AUTHOR=Chen Xi-Yuan , Wang Jia-Qi , Cheng Si-Jing , Wang Yan , Deng Meng-Yuan , Yu Tian , Wang Hai-Ying , Zhou Wen-Jing 

TITLE=Diazoxide Post-conditioning Activates the HIF-1/HRE Pathway to Induce Myocardial Protection in Hypoxic/Reoxygenated Cardiomyocytes

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=8

YEAR=2021

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.711465

DOI=10.3389/fcvm.2021.711465

ISSN=2297-055X

ABSTRACT=<p><bold>Background:</bold> Previous studies have shown that diazoxide can protect against myocardial ischemia-reperfusion injury (MIRI). The intranuclear hypoxia-inducible factor-1 (HIF-1)/hypoxia-response element (HRE) pathway has been shown to withstand cellular damage caused by MIRI. It remains unclear whether diazoxide post-conditioning is correlated with the HIF-1/HRE pathway in protective effect on cardiomyocytes.</p><p><bold>Methods:</bold> An isolated cardiomyocyte model of hypoxia-reoxygenation injury was established. Prior to reoxygenation, cardiomyocytes underwent post-conditioning treatment by diazoxide, and 5-hydroxydecanoate (5-HD), N-(2-mercaptopropionyl)-glycine (MPG), or dimethyloxallyl glycine (DMOG) followed by diazoxide. At the end of reoxygenation, ultrastructural morphology; mitochondrial membrane potential; interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), reactive oxygen species (ROS), and HIF-1α levels; and downstream gene mRNA and protein levels were analyzed to elucidate the protective mechanism of diazoxide post-conditioning.</p><p><bold>Results:</bold> Diazoxide post-conditioning enabled activation of the HIF-1/HRE pathway to induce myocardial protection. When the mitoK<sub>ATP</sub> channel was inhibited and ROS cleared, the diazoxide effect was eliminated. DMOG was able to reverse the effect of ROS absence to restore the diazoxide effect. MitoK<sub>ATP</sub> and ROS in the early reoxygenation phase were key to activation of the HIF-1/HRE pathway.</p><p><bold>Conclusion:</bold> Diazoxide post-conditioning promotes opening of the mitoK<sub>ATP</sub> channel to generate a moderate ROS level that activates the HIF-1/HRE pathway and subsequently induces myocardial protection.</p>