Estrogen improves cardiac recovery after ischemia/reperfusion by decreasing tumor necrosis factor-alpha.
BACKGROUND
Estrogen has cardioprotective effects on ischemia/reperfusion (I/R). Tumor necrosis factor alpha (TNFalpha) is an inflammatory cytokine with depressor effects on myocardial function and has been suggested to mediate I/R injury. Whether cardiac TNFalpha levels are influenced by estrogen status is unknown. We investigated the effect of estrogen on TNFalpha levels and TNFalpha 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 TNFalpha 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 TNFalpha in I/R injury, a selective TNFalpha inhibitor (etanercept) was used in vitro before the ischemic insult. TNFalpha 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 TNFalpha and TNFalpha receptors. Moreover, the cardioprotective effects of estrogen are in part mediated by regulation of TNFalpha levels in the ischemic heart.
Xu
Yi
Y
232 HMRC Departments of Obstetrics/Gynecology and Physiology, Perinatal Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
Arenas
Ivan A
IA
Armstrong
Stephen J
SJ
Plahta
Wayne C
WC
Xu
Han
H
Davidge
Sandra T
ST
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western / Q000379:methods; D020169:Caspases / Q000032:analysis / Q000378:metabolism; D053938:DNA Fragmentation; D004967:Estrogens / Q000494:pharmacology*; D000068800:Etanercept; D005260:Female; D006352:Heart Ventricles / Q000737:chemistry / Q000378:metabolism; D007074:Immunoglobulin G / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000032:analysis / Q000378:metabolism; D017202:Myocardial Ischemia / Q000097:blood / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004967:Estrogens; D007074:Immunoglobulin G; D011960:Receptors, Estrogen; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D007770:L-Lactate Dehydrogenase; D020169:Caspases; D000068800:Etanercept