Mitochondrial ATP-sensitive potassium channels inhibit apoptosis induced by oxidative stress in cardiac cells
Mitochondrial ATP-sensitive potassium channels inhibit apoptosis induced by oxidative stress in cardiac cells
复制标题
DOI：
10.1161/hh1201.092094
复制
发表时间：
2001-06-22
影响因子：
20.1
通讯作者：
Marbán, E
中科院分区：
文献类型：
--
作者：
Akao, M;Ohler, A;Marbán, E
线粒体可以促进或抑制细胞死亡，线粒体释放细胞色素c和线粒体膜电位去极化（Delta Psi）是触发细胞凋亡的关键事件。相反，线粒体ATP敏感钾通道（mitoK(ATP)）的激活可以防止体内致命的缺血损伤，暗示这些通道在缺血预处理过程中起关键作用。我们探讨了mitoK（ATP）通道与培养的新生大鼠心室肌细胞凋亡的关系。200 μ mol/L过氧化氢诱导TUNEL阳性、细胞色素c易位、caspase-3活化、聚（ADP核糖）聚合酶裂解和δ Psi消散。二氮氧化物（100 μ mol/L）药理学打开mitoK（ATP）通道，保持线粒体完整性，抑制所有凋亡标志物。通过流式细胞术和荧光Delta Psi染色细胞的定量图像分析显示，二氮氧化物以浓度依赖的方式阻止Delta Psi去极化（EC50约为40 μ mol/L，饱和为100 μ mol/L）。这些细胞保护作用被另一种mitoK（ATP）激动剂pinacidil复制，并被mitoK（ATP）通道拮抗剂5-羟癸酸酯（500 μ mol/L）阻断。我们的发现确定了一种新的线粒体途径，可以防止细胞凋亡。结果还指出mitoK（ATP）通道是细胞凋亡和氧化应激增强疾病的逻辑治疗靶点。
Mitochondria can either enhance or suppress cell death, Cytochrome c release from mitochondria and depolarization of the mitochondrial membrane potential (Delta Psi) are crucial events in triggering apoptosis, In contrast, activation of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels prevents lethal ischemic injury in vivo, implicating these channels as key players in the process of ischemic preconditioning. We probed the relationship between mitoK(ATP) channels and apoptosis in cultured neonatal rat cardiac ventricular myocytes. Incubation with 200 mu mol/L, hydrogen peroxide induced TUNEL positivity, cytochrome c translocation, caspase-3 activation, poly(ADP ribose) polymerase cleavage, and dissipation of Delta Psi. Pharmacological opening of mitoK(ATP) channels by diazoxide (100 mu mol/L) preserved mitochondrial integrity and suppressed all markers of apoptosis. Diazoxide prevented Delta Psi depolarization in a concentration-dependent manner (EC50 approximate to 40 mu mol/L, with saturation by 100 mu mol/L), as shown by both flow cytometry and quantitative image analysis of cells stained with fluorescent Delta Psi indicators. These cytoprotective effects of diazoxide were reproduced by pinacidil, another mitoK(ATP) agonist, and blocked by the mitoK(ATP) channel antagonist 5-hydroxydecanoate (500 mu mol/L). Our findings identify a novel mitochondrial pathway that is protective against apoptosis. The results also pinpoint mitoK(ATP) channels as logical therapeutic targets in diseases of enhanced apoptosis and oxidative stress.