Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Cardiovasc Res. 2010 Jan 1;85(1):28-37. doi: 10.1093/cvr/cvp261.
The caspases are thought to be central mediators of the apoptotic program, but recent data indicate that apoptosis may also be mediated by caspase-independent mechanisms such as apoptosis-inducing factor (AIF). The role of AIF-induced apoptosis in heart, however, is currently not well understood. The aim of this study was to investigate the presence of and conditions for AIF-induced cardiac apoptosis in vitro.
Hypertrophic cardiomyocyte (H-CM) cultures were prepared from the hearts of Dahl salt-sensitive rats fed a high salt diet. Apoptotic stimulation induced by hypoxia/reoxygenation or staurosporine (1 microM) enhanced AIF release in H-CMs compared with non-hypertrophic cardiomyocytes (N-CMs). Caspase inhibition using zVAD.fmk (25 microM) or overexpression of CrmA using recombinant adenovirus only partially protected N-CMs from apoptosis (63 +/- 0.93%) and provided no significant protection against apoptosis in hypertrophic cells (23 +/- 1.03%). On the other hand, poly-ADP-ribose polymerase inhibition using 4-AN (20 microM) during apoptotic stimulation blocked the release of AIF from mitochondria and significantly improved cell viability in hypertrophied cardiomyocytes (74 +/- 1.18%).
A caspase-dependent, apoptotic pathway is important for N-CM death, whereas a caspase-independent, AIF-mediated pathway plays a critical role in H-CMs.
半胱天冬酶被认为是细胞凋亡程序的核心介质，但最近的数据表明，细胞凋亡也可能通过细胞凋亡诱导因子（AIF）等无半胱天冬酶依赖性机制来介导。然而，AIF 诱导的凋亡在心脏中的作用目前尚不清楚。本研究旨在探讨体外 AIF 诱导的心肌细胞凋亡的存在和条件。
从高盐饮食喂养的 Dahl 盐敏感大鼠心脏中制备肥厚型心肌细胞（H-CM）培养物。与非肥厚型心肌细胞（N-CM）相比，缺氧/复氧或星形孢菌素（1μM）诱导的凋亡刺激增强了 H-CM 中 AIF 的释放。使用 zVAD.fmk（25μM）抑制半胱天冬酶或使用重组腺病毒过表达 CrmA 仅部分保护 N-CM 免于凋亡（63±0.93%），并且对肥厚细胞的凋亡没有提供显著保护（23±1.03%）。另一方面，在凋亡刺激过程中使用 4-AN（20μM）抑制多聚 ADP-核糖聚合酶可阻止 AIF 从线粒体释放，并显著提高肥厚型心肌细胞的细胞活力（74±1.18%）。
依赖半胱天冬酶的凋亡途径对 N-CM 死亡很重要，而不依赖半胱天冬酶的 AIF 介导途径在 H-CM 中起着关键作用。
