Melatonin inhibits ferroptosis through the ATF3/GPX4 signaling pathway to relieve myocardial ischemia-reperfusion injury in rats.

Abstract

Melatonin (MEL), functioning as a circulating hormone, is important for the regulation of ferroptosis in different health scenarios and acts as a crucial antioxidant in cardiovascular diseases. However, its specific function in ferroptosis related to myocardial ischemia-reperfusion injury (MIRI) remains to be fully elucidated. In our research, we utilized a rat model of MIRI induced by coronary artery ligation, along with a cell model subjected to hypoxia/reoxygenation (H/R). We evaluated relevant genes and proteins by real-time fluorescent quantitative PCR and Western blot analysis. To evaluate myocardial tissue damage and cell injury, we employed cell counting kit-8 assays, flow cytometry, hematoxylin-eosin staining, and 2,3,5-triphenyltetrazolium chloride staining techniques. Our results show that administering MEL notably reduces the concentrations of cTnT, CK-MB, and lactate dehydrogenase in the serum of MIRI rats, mitigates the extent of myocardial infarction, improves the recovery of pathological conditions in myocardial tissues, and reduces the concentrations of Fe²⁺, malondialdehyde (MDA), and reactive oxygen species (ROS) in the myocardial tissue, while also promoting increased glutathione levels. Moreover, MEL can also restore the reduced viability of H9C2 cells caused by H/R or ferroptosis inducers (RSL3), reduce the cellular content of Fe²⁺, MDA, and ROS, and inhibit ferroptosis. Mechanistically, MEL promotes the expression of GPX4 by downregulating the expression of ATF3, thereby inhibiting ferroptosis in cardiomyocytes and ultimately alleviating the process of MIRI. Our study demonstrates that MEL ameliorates MIRI by inhibiting ferroptosis.