Melatonin inhibits ferroptosis in myocardial ischemia/reperfusion injury by inhibiting the ATM/p53 signaling pathway

Melatonin is a powerful free radical scavenger, with cardioprotective effects; however, the mechanism of this cardioprotective activity remains unclear. We hypothesized that melatonin inhibits ferroptosis and protects cardiomyocytes through suppression of the ataxia telangiectasia mutated (ATM)/p53 signaling pathway and reduction of lipid peroxidation. Forty-two rat hearts were randomly assigned to a control group or one of six experimental groups (I/R, I/R + melatonin, I/R + melatonin + chloroquine diphosphate5, I/R + chloroquine diphosphate1, I/R + chloroquine diphosphate5, I/R + chloroquine diphosphate25). Thirty C57/BL6 male mice were assigned to 5 groups, with the same grouping as rats. The hearts were reperfused, after which the levels of creatine kinase MB, malondialdehyde, superoxide dismutase, iron, and glutathione/ glutathione oxidized were measured. Triphenyl tetrazolium chloride (TTC) staining, Hematoxylin and eosin staining, X-ray electron microscopy, western blotting, and immunofluorescence were performed to evaluate the effects of melatonin treatment on the pathology, microstructure, and antioxidant enzymes of the myocardium (ferritin heavy chain 1 (FTH1), SLC7A11 (XCT), superoxide dismutase-2 (SOD-2), and glutathione peroxidase 4 (GPX4), p53, and p-p53). Ischemia/reperfusion increased myocardial lipid peroxidation, iron and p53 contents, as well as damage to the myocardial pathology and mitochondrial structure, and decreased the expression levels of antioxidant enzymes. Melatonin treatment alleviated these effects, which were reversed by chloroquine diphosphate. These findings suggest that melatonin pretreatment protects cardiomyocytes from I/R injury by inhibiting cell ferroptosis via suppression of the ATM/p53 signaling pathway.