Necrotic death without mitochondrial dysfunction-delayed death of cardiac myocytes following oxidative stress.
Oxidative stress has been implicated in cell death in range of disease states including ischemia/reperfusion injury of the heart and heart failure. Here we have investigated the mechanisms of cell death following chronic exposure of cardiac myocytes to oxidative stress initiated by hydrogen peroxide. This exposure induced a delayed form of cell death with ultrastructural changes typical of necrosis, and that was accompanied by the release of lactate dehydrogenase and increased lipid peroxidation. However, this delayed death was not accompanied by the loss of mitochondrial membrane potential or caspase-3 activation. Furthermore, we could demonstrate that this delayed necrosis was at least partially prevented by pre-treatment with the hypertrophic stimuli endothelin-1 or leukemic inhibitory factor. Our results suggest that this delayed form necrosis may also comprise an ordered series of events involving pathways amenable to therapeutic modulation.
Casey
Tammy M
TM
Biochemistry and Molecular Biology, School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, Crawley, Western Australia 6009, Australia.
Arthur
Peter G
PG
Bogoyevitch
Marie A
MA
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D004317:Doxorubicin / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009336:Necrosis / Q000139:chemically induced / Q000473:pathology; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley
D000975:Antioxidants; D019332:Endothelin-1; D053605:Leukemia Inhibitory Factor; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D002403:Cathepsins; D002154:Calpain; D053148:Caspase 3