S-nitrosothiol-induced rapid cytochrome c release, caspase activation and mitochondrial permeability transition in perfused heart.
Nitric oxide (NO) is a physiological signalling molecule, however, at high concentrations NO is cytotoxic, and has been implicated in a wide range of inflammatory, ischaemic and degenerative diseases, including heart failure. We investigated whether NO or S-nitrosothiols can induce apoptosis in perfused heart, and whether it is mediated via the mitochondrial pathway of caspase activation. We found that perfusion of rat hearts with a physiological S-nitrosothiol, S-nitrosoglutathione, at 0.4-1mM concentrations for just 10 min caused the release of cytochrome c from mitochondria into the cytosol, inhibition of mitochondrial respiration and caspase activation. Inhibited mitochondrial respiration was restored when exogenous cytochrome c was added to mitochondria, indicating that respiratory inhibition was caused by lack of cytochrome c in mitochondria. Release of cytochrome c, respiratory inhibition and caspase activation were prevented when hearts were pre-perfused with cyclosporin A, suggesting that mitochondrial permeability transition pore was involved. In contrast, perfusion of the hearts with diethylenetriamine/NO adduct releasing similar levels of NO to the S-nitrosoglutathione had no measurable effect on the heart. These data suggest that S-nitrosothiols are potent inducers of apoptosis in the heart and that S-nitrosothiol-induced apoptosis is mediated by mitochondrial permeability transition but not via NO.
Jekabsone
Aiste
A
Institute for Biomedical Research, Kaunas University of Medicine, Kaunas, Lithuania.
Dapkunas
Zilvinas
Z
Brown
Guy C
GC
Borutaite
Vilmante
V
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006321:Heart; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010477:Perfusion; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D026403:S-Nitrosothiols / Q000494:pharmacology*
D020030:Nitric Oxide Donors; D026403:S-Nitrosothiols; D026422:S-Nitrosoglutathione; D045304:Cytochromes c; D020169:Caspases