Opening of mitoKATP improves cardiac function and inhibits apoptosis via the AKT-Foxo1 signaling pathway in diabetic cardiomyopathy

Decreasing phosphorylation of AKT-Foxo1 is closely associated with the onset of insulin resistance and apoptosis during diabetic cardiomyopathy (DCM). Opening of mitochondrial ATP-sensitive potassium channels (mitoK(ATP)) increases the expression of p-AKT in the process of reperfusion injury. It was therefore hypothesized that opening of mitoK(ATP) may regulate the AKT-Foxo1 signaling pathway and improve cardiac function in DCM. In the present study, opening of mitoK(ATP) by diazoxide (DZX) was found to improve cardiac function and attenuate cardiomyocyte apoptosis in db/db mice. DZX also significantly increased the expression of p-AKT and p-Foxo1. Similarly, DZX decreased the expression of the heart failure marker NT-proBNP, increased mitochondrial membrane potential, inhibited apoptosis, and increased the expression of p-AKT and p-Foxo1 when mimicking insulin resistance in cultured cardiomyocytes. Moreover, the protective effects of DZX were completely blocked by the specific AKT inhibitor MK-2206. These data suggest that the regulation of the AKT-Foxo1 signaling pathway by mitoK(ATP) plays an important role in improving cardiac function and inhibiting apoptosis in DCM, and may therefore be a new potential therapeutic target for DCM.