Membrane receptor‐dependent N otch1/ H es1 activation by melatonin protects against myocardial ischemia–reperfusion injury: in vivo and in vitro studies

Melatonin confers profound protective effect against myocardial ischemia–reperfusion injury ( MI / RI ). Activation of N otch1/ H airy and enhancer of split 1 ( H es1) signaling also ameliorates MI / RI . We hypothesize that melatonin attenuates MI / RI ‐induced oxidative damage by activating N otch1/ H es1 signaling pathway with phosphatase and tensin homolog deleted on chromosome 10 ( P ten)/ A kt acting as the downstream signaling pathway in a melatonin membrane receptor‐dependent manner. Male S prague D awley rats were treated with melatonin (10 mg/kg/day) for 4 wk and then subjected to MI / R surgery. Melatonin significantly improved cardiac function and decreased myocardial apoptosis and oxidative damage. Furthermore, in cultured H 9 C 2 cardiomyocytes, melatonin (100  μ mol/L) attenuated simulated ischemia–reperfusion ( SIR )‐induced myocardial apoptosis and oxidative damage. Both in vivo and in vitro study demonstrated that melatonin treatment increased N otch1, N otch1 intracellular domain ( NICD ), H es1, B cl‐2 expressions, and p‐ A kt/ A kt ratio and decreased P ten, B ax, and caspase‐3 expressions. However, these protective effects conferred by melatonin were blocked by DAPT (the specific inhibitor of N otch1 signaling), luzindole (the antagonist of melatonin membrane receptors), N otch1 si RNA , or H es1 si RNA administration. In summary, our study demonstrates that melatonin treatment protects against MI / RI by modulating N otch1/ H es1 signaling in a receptor‐dependent manner and P ten/ A kt signaling pathways are key downstream mediators.