Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10954270 | Journal of Molecular and Cellular Cardiology | 2007 | 9 Pages |
Abstract
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 μg/kg of genistein (Geni100 and Geni1000, respectively), and 10 or 100 μg/kg of 17β-estradiol (17β10 and 17β100, respectively). Infarct size (IS, % area at risk) was significantly reduced in Gen100, Gen1000 and 17β100 but not in 17β10 (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 Gen100 and 17β100 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 Gen100. 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 17β-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.
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Authors
R. Tissier, X. Waintraub, N. Couvreur, M. Gervais, P. Bruneval, C. Mandet, R. Zini, B. Enriquez, A. Berdeaux, B. Ghaleh,