期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2002
卷号：99
期号：5
页码：3312-3317
DOI：10.1073/pnas.052713199
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Mitochondrial ATP-sensitive K (mitoKATP) channels play a central role in protecting the heart from injury in ischemic preconditioning. In isolated mitochondria exposed to elevated extramitochondrial Ca, Pi, and anoxia to simulate ischemic conditions, the selective mitoKATP channel agonist diazoxide (25-50 {micro}M) potently reduced mitochondrial injury by preventing both the mitochondrial permeability transition (MPT) and cytochrome c loss from the intermembrane space. Both effects were blocked completely by the selective mitoKATP antagonist 5-hydroxydecanoate. The protective effect against Ca-induced MPT was most evident under conditions in which the ability of electron transport to support membrane potential ({Delta}{psi}m) was decreased and inner membrane leakiness was increased moderately. Under these conditions, mitoKATP channel activity strongly regulated {Delta}{psi}m, and diazoxide prevented MPT by inhibiting the driving force for Ca uptake. Phorbol 12-myristate 13-acetate mimicked the protective effects of diazoxide, unless 5-hydroxydecanoate was present, indicating that protein kinase C activation also protects mitochondria by activating mitoKATP channels. Because {Delta}{psi}m recovery ultimately is required for heart functional recovery, these results may explain how mitoKATP channel activation mimics ischemic preconditioning by protecting mitochondria as they pass through a critical vulnerability window during ischemia/reperfusion.
