Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
Am J Physiol Heart Circ Physiol. 2009 Dec;297(6):H2262-9. doi: 10.1152/ajpheart.00817.2009. Epub 2009 Oct 23.
Mitochondrial reactive oxygen species (ROS) are potentially important in vascular oxygen-sensing mechanisms because hypoxia appears to be a stimulus for mitochondrial ROS generation; however, scavenging of endogenous ROS does not alter relaxation of endothelium-denuded bovine coronary arteries (BCA) to hypoxia. The purpose of this study was to investigate the influence of increasing mitochondrial ROS on the relaxation of BCA to hypoxia. Increasing mitochondrial superoxide with inhibitors of electron transport (10 microM rotenone and antimycin) and by opening mitochondrial ATP-dependent K+ channels with 100 microM diazoxide were observed in this study to attenuate relaxation of BCA precontracted with 30 mM KCl to hypoxia by 68-76% and 38%, respectively. This effect of rotenone is not prevented by inhibiting NADPH oxidase (Nox) activation or scavenging superoxide with Peg-SOD; however, it is reversed 85% and 26% by increasing the consumption of intracellular peroxide by 0.1 mM ebselen and 32.5 U/ml Peg-catalase. Because inhibition of extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase (10 microM PD-98059), but not src kinase or rho kinase, also reverses the effects of rotenone by 69%, the peroxide-elicited force-enhancing effects of ERK appear to be attenuating the response to hypoxia. Rotenone increased the phosphorylation of ERK (by 163%). Activation of ERK in BCA with 0.1 mM peroxide or endogenous peroxide generated by stimulating Nox2 with a stretch treatment or contraction with 100 nM U-46619 also attenuated relaxation to hypoxia. Thus coronary arterial relaxation to hypoxia may be attenuated by pathophysiological conditions associated with increased peroxide generation by mitochondria or other sources that stimulate ERK.
线粒体活性氧（ROS）在血管氧感应机制中可能很重要，因为缺氧似乎是线粒体 ROS 产生的刺激因素；然而，清除内源性 ROS 不会改变内皮细胞剥脱的牛冠状动脉（BCA）对缺氧的松弛。本研究的目的是研究增加线粒体 ROS 对 BCA 对缺氧松弛的影响。本研究观察到，用电子传递抑制剂（10μM 鱼藤酮和抗霉素）增加线粒体超氧化物，并用 100μM 二氮嗪打开线粒体 ATP 依赖性 K+通道，分别使 30mM KCl 预收缩的 BCA 对缺氧的松弛作用减弱 68-76%和 38%。鱼藤酮的这种作用不能通过抑制 NADPH 氧化酶（Nox）激活或用 Peg-SOD 清除超氧阴离子来预防；然而，通过增加 0.1mM ebselen 和 32.5U/ml Peg-过氧化氢酶对细胞内过氧化物的消耗，可分别逆转 85%和 26%。由于抑制细胞外信号调节激酶（ERK）丝裂原激活蛋白（MAP）激酶（10μM PD-98059），但不是 src 激酶或 rho 激酶，也可使鱼藤酮的作用逆转 69%，ERK 引起的过氧化物增强力的作用似乎减弱了对缺氧的反应。鱼藤酮使 ERK 磷酸化增加了 163%。用 0.1mM 过氧化物或通过刺激 Nox2 进行拉伸处理或用 100nM U-46619 收缩产生的内源性过氧化物激活 BCA 中的 ERK，也可减弱对缺氧的松弛作用。因此，与线粒体或其他刺激 ERK 的来源引起的过氧化物生成增加相关的病理生理条件可能会减弱冠状动脉对缺氧的松弛作用。
