Remote Postconditioning Cardio-protection After Myocardial Ischemia/reperfusion Injury by Eliminating 4-HNE and Regulating Autophagy Through ALDH2/SIRT3/HIF1α Signaling Pathway

Abstract Purpose Remote postconditioning (Rpost) was proposed based on postconditioning studies. Aldehyde dehydrogenase 2 (ALDH2) is a unique endogenous cardioprotective enzyme in the mitochondria, associated with various cardiovascular diseases. However, whether Rpost exerts myocardial protection through ALDH2 has not been systematically reported. Methods C57BL/6 and ALDH2 knockout (ALDH2-KO) mice were subjected to left anterior descending ligation to construct ischemic/reperfusion (I/R) models. Before the start of reperfusion after myocardial ischemia in mice, the bilateral hindlimbs were used as target organs to undergo Rpost. Results Echocardiography and single-cell contraction experiments showed that Rpost significantly improved myocardial function and alleviated myocardial ischemia-reperfusion injury in C57BL/6 mice after I/R, but it was challenging to exert myocardial protection in ALDH2-KO mice. TUNEL, Evans blue/TTC, and reactive oxygen species (ROS) assay results showed that the effect of Rpost on reducing myocardial cell apoptosis, myocardial infarction area, and myocardial ROS levels was not significantly different in the MI/RI in ALDH2-KO mice. Electron microscopy and western blotting showed that Rpost could upregulate ALDH2 expression, activate sirtuin 3 (SIRT3)/hypoxia-inducible factor 1-alpha (HIF1α), regulate autophagy, and exert myocardial protection. However, this protective effect may be blocked in the absence of ALDH2. Furthermore, we found that Rpost can upregulate the expression of ALDH2 and inhibit the production of 4-hydroxynonenal (4-HNE), playing a protective role in the myocardium. Conclusion This study revealed that Rpost could exert myocardial protection through the ALDH2/SIRT3/HIF1α signaling pathway by reducing 4-HNE secretion. The study explores the feasibility of Rpost in ALDH2-deficient populations, thereby providing a basis for the targeted clinical application of Rpost.