Circulation Research. 2004
Published online before print September 2, 2004, doi: 10.1161/01.RES.0000144126.57786.89
Published online before print September 2, 2004, doi: 10.1161/01.RES.0000144126.57786.89
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Submitted on March 23, 2004
Revised on August 5, 2004
Accepted on August 26, 2004
17
-Estradiol Reduces Cardiomyocyte Apoptosis In Vivo and In Vitro via Activation of Phospho-Inositide-3 Kinase/Akt Signaling
Richard D. Patten *;
From the Molecular Cardiology Research Institute (R.D.P., I.P., M.J.A., J.B., F.C., X.C., A.M., S.H., T.F., M.E.M., R.H.K.), Tufts-New England Medical Center, Boston, Mass; and Medizinische Universitäts-Poliklinik (S.N., C.G.), Bonn, Germany.
* To whom correspondence should be addressed. E-mail: rpatten{at}tufts-nemc.org.
Female gender and estrogen-replacement therapy in postmenopausal women are associated with improved heart failure survival, and physiological replacement of 17
-estradiol (E2) reduces infarct size and cardiomyocyte apoptosis in animal models of myocardial infarction (MI). Here, we characterize the molecular mechanisms of E2 effects on cardiomyocyte survival in vivo and in vitro. Ovariectomized female mice were treated with placebo or physiological E2 replacement, followed by coronary artery ligation (placebo-MI or E2-MI) or sham operation (sham) and hearts were harvested 6, 24, and 72 hours later. After MI, E2 replacement significantly increased activation of the prosurvival kinase, Akt, and decreased cardiomyocyte apoptosis assessed by terminal deoxynucleotidyltransferase dUTP nick-end labeling (TUNEL) staining and caspase 3 activation. In vitro, E2 at 1 or 10 nmol/L caused a rapid 2.7-fold increase in Akt phosphorylation and a decrease in apoptosis as measured by TUNEL staining, caspase 3 activation, and DNA laddering in cultured neonatal rat cardiomyocytes. The E2-mediated reduction in apoptosis was reversed by an estrogen receptor (ER) antagonist, ICI 182,780, and by phospho-inositide-3 kinase inhibitors, LY294002 and Wortmannin. Overexpression of a dominant negative-Akt construct also blocked E2-mediated reduction in cardiomyocyte apoptosis. These data show that E2 reduces cardiomyocyte apoptosis in vivo and in vitro by ER- and phospho-inositide-3 kinase-Akt-dependent pathways and support the relevance of these pathways in the observed estrogen-mediated reduction in myocardial injury.
Key words: estrogen • estrogen receptors • myocardial infarction • cardiomyocyte • apoptosis • Akt • PI3 kinase
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