Pinacidil postconditioning activates HIF-1/HRE signaling and alleviate myocardial ischemia-reperfusion injury

Abstract

Abstract Background Myocardium ischemia/reperfusion (I/R) injury can be fatal in cardiac operations. Pinacidil postconditioning (PPO) could effectively alleviate I/R injury. however, the mechanisms are still not clear. Hypoxia-inducible factor-1 (HIF-1) acted as a mediator of ischemic postconditioning and protected the heart against the detrimental acute I/R injury. This study aims at observing the effects of PPO on I/R injury, and exploring the function of HIF-1/hypoxia response element (HRE) pathway in PPO’s myocardial protective effects. Methods and Results HIF-1α inhibitor 2-methoxyestradiol (2ME2), and mitoKATP channel blocker 5-hydroxy decanoic acid (5-HD) were given before PPO to evaluate the contribution of HIF-1α and mitoKATP respectively. Cardiac function parameters (HR, LVDP, LVEDP, and dp/dtmax), infarct size, and myocardium and mitochondrial ultrastructure were evaluated. Additionally, expression of HIF-1α, and HRE related genes, i.e., VEGF, iNOS and HO-1，were detected. PPO not only improved cardiac function and ultrastructure of I/R hearts, but also reduced the infarct size in the I/R heart. In addition, PPO increased the expression of HRE related genes. These protective effects of PPO were partially reversed by HIF-1α inhibitor, and completely reversed by mitoKATP channel blocker. Conclusion These results indicate that PPO protects I/R myocardium depending on mitoKATP opening and HIF-1/HRE pathway.