期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 42, 期 1, 页码 79-87出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2006.10.007
关键词
estrogens; infarction; mitochondria; reperfusion; ischemia; postconditioning; phytoestrogens; estradiol; genistein; rabbit; cardioprotection
Estrogens are known to activate the phosphatidyl-inosityl 3-kinase (PI3K)/Akt pathway, which is central in the cardioprotection afforded by ischemic postconditioning. Therefore, our goal was to investigate whether a phytoestrogen, genistein, could induce a pharmacological postconditioning and to investigate potential mechanisms. We used low doses of genistein in order to avoid tyrosine kinases inhibition. Thus, pentobarbital-anesthetized rabbits underwent a coronary artery occlusion followed by 4 h of reperfusion. Prior to reperfusion, they randomly received an i.v. injection of either saline (Control), 100 or 1000 mu g/kg of genistein (Geni(100) and Geni(1000), respectively), and 10 or 100 mu g/kg of 17 beta-estradiol (17 beta(10) and 17 beta(100), respectively). Infarct size (IS, % area at risk)was significantly reduced in Gen(100), Gen(1000) and 17 beta(100) but not in 17 beta(10),o (6 +/- 2, 16 +/- 5, 12 +/- 3 and 29 +/- 7%, respectively) vs. Control (35 +/- 4%). A significant decrease in the percentage of TUNEL-positive nuclei within infarcted area was observed in Gen(1000) and 17 beta(100) vs. Controls. The estrogen receptor antagonist fulvestrant (1 mg/kg i.v.) and the PI3K inhibitor wortmaninn (0.6 mg/kg) abolished the cardioprotective effect of genistein. Western blots also demonstrated an increase in Akt posphorylation in Gen(100). In the same group, in vitro mitochondrial swelling studies demonstrated a significant inhibition of calcium-induced opening of mitochondrial transition pore vs. Controls. In conclusion, genistein exerts pharmacological postconditioning with a similar potency as 17 beta-estradiol through a pathway involving activation of the estrogen receptor, of PI3K/Akt and mitochondrial preservation. Therefore, genistein should not be only considered as an inhibitor of tyrosine kinase but also as a cardioprotective estrogen. (c) 2006 Elsevier Inc. All rights reserved.
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