Contibution of cardiomyocyte apoptosis to development of congestive heart failure

细胞凋亡不仅在生理现象如组织的正常更新中，而且在许多病理生理现象中在细胞损失中起关键作用。越来越多的证据表明，凋亡机制参与了各种心脏疾病。Fas/FasL系统在人类心力衰竭中被激活。我们观察到，心肌细胞一般抵抗Fas介导的凋亡在体外，然而，亚致死剂量的阿霉素治疗后，心肌细胞凋亡显着促进重组FasL。这一发现是有趣的，因为多柔比星诱导的心肌细胞对Fas的敏感性可以由一种分子诱导，该分子可能是治疗多柔比星相关性心肌病的靶点。最近，FLICE抑制蛋白（FLIP），一种与caspase-8（FLICE）具有序列同源性的分子，被鉴定为抗凋亡蛋白。FLIP能够结合FADD，但不能被切割成活性半胱天冬酶-8，从而关闭死亡途径的起始。我们观察FLIP水平是否与阿霉素诱导的培养乳鼠心肌细胞对Fas的敏感性有关。此外，FLIP的表达下调氧化应激。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.