Contibution of cardiomyocyte apoptosis to development of congestive heart failure

细胞凋亡不仅在组织的正常周转等生理现象中，而且在许多病理生理现象中都起着至关重要的作用。越来越多的证据表明，细胞凋亡机制与多种心脏疾病有关。据报道，Fas/FasL系统在人类心力衰竭中被激活。我们观察到，心肌细胞对fas介导的体外凋亡普遍具有抗性；然而，在亚致死剂量的阿霉素处理后，重组FasL显著促进心肌细胞凋亡。这一发现很有趣，因为阿霉素诱导的心肌细胞对Fas的敏感性可以由一种分子诱导，这种分子可能是治疗阿霉素相关心肌病的靶点。近年来，与caspase-8 （FLICE）序列同源的FLICE-inhibitory protein （FLIP）被发现是一种抗凋亡蛋白。FLIP能够结合FADD，但不能与活性caspase-8结合，从而关闭死亡途径的启动。我们观察了FLIP水平是否与阿霉素诱导的新生大鼠心肌细胞对Fas的敏感性有关。此外，氧化应激可下调FLIP的表达。FLIP可能是dox诱导的心肌病的治疗靶点。

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.