AMPKα2 Overexpression Reduces Cardiomyocyte Ischemia-Reperfusion Injury Through Normalization of Mitochondrial Dynamics.

Cardiac ischemia-reperfusion (I/R) injury is associated with mitochondrial dysfunction. Recent studies have reported that mitochondrial function is determined by mitochondrial dynamics. Here, we hypothesized that AMPK alpha 2 functions as an upstream mediator that sustains mitochondrial dynamics in cardiac I/R injury and cardiomyocyte hypoxia-reoxygenation (H/R)in vitro. To test this, we analyzed cardiomyocyte viability and survival along with mitochondrial dynamics and function using western blots, qPCR, immunofluorescence, and ELISA. Our results indicated that both AMPK alpha 2 transcription and translation were reduced by H/R injury in cardiomyocytes. Decreased AMPK alpha 2 levels were associated with cardiomyocyte dysfunction and apoptosis. Adenovirus-mediated AMPK alpha 2 overexpression dramatically inhibited H/R-mediated cardiomyocyte damage, possibly by increasing mitochondrial membrane potential, inhibiting cardiomyocyte oxidative stress, attenuating intracellular calcium overload, and inhibiting mitochondrial apoptosis. At the molecular level, AMPK alpha 2 overexpression alleviated abnormal mitochondrial division and improved mitochondrial fusion through activation of the Sirt3/PGC1 alpha pathway. This suggests AMPK alpha 2 contributes to maintaining normal mitochondrial dynamics. Indeed, induction of mitochondrial dynamics disorder abolished the cardioprotective effects afforded by AMPK alpha 2 overexpression. Thus, cardiac I/R-related mitochondrial dynamics disorder can be reversed by AMPK alpha 2 overexpression in a manner dependent on the activation of Sirt3/PGC1 alpha signaling.