Nitric oxide-induced cell death in the heart: the role of autophagy.
There is unequivocal evidence of autophagy in the heart, both in human hearts from patients who experienced heart failure and in experimental models of myocardial ischemia and reperfusion. Whether autophagy is involved in the pathophysiology of these conditions is controversial as studies suggest inhibition of Beclin 1 can increase or decrease cardiomyocyte cell injury. Increased beclin 1 expression, however, has been consistently identified in myocardial ischemia/reperfusion. Because of the role of nitric oxide (NO) in myocardial ischemia/reperfusion as well as in heart failure, we sought to determine whether NO and its byproduct peroxynitrite alter the expression of some genes involved in autophagy in the heart. Neonatal mouse cardiomyocytes were treated with SIN-1 (3-morpholinosydnonimine), which releases NO and accelerates formation of peroxynitrite. Gene expression was evaluated using RNA labeled and hybridized to cDNA microarrays. SIN-1 treatment induced significant changes in five caspases. In contrast, there were no changes in three genes involved in autophagy, namely beclin 1, Atg5l and Atg12l. Several different time periods were examined; a short time period, 2h, to more closely model myocardial ischemia reperfusion and a long time period, 20 h, that more closely represents sustained injury. In summary, evidence to date suggests that NO is not involved in increased beclin 1 expression in ischemia/reperfusion injury in the heart and would be unlikely to account for the signs of autophagy in the hearts of patients with heart failure.
Rabkin
Simon W
SW
Department of Medicine, University of British Columbia, Vancouver, Canada. rabkin@interchange.ubc.ca
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000235:genetics*; D000071186:Beclin-1; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D018076:DNA, Complementary; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D017202:Myocardial Ischemia / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D030421:Peroxynitrous Acid / Q000096:biosynthesis; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D013997:Time Factors
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D018076:DNA, Complementary; D020030:Nitric Oxide Donors; D011506:Proteins; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002385:linsidomine; D012313:RNA; D008981:Molsidomine; D020169:Caspases