Diurnal Variation in Melatonin‐Mediated Cardiac Protection via Per2 Expression in Heart

Myocardial ischemia/reperfusion (MIR) injury, a primary cause of mortality in acute myocardial infarction, exhibits diurnal variation associated with disruptions in diurnal rhythm. Melatonin (MLT), a potent antioxidant known for its cardioprotective properties, also demonstrates diurnal rhythmicity. This study aimed to investigate the time-dependent cardioprotective effects of MLT in MIR and to clarify the role of the circadian gene Per2 in mediating these effects. Using in vivo (mice) and in vitro (H9c2 cardiomyocytes) models of MIR, we administered MLT at two distinct diurnal time points: ZT1 and ZT13. We evaluated infarct size, cardiac function, apoptosis, and the expression levels of Per2 and other circadian genes. Pretreatment with MLT at ZT13 significantly reduced infarct size and enhanced cardiac function compared to ZT1 administration. This time-dependent cardioprotective effect correlated with the diurnal expression pattern of Per2, which was notably augmented by dark phase administration of MLT without phase alteration. Crucially, Per2 knockdown in both models abrogated the cardioprotective effects of MLT. Our findings underscore that MLT confers superior cardioprotection against MIR injury when administered at dark phase, aligning with the circadian variation of Per2 expression. These effects reveal the therapeutic potential of targeting the MLT-Per2 axis in chronotherapy to mitigate MIR injury.