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物种(ROS)参与Ang II的信号转导和血管收缩机制。采用线粒体ATP敏感性钾通道(MitoKATP)的特异性抑制剂5-羟基癸酸(5-HD)和超氧化物歧化酶模拟物temol，比较Ang II和二氮嗪(mitoKATP开放剂)对大鼠血管平滑肌细胞(RVSMC)氧化还原敏感型丝裂原激活蛋白激酶(MAPK)激活的影响。Ang II或二氮卓刺激RVSMC后，MAPK(ERK1/2、p38和JNK)磷酸化及超氧化物生成增加，5-HD可剂量依赖性地抑制ERK1/2的生成，但Ang II不激活ERK1/2。血管紧张素Ⅱ样二氮卓能去极化RVSMC线粒体膜电位(ΔΨ_M)，该作用可被5-HD抑制。5-HD不调节血管紧张素转换酶II诱导…在Ang II诱导的高血压急性期和慢性期，RVSMC的钙动员增加，对血管收缩效应无影响。这些结果表明，血管紧张素转换酶II通过开放血管内有丝分裂素三磷酸腺苷来刺激线粒体产生ROS，导致ΔΨ_M减少和氧化还原敏感的MAPK激活，但线粒体产生的ROS不参与血管紧张素转换酶诱导的血管收缩。详见《高血压》2005；45(3)：438-44和《高血压》2005(印刷中)。相关文献如下：1)清醒大鼠急性给予血管紧张素转换酶II和苯肾上腺素可引起心脏和主动脉MAPK氧化还原敏感性激活。(高血压。2004年；43：117-24，《药学杂志》。2004；96；406-10)2)Ang II诱导的血管收缩机制可能在12小时内从对ROS不敏感转变为敏感。(J Hyperten)(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。(《心脏病研究》2005；65：230-8。)较少

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