Caspase inhibition reduces myocyte cell death induced by myocardial ischemia and reperfusion in vivo
Caspase inhibition reduces myocyte cell death induced by myocardial ischemia and reperfusion in vivo
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DOI：
10.1006/jmcc.1999.1006
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发表时间：
1999-09-01
影响因子：
5
通讯作者：
Cryns, VL
中科院分区：
文献类型：
--
作者：
Holly, TA;Drincic, A;Cryns, VL
心肌缺血和再灌注导致心肌细胞死亡，至少部分死亡。通过细胞凋亡机制。 Caspases 是一个保守的蛋白酶家族，在细胞凋亡的执行中发挥着重要作用：然而，它们对缺血性心肌细胞死亡的潜在贡献在很大程度上尚不清楚。为了检查它们在此过程中的作用，我们对兔子进行 30 分钟的冠状动脉闭塞，然后再灌注 3 小时。免疫印迹分析显示 caspase-2。 -3和-7在体内心肌缺血和再灌注期间被蛋白水解激活。此外，在缺血/再灌注心肌中，充分表征的半胱天冬酶底物聚（ADP-核糖）聚合酶（PARP）被选择性清除为其标志性凋亡片段。全身施用广谱 caspase 抑制剂乙酰基-Tyr Val-Ala-Asp 氯甲基酮 (YVAD-cmK 4.8 mg/kg) 部分阻断 caspase 激活，并显着降低梗塞区域末端 dUTP 脱氧核苷酸转移酶切口、末端标记 (TUNEL) 阳性肌细胞核的百分比 （对照动物为 3.9+/-0.8% vs 13.0+/-2.2%，P=0.012）。此外，YVAD-cmk 使心肌梗塞面积减少约 31%（对照组动物为 31.1+/-3.3% vs 45.3+/-4.9%，P = 0.032）。这些结果表明半胱天冬酶是体内缺血和再灌注引起的心肌损伤的关键介质，并且表明半胱天冬酶抑制可能对心肌梗塞有治疗作用。 (C) 1999 年学术出版社。
Myocardial ischemia and reperfusion lead to myocyte cell death, at least in part. by an apoptotic mechanism. Caspases are a conserved family of proteases that play an essential role in the execution of apoptosis: however, their potential contribution to ischemic myocardial cell death is largely unknown. To examine their role in this process, we subjected rabbits to 30 min of coronary artery occlusion followed by 3 h of reperfusion. Immunoblot analyses revealed that caspases-2. -3 and -7 were proteolytically activated during myocardial ischemia and reperfusion in vivo. In addition, the well-characterized caspase substrate poly (ADP-ribose) polymerase (PARP) was selectively cleared into its signature apoptotic fragment in ischemic/reperfused myocardium. Systemic administration of the broad-spectrum caspase inhibitor acetyl-Tyr Val-Ala-Asp chloromethylketone (YVAD-cmK 4.8 mg/kg) partially blocked caspase activation and dramatically reduced the percentage of terminal dUTP deoyxynucleotidyl-transferase nick, end-labeling (TUNEL)-positive myocyte nuclei in the infarct region (3.9+/-0,8% v 13.0+/-2.2% in control animals, P=0.012). Moreover, YVAD-cmk reduced myocardial infarct size by approximately 31%, (31.1+/-3.3% v 45.3+/-4.9% in control animals, P = 0.032). These results indicate that caspases are critical mediators of myocardial injury induced by ischemia and reperfusion in vivo, and they suggest that caspase inhibition may be therapeutically beneficial in myocardial infarction. (C) 1999 Academic Press.