Mechanisms Of Cardiomyocyte Cell Death By Apoptosis

工作概述心脏细胞丢失发生在急性缺血损伤、心力衰竭期间和心脏正常老化期间。细胞的丢失主要是由于心肌细胞的死亡，并在很大程度上是由细胞凋亡所介导的。我们已经证明，心脏和骨骼肌中含有caspase2和caspase8的特异性抑制物，称为ARC(带有CARD的凋亡抑制因子)，并且在缺血应激时，培养的心肌细胞和完整的心脏中ARC的表达都显著减少。使用重组腺病毒恢复ARC水平可以完全防止细胞死亡，而直接和完全抑制caspase只能提供有限的保护。通过ARC的保护与线粒体功能的保存有关。ARC还通过改变核因子-kB的p65/relA转录激活域来调节核因子-kB的活性，以促进生存。在终末生长受阻的细胞中，如心脏细胞，ARC的表达与终末分化增加和细胞大小或肥大有关。ARC的强制表达促进了骨骼肌的分化，在H9c2细胞中，ARC的细胞定位会短暂地转移到细胞核。在心脏和心肌细胞中，肥大诱导剂增加ARC的表达，并在培养的扩大的心肌细胞和体内扩大的心脏中形成ARC结果的表达。在许多增殖细胞中，ARC是一种有效的细胞增殖抑制因子。这些结果表明，与其独特的表达模式有关，它们的凋亡抑制因子发挥了新的和不同寻常的作用。ARC可能提供了心肌和骨骼肌中细胞分化、增殖和对细胞凋亡的敏感性之间缺失的机制联系。

SUMMARY 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.We have shown that heart and skeletal muscle contain a specific inhibitor of caspases 2 and 8, known as ARC (Apoptosis repressor with CARD), and that ARC expression is dramatically reduced during ischemic stress both in cultured myocytes and the intact heart. Restoring ARC levels using recombinant adenoviruses completely prevents cell death, while direct and complete caspase inhibition provides only limited protection. Protection through ARC is associated with preservation of mitochondrial function. ARC also regulates NF-kB activity by altering the transcriptional activation domain of the p65/RelA component of NF-kB to promote survival. In cells that are terminally growth-arrested, such as heart cells, ARC expression is associated with increased termination differentiation and increased cellular size or hypertrophy. Forced expression of ARC promotes skeletal muscle muscle differentiation, an event that in H9c2 cells is accompanied by a transient shift in ARC's cellular localization to the nucleus. In hearts and heart cells, hypertrophy-inducing agents increase ARC expression and formed expression of ARC results in enlarged myocytes in culture and enlarged hearts in vivo. In many proliferating cells, ARC is a potent suppressor of cell proliferation. These results demonstrate novel and unexepcted roles for thei apoptosis repressor, linked to its peculiar pattern of expression. ARC may provide the missing mechanistic link between cellular differentiation, proliferation, and sensitivity to apoptosis in the heart and skeletal muscle.