Abstract 12009: Hypoadiponectinemia-Induced Ampk-pgc-1α Signaling Impairment and Mitochondrial Biogenesis Dysfunction as a Novel Mechanism Responsible for Enhanced Susceptibility to Ischemia in Diabetic Hearts
Adiponectin (APN) is an anti-diabetic adipokine and its level is significantly reduced in patients with type 2 diabetes (T2DM). Mitochondrial biogenesis dysfunction has been reported to cause skeletal muscle damage in T2DM. However, the relation between decreased APN level and mitochondrial biogenesis dysfunction in the diabetic hearts and their roles in susceptibility to myocardial ischemia (MI) has not been investigated. Male ob/ob (OB, age 9 weeks) mice and C57BL/6J wild type mice (WT) were subjected to coronary artery occlusion for 3 days. Compared to WT, the OB mice exhibited decreased plasma APN level (56% of control), cardiomyocyte mitochondrial derangement, and lower mRNA and protein expression of molecules involved in mitochondrial biogenesis (% of reduction: Ppargc1a 33%, Nrf1 44%; PGC-1α 54%, all P<0.05) before MI. After MI, the OB mice had decreased survival rate, ejection fraction (EF: 30.8%±1.8% vs. 39.1%±3.0%, n=8, P<0.05), and more severe MI injury as evidenced by increased infarct size compared with WT mice. Treatment with recombinant human gAPN(1ug/g/d, 3 days) increased survival rate, improved cardiac function and reduced MI injury in OB mice, as indicated by increased EF (39.0%±2.4% vs. 30.8%±1.8%, P<0.05), and decreased infarct size and apoptosis. Mitochondrial biogenesis-related molecules were markedly increased in gAPN-treated OB mice (Ppargc1a 3.1-fold, Esrra 5.3-fold, Nrf1 2.0-fold, Tfam 1.4-fold, Cycs 5.9-fold, all P<0.05). Mechanistically, gAPN significantly increased AMPK phosphorylation and PGC-1α deacetylation (P<0.05). Most importantly, pretreatment with an AMPK inhibitor (Compound C,20ug/g/d, 3 days) not only inhibited gAPN stimulated PGC-1α deacetylation and mitochondrial biogenesis (all P<0.05), but also abolished its cardiac protection in OB mice (EF: 24.8%±3.5% vs. 39.0±2.4%, n=8, P<0.05). Collectively, we demonstrated for the first time that reduced APN level and subsequent impairment of AMPK-PGC-1α signaling and mitochondrial biogenesis dysfunction is a novel mechanism responsible for enhanced susceptibility to MI in diabetic hearts. Interventions targeted to restore this signaling axis may have therapeutic potential in the treatment of diabetic heart injury.
- © 2011 by American Heart Association, Inc.