Abstract 15905: Reduced Cardioprotective Action of Adiponectin in High Fat Diet Induced Type II Diabetic Mice and its Mechanisms Involved
Diabetes increases the morbidity/mortality of ischemic heart disease through incompletely understood mechanisms. Many studies in normal animals have demonstrated that adiponectin (APN) reduces myocardial ischemia/reperfusion (MI/R) injury. However, whether the cardioprotective actions of APN are altered in the diabetic state, a pathologic condition where endogenous APN is significantly reduced and APN supplementation is most appropriate, has never been previously investigated. High fat diet (HF) induced obesity/diabetic mice and age-matched control mice on normal diet (ND) were subjected to MI/R (LAD ligation model), and were treated with vehicle or globular domain of APN (gAPN) 10 minutes prior to R. Consistent with previous reports, treatment of ND mice with gAPN at 2μg/g exerted maximal cardioprotective effects, and increasing gAPN dose failed to further escalate the protective effect. In comparison to ND mice, HF mice endured greater MI/R injury. More importantly, administration of gAPN at 2 μg/g only minimally attenuated MI/R injury in HF mice. A 3-times higher dose of gAPN (6 μg/g) was required to achieve significant cardioprotection comparable to that observed in ND mice treated with low dose gAPN (infarct size: −40% vs. −15% in low dose APN treated ND mice; apoptosis: −60% vs. −25% in low dose APN treated ND mice; dp/dtmax +45% vs. 15% in low dose APN treated ND mice). APN is known to reduce MI/R injury via AMP-activated protein kinase (AMPK)-dependent metabolic regulation and AMPK-independent anti-oxidative/anti-nitrative pathways. Compared to ND mice, gAPN-induced cardiac AMPK activation was significantly blunted in HF mice (P<0.05). Moreover, although both low and high doses of gAPN was equally effective in attenuating MI/R-induced oxidative stress (NADPH oxidase expression and superoxide production) and nitrative stress (iNOS expression, NO production and peroxynitrite formation) in ND mice, only high dose gAPN effectively reduced MI/R-induced oxidative/nitrative stress in HF mice. Collectively, our Results demonstrated for the first time that HF-induced diabetes diminished both AMPK-dependent and AMPK-independent cardioprotection of gAPN, suggestive of an unreported APN resistance in diabetic heart.
- © 2010 by American Heart Association, Inc.