Improvement of Cardiac Functions by Chronic Metformin Treatment Is Associated With Enhanced Cardiac Autophagy in Diabetic OVE26 Mice
Open Access
- 21 May 2011
- journal article
- Published by American Diabetes Association in Diabetes
- Vol. 60 (6), 1770-1778
- https://doi.org/10.2337/db10-0351
Abstract
OBJECTIVE Autophagy is a critical cellular system for removal of aggregated proteins and damaged organelles. Although dysregulated autophagy is implicated in the development of heart failure, the role of autophagy in the development of diabetic cardiomyopathy has not been studied. We investigated whether chronic activation of the AMP-activated protein kinase (AMPK) by metformin restores cardiac function and cardiomyocyte autophagy in OVE26 diabetic mice. RESEARCH DESIGN AND METHODS OVE26 mice and cardiac-specific AMPK dominant negative transgenic (DN)-AMPK diabetic mice were treated with metformin or vehicle for 4 months, and cardiac autophagy, cardiac functions, and cardiomyocyte apoptosis were monitored. RESULTS Compared with control mice, diabetic OVE26 mice exhibited a significant reduction of AMPK activity in parallel with reduced cardiomyocyte autophagy and cardiac dysfunction in vivo and in isolated hearts. Furthermore, diabetic OVE26 mouse hearts exhibited aggregation of chaotically distributed mitochondria between poorly organized myofibrils and increased polyubiquitinated protein and apoptosis. Inhibition of AMPK by overexpression of a cardiac-specific DN-AMPK gene reduced cardiomyocyte autophagy, exacerbated cardiac dysfunctions, and increased mortality in diabetic mice. Finally, chronic metformin therapy significantly enhanced autophagic activity and preserved cardiac functions in diabetic OVE26 mice but not in DN-AMPK diabetic mice. CONCLUSIONS Decreased AMPK activity and subsequent reduction in cardiac autophagy are important events in the development of diabetic cardiomyopathy. Chronic AMPK activation by metformin prevents cardiomyopathy by upregulating autophagy activity in diabetic OVE26 mice. Thus, stimulation of AMPK may represent a novel approach to treat diabetic cardiomyopathy.Keywords
This publication has 51 references indexed in Scilit:
- Enhanced Tyrosine Nitration of Prostacyclin Synthase Is Associated with Increased Inflammation in Atherosclerotic Carotid Arteries from Type 2 Diabetic PatientsThe American Journal of Pathology, 2010
- Identification of the Serine 307 of LKB1 as a Novel Phosphorylation Site Essential for Its Nucleocytoplasmic Transport and Endothelial Cell AngiogenesisMolecular and Cellular Biology, 2009
- Upregulation of Mitochondrial Uncoupling Protein-2 by the AMP-Activated Protein Kinase in Endothelial Cells Attenuates Oxidative Stress in DiabetesDiabetes, 2008
- Acute Metformin Therapy Confers Cardioprotection Against Myocardial Infarction Via AMPK-eNOS–Mediated SignalingDiabetes, 2008
- Phosphorylation of LKB1 at Serine 428 by Protein Kinase C-ζ Is Required for Metformin-Enhanced Activation of the AMP-Activated Protein Kinase in Endothelial CellsCirculation, 2008
- Selective degradation of mitochondria by mitophagyArchives of Biochemistry and Biophysics, 2007
- Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphomaJCI Insight, 2007
- Diabetic Cardiomyopathy in OVE26 Mice Shows Mitochondrial ROS Production and Divergence Between In Vivo and In Vitro ContractilityThe Review of Diabetic Studies, 2007
- Osteopontin Modulates Myocardial Hypertrophy in Response to Chronic Pressure Overload in MiceHypertension, 2004
- Role of AMP-activated protein kinase in mechanism of metformin actionJCI Insight, 2001