Protective actions of epoxyeicosatrienoic acid: dual targeting of cardiovascular PI3K and KATP channels.
Protective actions of epoxyeicosatrienoic acid: dual targeting of cardiovascular PI3K and KATP channels.
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DOI：
10.1016/j.yjmcc.2009.01.009
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发表时间：
2009-06
影响因子：
5
通讯作者：
Medhora, Meetha M.
中科院分区：
文献类型：
--
作者：
Bodiga, Sreedhar;Zhang, Rong;Jacobs, Dexter E.;Larsen, Brandon T.;Tampo, Akihito;Manthati, Vijay L.;Kwok, Wai-Meng;Zeldin, Darryl C.;Falck, John R.;Gutterman, David D.;Jacobs, Elizabeth R.;Medhora, Meetha M.
关键词：
研究表明，环氧二碳三烯酸（EETs）通过激活atp敏感的K+ (KATP)通道（肌层和线粒体）、钙激活的K+通道、细胞外信号调节激酶或磷酸肌苷3激酶（PI3K）等靶点来保护心血管组织免受细胞凋亡的影响。我们测试了EETs是否能保护人心房组织免受缺氧/再氧化（H/R）损伤，并将我们的结果与大鼠和小鼠两种啮齿动物的心肌进行了比较。EETs降低了这三种动物心肌caspase 3活性，并保护新生大鼠心室肌细胞原代培养中线粒体膜电位的丧失。此外，EETs对体外暴露于H/R的小鼠肺动脉具有保护作用。与野生型对照相比，血浆EETs （Ephx2−/−）水平升高的基因工程小鼠的心肌和肺动脉对H/ r诱导的损伤具有保护作用，这表明内源性EETs可能具有促进生存的作用。肌细胞的电生理研究表明，在PI3K缺失的情况下，eet可以刺激KATP电流。同样，在KATP通道阻滞剂格列本脲存在时，PI3K/Akt也会激活。基于wortmannin（一种PI3K抑制剂）或格列本脲存在时EETs保护的丧失，同时激活至少2种途径，PI3K和KATP通道，似乎需要保护。总之，我们证明了外源性和内源性eet在心血管组织（包括患病的人心肌）中具有强大的促生存作用，其介导的激活途径不仅有一个，而且至少有两个，即PI3K和KATP通道。
Epoxyeicosatrienoic acid(s) (EETs) have been shown to protect cardiovascular tissue against apoptosis dependent on activation of targets such as ATP-sensitive K+ (KATP) channels (sarcolemmal and mitochondrial), calcium-activated K+ channels, extracellular signal-regulated kinase or phosphoinositide 3-kinase (PI3K). We tested if EETs protect human atrial tissue ex vivo from hypoxia/reoxygenation (H/R) injury, and compared our results with myocardium from two rodent species, rats and mice. EETs reduced myocardial caspase 3 activity in all three species and protected against loss of mitochondrial membrane potential in primary cultures of neonatal rat ventricular myocytes submitted to H/R. In addition, EETs protected mouse pulmonary arteries ex vivo exposed to H/R. Myocardium and pulmonary arteries from genetically engineered mice having elevated plasma levels of EETs (Ephx2−/−) exhibited protection from H/R-induced injury over that of wild type controls, suggesting that endogenously produced EETs may have pro-survival effects. Electrophysiological studies in myocytes demonstrated that EETs can stimulate KATP currents in the absence of PI3K. Similarly, activation of PI3K/Akt occurred in the presence of the KATP channel blocker glibenclamide. Based upon loss of EETs protection in the presence of either wortmannin (a PI3K inhibitor) or glibenclamide, simultaneous activation of at least 2 pathways, PI3K and KATP channels respectively, appears to be required for protection. In conclusion, we demonstrate that exogenous and endogenous EETs have powerful pro-survival effects in cardiovascular tissues including diseased human myocardium, mediated by activation of not only one but at least two pathways, PI3K and KATP channels.
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