Diabetic cardiomyopathy is associated with suppression of cardiac autophagy, and activation of
AMP-activated protein kinase (AMPK) restores cardiac autophagy and prevents
cardiomyopathy in diabetic mice, albeit by an unknown mechanism. We hypothesized that AMPK-induced autophagy ameliorates
diabetic cardiomyopathy by inhibiting cardiomyocyte apoptosis and examined the effects of AMPK on the interaction between
Beclin1 and Bcl-2, a switch between autophagy and apoptosis, in diabetic mice and high
glucose-treated H9c2 cardiac myoblast cells. Exposure of H9c2 cells to high
glucose reduced AMPK activity, inhibited Jun NH2-terminal
kinase 1 (JNK1)-B-cell
lymphoma 2 (Bcl-2) signaling, and promoted
Beclin1 binding to Bcl-2. Conversely, activation of AMPK by
metformin stimulated JNK1-Bcl-2 signaling and disrupted the Beclin1-Bcl-2 complex. Activation of AMPK, which normalized cardiac autophagy, attenuated high
glucose-induced apoptosis in cultured H9c2 cells. This effect was attenuated by inhibition of autophagy. Finally, chronic administration of
metformin in diabetic mice restored cardiac autophagy by activating JNK1-Bcl-2 pathways and dissociating
Beclin1 and Bcl-2. The induction of autophagy protected against cardiac apoptosis and improved cardiac structure and function in diabetic mice. We concluded that dissociation of Bcl-2 from
Beclin1 may be an important mechanism for preventing
diabetic cardiomyopathy via AMPK activation that restores autophagy and protects against cardiac apoptosis.