Dissociation of Bcl-2–Beclin1 Complex by Activated AMPK Enhances Cardiac Autophagy and Protects Against Cardiomyocyte Apoptosis in Diabetes
Year: 2012
Type: article
Abstract: 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.
Source: Diabetes
DOI: 10.2337/db12-0533
Institution: University of Oklahoma Health Sciences Center
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Awards: Prevention of High Fat Diet-Induced Vascular Injury, G2512249395, Mentoring Diabetes Research in Oklahoma, Autophagy and diabetic vascular diseases, G3596284906, G408709736, G5186065327, G538943195, Oxidant stress and diabetic endothelial dysfunction, AMP-activated protein kinase in diabetes, G788250836, Controlling atherosclerotic plaque stability, Inflammasome and unstable atherosclerotic plaques, Angiotensin-II, GTPCH1 and 26S Protesomes
OpenAlex ID: W2081706292