Abstract
Female gender and estrogen-replacement therapy in postmenopausal women are associated with improved heart failure survival, and physiological replacement of 17beta-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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Androstadienes / pharmacology
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Animals
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Apoptosis / drug effects*
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Cells, Cultured / cytology
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Cells, Cultured / drug effects
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Chromones / pharmacology
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Enzyme Activation
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Estradiol / analogs & derivatives*
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Estradiol / pharmacology*
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Estradiol / therapeutic use
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Estrogen Receptor Modulators / pharmacology
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Female
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Fulvestrant
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Mice
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Mitogen-Activated Protein Kinase 1 / physiology
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Mitogen-Activated Protein Kinase 3 / physiology
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Morpholines / pharmacology
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Myocardial Infarction / drug therapy
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Myocardial Infarction / metabolism
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Myocardial Infarction / pathology
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Myocytes, Cardiac / cytology
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Myocytes, Cardiac / drug effects*
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Myocytes, Cardiac / enzymology
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Ovariectomy
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Phosphatidylinositol 3-Kinases / physiology*
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation
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Protein Processing, Post-Translational
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / physiology*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-akt
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Rats
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Recombinant Fusion Proteins / physiology
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Signal Transduction / drug effects*
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Signal Transduction / physiology
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Wortmannin
Substances
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Amino Acid Chloromethyl Ketones
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Androstadienes
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Chromones
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Estrogen Receptor Modulators
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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Fulvestrant
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Estradiol
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Wortmannin