Mechanisms Of Cardiomyocyte Cell Death By Apoptosis

心肌细胞损失发生在急性缺血性损伤、心力衰竭和心脏正常衰老过程中。细胞损失主要是由于心肌细胞的死亡，并且在很大程度上是由细胞凋亡介导的。我们已经证明，心脏和骨骼肌含有一种特殊的半胱天蛋白酶2和8抑制剂，称为ARC（凋亡抑制因子与CARD），并且在培养的肌细胞和完整的心脏中，ARC的表达在缺血应激期间显着降低。使用重组腺病毒恢复ARC水平可以完全防止细胞死亡，而直接和完全的caspase抑制只能提供有限的保护。ARC的保护作用与线粒体功能的保存有关。ARC还通过改变NF-kB的p65/RelA组分的转录激活域来调节NF-kB的活性，从而促进生存。在终末生长停滞的细胞中，如心脏细胞，ARC的表达与终末分化增加、细胞大小增加或肥大有关。强制表达ARC促进骨骼肌肌肉分化，在H9c2细胞中，这一事件伴随着ARC的细胞定位向细胞核的短暂转移。在心脏和心脏细胞中，肥大诱导剂增加ARC的表达，形成ARC的表达导致培养心肌细胞增大和体内心脏增大。在许多增殖细胞中，ARC是一种有效的细胞增殖抑制因子。这些结果证明了它们的细胞凋亡抑制因子的新颖和意想不到的作用，与其独特的表达模式有关。ARC可能在心脏和骨骼肌细胞分化、增殖和对凋亡的敏感性之间提供了缺失的机制联系。

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.