OF WORK Cardiac cell loss occurs in response to acute ischemic injury, during heart failure, and during the normal aging of the heart. Cell loss is due predominantly to the death of cardiac myocytes and is mediated in large part by apoptosis and the activation of cysteine proteases known as caspases. We have shown that heart and skeletal muscle contain a specific inhibitor of caspases 2 and 8, known as ARC, and that ARC expression is dramatically reduced during ischemic stress both in cultured myocytes and the intact heart. Furthermore, overexpression of ARC in a heart myogenic cell line protects it from ischemia-induced cell death. Protection is associated with inhibition of caspase 2 activation and cytochrome c release, which occurs in a caspase-independent manner. We have also shown that various growth and neurohormonal factors also provide cardiomyocytes protection from ischemia-induced cell death through ARC-independent pathways. The common element in all such factors is their ability to activate phosphatidylinositol 3-kinase (PI-3K) activity, either directly through recruitment of PI-3K subunits to receptor docking sites (IGF-1) or through Gi-dependent signaling, such as that associated with the beta2- adrenergic receptor. Accordingly, inhibitors of PI-3K block the protective effects of the various survival factors. Current studies are focussed on assessing the role of NF-kB and the Forkhead transcription factors as possible downstream targets of PI-3K activation involved in cell survival. - Cardiomyocytes, Apoptosis, Ischemia, Hypoxia, Adrenergic Signaling, ARC
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