Dissociation of Bcl-2-Beclin1 complex by activated AMPK enhances cardiac autophagy and protects against cardiomyocyte apoptosis in diabetes.

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.

• Authors: Chaoyong He, Huaiping Zhu, Hongliang Li, Ming-Hui Zou, Zhonglin Xie
• Journal: Diabetes (Diabetes) Vol. 62 Issue 4 Pg. 1270-81 (Apr 2013) ISSN: 1939-327X [Electronic] United States
• PMID: 23223177 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• Beclin-1
• Becn1 protein, mouse
• Blood Glucose
• Proto-Oncogene Proteins c-bcl-2
• MAP Kinase Kinase 4
• Adenylate Kinase
• Glucose

Topics

• Adenylate Kinase (genetics, metabolism)
• Animals
• Apoptosis
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Autophagy
• Beclin-1
• Blood Glucose
• Cell Line
• Diabetes Mellitus, Experimental (complications, metabolism)
• Diabetic Cardiomyopathies (pathology, prevention & control)
• Friend murine leukemia virus
• Glucose (administration & dosage, metabolism, pharmacology)
• MAP Kinase Kinase 4 (antagonists & inhibitors, metabolism)
• Male
• Mice
• Mice, Transgenic
• Myocytes, Cardiac (physiology)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Rats