Relationship between mitochondrial ATP sensitive potassium channels and reactive oxygen species in cardiovascular tissue.

本研究旨在探讨线粒体源性活性氧（ROS）在Ang II信号通路中的作用及血管收缩机制。采用5-羟基十二酸酯（5-HD；线粒体atp敏感钾通道（mitoKATP）的特异性抑制剂）和tempol（一种超氧化物歧化酶模拟物），比较了Ang II和二氮氧化物（mitoKATP开启剂）对体外和体内大鼠血管平滑肌细胞（RVSMC）氧化还原敏感丝裂原激活蛋白激酶（MAPK）激活的影响。Ang II或二氮氧化物刺激RVSMC增加磷酸化的MAPK （ERK1/2、p38和JNK）以及超氧化物的产生；除了ERK1/2被Ang II激活外，5-HD预处理以剂量依赖的方式抑制了它们。同样的事件在大鼠体内主动脉中重现。Angⅱ样二氮氧化物使RVSMC线粒体膜电位去极化（ΔΨ_M），该过程被5-HD抑制。5-HD不调节Ang II诱导的RVSMC中更多的钙动员，也不影响Ang II诱导的高血压急性期和慢性期的血管收缩作用。这些结果表明，Ang II通过血管中mitoKATP的打开刺激线粒体ROS的产生，导致ΔΨ_M和MAPK氧化还原敏感激活的减少；然而，线粒体产生的ROS不会导致Ang ii诱导的血管收缩。见高血压2005；45(3):438-44和高血压2005（已出版）的详细资料。相关文章也演示如下；1)清醒大鼠急性给予Ang II和苯肾上腺素可引起心脏和主动脉MAPK的氧化还原敏感激活。（高血压，2004;43:117-24,J Pharmacol Sci. 2004;96;406-10）2) angii诱导血管收缩的机制可能在12小时内由对ROS不敏感转变为敏感。[J] .高血压杂志。2004;22:2161-8。3) β-肾上腺素能受体刺激引起心脏氧化应激，而产生的ROS负责激活MAPK级联反应。（心血管病杂志2005；65:230-8）少

This study aimed to examine the involvement of mitochondria-derived reactive oxygen species (ROS) in the signaling pathway and the vasoconstrictor mechanism of Ang II. Using 5-hydroxydecanoate (5-HD ; a specific inhibitor of mitochondrial ATP-sensitive potassium channels (mitoKATP)) and tempol (a superoxide dismutase mimetic), the effects of Ang II and diazoxide (a mitoKATP opener), were compared on redox-sensitive mitogen-activated protein kinase (MAPK) activation in rat vascular smooth muscle cells (RVSMC) in vitro and in rat aorta in vivo. Stimulation of RVSMC by Ang II or diazoxide increased phosphorylated MAPK (ERK1/2,p38 and JNK) as well as superoxide production ; which were then suppressed by 5-HD pretreatment in a dose dependent manner, except for ERK1/2 activation by Ang II. The same events were reproduced in rat aorta in vivo. Ang II like diazoxide depolarized the mitochondrial membrane potential (ΔΨ_M) of RVSMC, which was inhibited by 5-HD. 5-HD did not modulate Ang II induc … More ed calcium mobilization in RVSMC and did not affect on the vasoconstrictor effect in either acute or chronic phases of Ang II induced hypertension. These results reveal that Ang II stimulates mitochondrial ROS production through the opening of mitoKATP in the vasculature, leading to reduction of ΔΨ_M and redox-sensitive activation of MAPK ; however, generated ROS from mitochondria do not contribute to Ang II-induced vasoconstriction. See Hypertension 2005;45(3):438-44 and Hypertension 2005 (in press) in detail. The related articles also demonstrated as shown below ;1)Acute administration of Ang II and phenylephrine to conscious rats provoked redox-sensitive activation of MAPK in the heart and aorta. (Hypertension. 2004;43:117-24, J Pharmacol Sci. 2004;96;406-10)2)The mechanisms of Ang II induced vasoconstriction may shift from being non-sensitive to ROS to sensitive within 12 hours. (J Hypertens. 2004;22:2161-8.)3)(β-adrenoceptor stimulation provokes cardiac oxidative stress, while the generated ROS are responsible for the activation of MAPK cascade. (Cardiovasc Res. 2005;65:230-8.) Less