Mingchu Sun - Institute of Medical Research, Northwestern Polytechnical University, Xi’an Shaanxi, ۷۱۰۰۷۲ China
Zihui Zhang - Institute of Medical Research, Northwestern Polytechnical University, Xi’an Shaanxi, ۷۱۰۰۷۲ China
Yue Yin - Department of Physiology and Pathophysiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, ۷۱۰۰۳۲ China
Lu Yu - Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi’an ۷۱۰۰۳۲, China
Wenhua Jiang - Institute of Medical Research, Northwestern Polytechnical University, Xi’an Shaanxi, ۷۱۰۰۷۲ China
Chan Zhang - Institute of Medical Research, Northwestern Polytechnical University, Xi’an Shaanxi, ۷۱۰۰۷۲ China
Chunhu Gu - Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an ۷۱۰۰۳۲, China
Heng Ma - Department of Physiology and Pathophysiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, ۷۱۰۰۳۲ China
Yishi Wang - Department of Physiology and Pathophysiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, ۷۱۰۰۳۲ China

Objective(s): Cardiac arrest is a crucial procedure in various cardiac surgeries, during which the heart is subjected to an ischemic state. The occurrence of ischemia/reperfusion (I/R) injury is inevitable due to aortic blockage and opening. The Histidine-tryptophan-ketoglutarate (HTK) solution is commonly used as an organ protection liquid to mitigate cardiac injury during cardiac surgery. Despite its widespread use, there is significant potential for improving its protective efficacy.Materials and Methods: The cardioprotective effect of HTK solution with and without melatonin was evaluated using the isolated Langendorff-perfused mouse heart model. The isolated C۵۷bL/۶ mouse hearts were randomly divided into four groups: control, I/R, HTK solution treatment before reperfusion (HTK+I/R), and HTK solution combined with melatonin before reperfusion (HTK+M+I/R). Cardiac function and myocardial injury markers were then measured. AMP-activated protein kinase α۲ (AMPKα۲) KO mice were used to investigate the underlying mechanism.Results: In our study, we found that melatonin significantly improved the protective effects of HTK solution in an isolated Langendorff-perfused mouse model, mechanistically by reducing mitochondrial damage, improving energy metabolism, inhibiting cardiomyocyte apoptosis, and reducing myocardial infarction size. We also observed that the HTK solution alone was ineffective in inhibiting ER stress, but when melatonin was added, there was a significant reduction in ER stress. Furthermore, melatonin was found to alleviate carbonyl stress during cardiac I/R. Interestingly, our results showed that the cardioprotective properties of melatonin were dependent on AMPKα۲.Conclusion: The findings presented in this study offer a valuable empirical foundation for the development of perioperative cardioprotective strategies.

Endoplasmic reticulum-stress, Heart protection, Langendorff heart, Melatonin, Myocardial ischemia/reperfusion injury