20-Hydroxyeicosatetraenoic Acid Mediates Isolated Heart Ischemia/Reperfusion Injury by Increasing NADPH Oxidase-Derived Reactive Oxygen Species Production

Yong Han, Huiying Zhao, Hong Tang, Xinyu Li, Jiang Tan, Qinghua Zeng, Chengwen Sun
2013 Circulation Journal  
It has been reported that 20-hydroxyeicosatetraenoic acid (20-HETE) aggravates myocardial ischemia/reperfusion (I/R) injury, but the exact mechanism of action is still unclear. Methods and Results : Experiments were performed in isolated rat hearts subjected to 35 min of ischemia followed by 40 min of reperfusion in Langendorff preparations. Perfusion with HET0016, an inhibitor of 20-HETE production, significantly improved I/R-induced reduction in cardiac contractility, myocardial infarction,
more » ... rdial infarction, and myocardial apoptosis. In contrast, administration of 20-HETE aggravated I/R-induced myocardial injury and enhanced apoptosis. I/R significantly increased production of reactive oxygen species (ROS) and oxidative stress, both of which were significantly inhibited by HET0016 and enhanced by 20-HETE administration. Apocynin, an inhibitor of NADPH oxidase, blocked 20-HETE-induced ROS production in the I/R hearts. 20-HETE increased the expression of gp91 phox and p22 phox , the subunits of NADPH oxidase; and stimulated NADPH oxidase activity. In addition, GF-109203 significantly attenuated the 20-HETE-induced increases in the NADPH oxidase expression and activity. Finally, in the Langendorff I/R preparation, both apocynin and tempol, ROS scavengers, significantly blocked 20-HETE-induced myocardial dysfunction. Conclusions: All of the results demonstrated that in isolated rat hearts 20-HETE stimulates NADPH oxidase-derived superoxide production, which aggravates I/R-induced myocardial injury via a PKC-dependent mechanism. (Circ J 2013; 77: 1807 -1816
doi:10.1253/circj.cj-12-1211 pmid:23585488 fatcat:xqdyhfnkpfa2jdmywxvb34fvje