Prostacyclin attenuates oxidative damage of myocytes by opening mitochondrial ATP-sensitive K+ channels via the EP3 receptor
Prostacyclin attenuates oxidative damage of myocytes by opening mitochondrial ATP-sensitive K+ channels via the EP3 receptor
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DOI：
10.1152/ajpheart.01003.2004
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发表时间：
2005-05-01
影响因子：
4.8
通讯作者：
Bolli, R
中科院分区：
文献类型：
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作者：
Shinmura, K;Tamaki, K;Bolli, R
前列环素（PGI（2））和PGE家族减轻心肌缺血-再灌注损伤和限制氧化损伤。PGI（2）的心脏保护作用传统上归因于IP受体的激活。前列腺素类研究的最新进展表明，PGI（2）不仅可以与IP结合，还可以与EP受体结合，这表明PGI（2）和PGEs之间存在相互作用。PGI（2）保护心肌细胞免受氧化损伤的机制和相关的特异性受体仍然未知。因此，将新鲜分离的成年大鼠心肌细胞暴露于200 μ M H2 O2，其中有或没有卡前列环素（cPGI（2））、IP选择性激动剂和ONO-AE-248（一种EP 3选择性激动剂）。H2 O2超融合30分钟后，通过台盼蓝拒染法评估细胞活力。cPGI（2）和ONO-AE-248显著改善H2 O2灌流期间的细胞存活; IP选择性激动剂没有。cPGI（2）和ONO-AE-248的保护作用被5-羟基癸酸或格列本脲预处理完全消除。在第二系列实验中，线粒体ATP敏感性K+（K-ATP）通道开放剂二氮嗪（Dx）可逆地氧化对照心肌细胞中的黄素蛋白。单独暴露于前列腺素类似物对黄素蛋白荧光没有影响。与单独Dx相比，在cPGI（2）或ONO-AE-248存在下第二次应用Dx显著增加了黄素蛋白荧光，但IP选择性激动剂没有。这项研究表明，PGI（2）类似物主要通过激活EP 3来保护心肌细胞免受氧化应激。这些数据还表明，EP 3受体的激活引发线粒体KATP通道的开放，并且该机制对于EP 3依赖性保护是必需的。
Prostacyclin (PGI(2)) and the PGE family alleviate myocardial ischemia-reperfusion injury and limit oxidative damage. The cardioprotective effects of PGI(2) have been traditionally ascribed to activation of IP receptors. Recent advances in prostanoid research have revealed that PGI(2) can bind not only to IP, but also to EP, receptors, suggesting cross talk between PGI(2) and PGEs. The mechanism(s) whereby PGI(2) protects myocytes from oxidative damage and the specific receptors involved remain unknown. Thus fresh isolated adult rat myocytes were exposed to 200 mu M H2O2 with or without carbaprostacyclin (cPGI(2)), IP-selective agonists, and ONO-AE-248 (an EP3-selective agonist). Cell viability was assessed by trypan blue exclusion after 30 min of H2O2 super-fusion. cPGI(2) and ONO-AE-248 significantly improved cell survival during H2O2 superfusion; IP-selective agonists did not. The protective effect of cPGI(2) and ONO-AE-248 was completely abrogated by pretreatment with 5-hydroxydecanoate or glibenclamide. In the second series of experiments, the mitochondrial ATP-sensitive K+ (K-ATP) channel opener diazoxide (Dx) reversibly oxidized flavoproteins in control myocytes. Exposure to prostanoid analogs alone had no effect on flavoprotein fluorescence. A second application of Dx in the presence of cPGI(2) or ONO-AE-248 significantly increased flavoprotein fluorescence compared with Dx alone, but IP-selective agonists did not. This study demonstrates that PGI(2) analogs protect cardiac myocytes from oxidative stress mainly via activation of EP3. The data also indicate that activation of EP3 receptors primes the opening of mitochondrial KATP channels and that this mechanism is essential for EP3-dependent protection.