Estradiol-induced protection against ischemia-induced heart mitochondrial damage and caspase activation is mediated by protein kinase G.

Abstract

We have previously reported that estradiol can protect heart mitochondria from the ischemia-induced mitochondrial permeability transition pore-related release of cytochrome c and subsequent apoptosis. In this study we investigated whether the effect of 17-beta-estradiol on ischemia-induced mitochondrial dysfunctions and apoptosis is mediated by activation of signaling protein kinases in a Langendorff-perfused rat heart model of stop-flow ischemia. We found that pre-perfusion of non-ischemic hearts with 100nM estradiol increased the resistance of subsequently isolated mitochondria to the calcium-induced opening of mitochondrial permeability transition pore and this was mediated by protein kinase G. Loading of the hearts with estradiol prevented ischemia-induced loss of cytochrome c from mitochondria and respiratory inhibition and these effects were reversed in the presence of the inhibitor of Akt kinase, NO synthase inhibitor L-NAME, guanylyl cyclase inhibitor ODQ and protein kinase G inhibitor KT5823. Estradiol prevented ischemia-induced activation of caspases and this was also reversed by KT5823. These findings suggest that estradiol may protect the heart against ischemia-induced injury activating the signaling cascade which involves Akt kinase, NO synthase, guanylyl cyclase and protein kinase G, and results in blockage of mitochondrial permeability transition pore-induced release of cytochrome c from mitochondria, respiratory inhibition and activation of caspases.

• Authors: Ramune Morkuniene, Odeta Arandarcikaite, Laima Ivanoviene, Vilmante Borutaite
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) 2010 Jun-Jul Vol. 1797 Issue 6-7 Pg. 1012-7 ISSN: 0006-3002 [Print] Netherlands
• PMID: 20381450 (Publication Type: Journal Article)
• Copyright: Copyright © 2010 Elsevier B.V. All rights reserved.

Chemical References

• Carbazoles
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• KT 5823
• Estradiol
• Cytochromes c
• Cyclic GMP-Dependent Protein Kinases
• Caspases
• Calcium
• NG-Nitroarginine Methyl Ester

Topics

• Animals
• Apoptosis (drug effects)
• Calcium (metabolism)
• Carbazoles (pharmacology)
• Caspases (metabolism)
• Cyclic GMP-Dependent Protein Kinases (metabolism)
• Cytochromes c (metabolism)
• Enzyme Activation (drug effects)
• Estradiol (pharmacology)
• Female
• In Vitro Techniques
• Mitochondria, Heart (drug effects, metabolism)
• Mitochondrial Membrane Transport Proteins (metabolism)
• Mitochondrial Permeability Transition Pore
• Models, Cardiovascular
• Myocardial Reperfusion Injury (metabolism, pathology, prevention & control)
• NG-Nitroarginine Methyl Ester (pharmacology)
• Rats
• Rats, Wistar
• Signal Transduction (drug effects)