Contibution of cardiomyocyte apoptosis to development of congestive heart failure

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Apoptosis plays a pivotal role in loss of cells not only during physiological phenomena, such as normal turnover of tissues, but also in many pathophysiological phenomena. Evidence is accumulating that the apoptotic mechanism is involved in various heart disorders. The Fas/FasL system has been reported to be activated in human heart failure. We observed that cardiomyocyte was generally resistant to Fas-mediated apoptosis in vitro; however, after treatment of sublethal dose of doxorubicin, cardiomyocyte apoptosis was dramatically facilitated by recombinant FasL. This finding is intriguing, because the doxorubicin-induced sensitivity to Fas in cardiomyocyte can be induced by a molecule which may be a target for treating doxorubicin-associated cardiomyopathy. Recently, FLICE-inhibitory protein (FLIP), a molecule with sequence homology to caspase-8 (FLICE), was identified as an anti-apoptotic protein. FLIP is capable of binding FADD, yet is unable to be cleaved to an active caspase-8, thus shutting off the initiation of the death pathway. We observed whether FLIP levels are related to the doxorubicin-induced sensitivity to Fas in cultured neonatal rat cardiomyocyte. Moreover, the expression of FLIP was down-regulated by oxidative stress. FLIP may be a therapeutic target for Dox-induced cardiomyopathy.