Scarabelli Tiziano M, Stephanou Anastasis, Pasini Evasio, Comini Laura, Raddino Riccardo, Knight Richard A, Latchman David S
Medical Molecular Biology Unit, Institute of Child Health, University College London, UK.
Circ Res. 2002 Apr 5;90(6):745-8. doi: 10.1161/01.res.0000015224.07870.9a.
Apoptosis contributes, with necrosis, to the cardiac cell loss after ischemia/reperfusion injury. The apoptotic cascade is initiated either by mitochondrial damage and activation of caspase-9 or by death receptor ligation and activation of caspase-8. In the present study, performed in the isolated rat heart exposed either to ischemia alone or ischemia followed by reperfusion, cleavage of caspase-9 was observed primarily in endothelial cells. Conversely, caspase-8 cleavage was only found in cardiomyocytes, where it progressively increased throughout reperfusion. Addition of a specific caspase-9 inhibitor to the perfusate before ischemia prevented endothelial apoptosis, whereas preischemic infusion of a specific caspase-8 inhibitor affected only myocyte apoptosis. Additionally, caspase-8-mediated BID processing was observed only during reperfusion. Production of tBID then sustains mitochondrial injury and perpetuates caspase-9 activation.
凋亡与坏死共同导致缺血/再灌注损伤后心肌细胞的丢失。凋亡级联反应可由线粒体损伤和半胱天冬酶-9的激活引发，也可由死亡受体连接和半胱天冬酶-8的激活引发。在本研究中，对单独经历缺血或缺血后再灌注的离体大鼠心脏进行实验，发现半胱天冬酶-9的切割主要在内皮细胞中观察到。相反，半胱天冬酶-8的切割仅在心肌细胞中发现，并且在整个再灌注过程中逐渐增加。在缺血前向灌注液中添加特异性半胱天冬酶-9抑制剂可防止内皮细胞凋亡，而缺血前输注特异性半胱天冬酶-8抑制剂仅影响心肌细胞凋亡。此外，仅在再灌注期间观察到半胱天冬酶-8介导的BID加工。tBID的产生随后维持线粒体损伤并使半胱天冬酶-9的激活持续存在。
