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。细胞丢失主要是由于心肌细胞的死亡，在很大程度上是由细胞凋亡和半胱氨酸蛋白酶的激活所介导的，即半胱氨酸蛋白酶。我们已经证明，心脏和骨骼肌含有caspase2和caspase8的特异性抑制剂，称为ARC，并且在培养的心肌细胞和完整的心脏中，ARC的表达在缺血应激期间都显著减少。此外，在心脏肌源性细胞系中过表达ARC可以保护其免受缺血诱导的细胞死亡。保护与抑制caspase 2的激活和细胞色素c的释放有关，这是以caspase不依赖的方式发生的。我们还表明，不同的生长和神经激素因素也通过ARC非依赖的途径保护心肌细胞免受缺血诱导的细胞死亡。所有这些因子的共同点是它们激活磷脂酰肌醇3-激酶(PI-3K)活性的能力，要么直接通过PI-3K亚单位与受体对接位点(IGF-1)重新募集，要么通过GI依赖的信号，如与β2-肾上腺素能受体相关的信号。因此，PI-3K的抑制剂阻断了各种生存因子的保护作用。目前的研究集中在评估核因子-kB和Forkhead转录因子作为PI-3K激活的可能下游靶点参与细胞生存的作用。-心肌细胞，凋亡，缺血，缺氧，肾上腺素能信号，ARC

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 and the activation of cysteine proteases known as caspases. We have shown that heart and skeletal muscle contain a specific inhibitor of caspases 2 and 8, known as ARC, and that ARC expression is dramatically reduced during ischemic stress both in cultured myocytes and the intact heart. Furthermore, overexpression of ARC in a heart myogenic cell line protects it from ischemia-induced cell death. Protection is associated with inhibition of caspase 2 activation and cytochrome c release, which occurs in a caspase-independent manner. We have also shown that various growth and neurohormonal factors also provide cardiomyocytes protection from ischemia-induced cell death through ARC-independent pathways. The common element in all such factors is their ability to activate phosphatidylinositol 3-kinase (PI-3K) activity, either directly through recruitment of PI-3K subunits to receptor docking sites (IGF-1) or through Gi-dependent signaling, such as that associated with the beta2- adrenergic receptor. Accordingly, inhibitors of PI-3K block the protective effects of the various survival factors. Current studies are focussed on assessing the role of NF-kB and the Forkhead transcription factors as possible downstream targets of PI-3K activation involved in cell survival. - Cardiomyocytes, Apoptosis, Ischemia, Hypoxia, Adrenergic Signaling, ARC