title: Pharmacological postconditioning with the phytoestrogen genistein.
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 microg/kg of genistein (Geni(100) and Geni(1000), respectively), and 10 or 100 microg/kg of 17beta-estradiol (17beta(10) and 17beta(100), respectively). Infarct size (IS, % area at risk) was significantly reduced in Gen(100), Gen(1000) and 17beta(100) but not in 17beta(10) (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(100) and 17beta(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 17beta-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.
authors.affiliation: INSERM, U 660, Créteil, F-94010, France.
authors.forename: R
authors.initials: R
authors.lastname: Tissier
authors.forename: X
authors.initials: X
authors.lastname: Waintraub
authors.forename: N
authors.initials: N
authors.lastname: Couvreur
authors.forename: M
authors.initials: M
authors.lastname: Gervais
authors.forename: P
authors.initials: P
authors.lastname: Bruneval
authors.forename: C
authors.initials: C
authors.lastname: Mandet
authors.forename: R
authors.initials: R
authors.lastname: Zini
authors.forename: B
authors.initials: B
authors.lastname: Enriquez
authors.forename: A
authors.initials: A
authors.lastname: Berdeaux
authors.forename: B
authors.initials: B
authors.lastname: Ghaleh
mesh_terms: D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology*; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects; D008933:Mitochondrial Swelling / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000517:prevention & control; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D048789:Phytoestrogens / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011817:Rabbits; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D048789:Phytoestrogens; D011960:Receptors, Estrogen; D004958:Estradiol; D019833:Genistein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D002118:Calcium