Sevoflurane Alleviates Myocardial Ischemia/Reperfusion Injury Via Regulating TRIM65-Mediated Ubiquitination Modification of ALOX5

Background As a commonly used anesthetic in clinical practice, sevoflurane (Sevo) has been found to have a certain protective effect on myocardial ischemia/reperfusion (MI/R) injury. However, the underlying molecular mechanisms deserve further elucidation. Methods Human cardiomyocytes were induced by hypoxia/reoxygenation (H/R), and MI/R rat model was established by ligation of left coronary artery. Cell viability and Apoptosis were tested using CCK8 assay and flow cytometry. Inflammatory factors and ferroptosis-related markers were tested by corresponding kit. The levels of ALOX5, ferroptosis-related markers, and tripartite motif 65 (TRIM65) were determined by qRT-PCR or western blot. The interaction between TRIM65 and ALOX5 was evaluated by Co-IP assay. Results Sevo repressed H/R-induced cardiomyocyte Apoptosis, inflammation, and Ferroptosis. Sevo reduced the ALOX5 protein level, and ALOX5 overexpression reversed the inhibitory effects of Sevo on H/R-induced cardiomyocyte injury. E3 ubiquitin Ligase TRIM65 could decrease ALOX5 protein stability by promoting its ubiquitination level. TRIM65 inhibited H/R-induced cardiomyocyte Apoptosis, inflammation, and Ferroptosis by downregulating ALOX5. Furthermore, TRIM65 knockdown reversed the protective effects of Sevo on H/R-induced cardiomyocyte injury. Additionally, Sevo alleviated MI/R injury in rat models by activating TRIM65-mediated ubiquitination of ALOX5. Conclusion Sevo restrained H/R-induced cardiomyocyte Apoptosis, inflammation, and Ferroptosis to alleviate MI/R injury, which might be associated with the TRIM65/ALOX5 axis.

ALOX5; Myocardial ischemia/reperfusion injury; Sevoflurane; TRIM65.