra.davidge{at}ualberta.ca

Background: Estrogen has cardioprotective effects on ischemia/reperfusion (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 TNF{alpha}receptors in the ischemic 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 TNF{alpha}levels 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 ischemic 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 TNF{alpha}levels in the ischemic heart.

KEYWORDS Cytokines; Inflammation; Ischemia; Reperfusion; Hormones

1 Both authors have contributed equally to this work.

Time for primary review 47 days


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