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17beta-estradiol reduces cardiomyocyte apoptosis in vivo and in vitro via activation of phospho-inositide-3 kinase/Akt signaling
- Source :
- Circulation research. 95(7)
- Publication Year :
- 2004
-
Abstract
- Female gender and estrogen-replacement therapy in postmenopausal women are associated with improved heart failure survival, and physiological replacement of 17β-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.
- Subjects :
- medicine.medical_specialty
Physiology
Morpholines
Ovariectomy
Recombinant Fusion Proteins
Myocardial Infarction
Caspase 3
Apoptosis
Pharmacology
Biology
DNA laddering
Protein Serine-Threonine Kinases
Amino Acid Chloromethyl Ketones
Wortmannin
chemistry.chemical_compound
Mice
Phosphatidylinositol 3-Kinases
Estrogen Receptor Modulators
In vivo
Internal medicine
Proto-Oncogene Proteins
medicine
Animals
Myocytes, Cardiac
Phosphorylation
Protein kinase B
Fulvestrant
Cells, Cultured
Phosphoinositide-3 Kinase Inhibitors
Mitogen-Activated Protein Kinase 1
TUNEL assay
Mitogen-Activated Protein Kinase 3
Estradiol
Rats
Androstadienes
Enzyme Activation
Endocrinology
chemistry
Chromones
Female
Signal transduction
Cardiology and Cardiovascular Medicine
Protein Processing, Post-Translational
Proto-Oncogene Proteins c-akt
Signal Transduction
Subjects
Details
- ISSN :
- 15244571
- Volume :
- 95
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Circulation research
- Accession number :
- edsair.doi.dedup.....6eb158f591e18fc2c7e548b06904045a