Korge Paavo, Honda Henry M, Weiss James N
Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, California 90095-17690, USA.
Am J Physiol Heart Circ Physiol. 2003 Jul;285(1):H259-69. doi: 10.1152/ajpheart.01028.2002.
Fatty acids accumulate during myocardial ischemia and are implicated in ischemia-reperfusion injury and mitochondrial dysfunction. Because functional recovery after ischemia-reperfusion ultimately depends on the ability of the mitochondria to recover membrane potential (DeltaPsim), we studied the effects of fatty acids on DeltaPsim regulation, cytochrome c release, and Ca2+ handling in isolated mitochondria under conditions that mimicked aspects of ischemia-reperfusion. Long-chain but not short-chain free fatty acids caused a progressive and reversible (with BSA) increase in inner membrane leakiness (proton leak), which limited mitochondrial ability to support DeltaPsim. In comparison, long-chain activated fatty acids promoted 1). a slower depolarization that was not reversible with BSA, 2). cytochrome c loss that was unrelated to permeability transition pore opening, and 3). inhibition of the adenine nucleotide translocator. Together, these results impaired both mitochondrial ATP production and Ca2+ handling. Diazoxide, a selective opener of mitochondrial ATP-dependent potassium (KATP) channels, partially protected against these effects. These findings indicate that long-chain fatty acid accumulation during ischemia-reperfusion may predispose mitochondria to cytochrome c loss and irreversible injury and identify a novel cardioprotective action of diazoxide.
脂肪酸在心肌缺血期间会蓄积，并与缺血再灌注损伤及线粒体功能障碍有关。由于缺血再灌注后的功能恢复最终取决于线粒体恢复膜电位（ΔΨm）的能力，我们在模拟缺血再灌注某些方面的条件下，研究了脂肪酸对分离线粒体中ΔΨm调节、细胞色素c释放及Ca2+处理的影响。长链而非短链游离脂肪酸导致内膜渗漏（质子泄漏）逐渐且可逆地（加入牛血清白蛋白后）增加，这限制了线粒体维持ΔΨm的能力。相比之下，长链活化脂肪酸促进了：1）一种加入牛血清白蛋白后不可逆的较慢去极化；2）与通透性转换孔开放无关的细胞色素c丢失；3）腺嘌呤核苷酸转位酶的抑制。这些结果共同损害了线粒体ATP生成及Ca2+处理。二氮嗪是线粒体ATP依赖性钾（KATP）通道的选择性开放剂，可部分预防这些效应。这些发现表明，缺血再灌注期间长链脂肪酸的蓄积可能使线粒体易于发生细胞色素c丢失及不可逆损伤，并确定了二氮嗪一种新的心脏保护作用。
