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  • Title: S-nitrosothiol-induced rapid cytochrome c release, caspase activation and mitochondrial permeability transition in perfused heart.
    Author: Jekabsone A, Dapkunas Z, Brown GC, Borutaite V.
    Journal: Biochem Pharmacol; 2003 Oct 15; 66(8):1513-9. PubMed ID: 14555229.
    Abstract:
    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.
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