title: Reduced cardioprotective action of adiponectin in high-fat diet-induced type II diabetic mice and its underlying mechanisms.
abstract: Diabetes exacerbates ischemic heart disease morbidity and mortality via incompletely understood mechanisms. Although adiponectin (APN) reduces myocardial ischemia/reperfusion (MI/R) injury in nondiabetic animals, whether APN's cardioprotective actions are altered in diabetes, a pathologic condition with endogenously reduced APN, has never been investigated. High-fat diet (HD)-induced diabetic mice and normal diet (ND) controls were subjected to MI via coronary artery ligation, and given vehicle or APN globular domain (gAPN, 2 μg/g) 10 min before reperfusion. Compared to ND mice (where gAPN exerted pronounced cardioprotection), HD mice manifested greater MI/R injury, and a tripled gAPN dose was requisite to achieve cardioprotective extent seen in ND mice (i.e., infarct size, apoptosis, and cardiac function). APN reduces MI/R injury via AMP-activated protein kinase (AMPK)-dependent metabolic regulation and AMPK-independent antioxidative/antinitrative pathways. Compared to ND, HD mice manifested significantly blunted gAPN-induced AMPK activation, basally and after MI/R (p<0.05). Although both low- and high-dose gAPN equally attenuated MI/R-induced oxidative stress (i.e., NADPH oxidase expression and superoxide production) and nitrative stress (i.e., inducible nitric oxide synthase expression, nitric oxide production, and peroxynitrite formation) in ND mice, only high-dose gAPN efficaciously did so in HD mice. We demonstrate for the first time that HD-induced diabetes diminished both AMPK-dependent and AMPK-independent APN cardioprotection, suggesting an unreported diabetic heart APN resistance.
authors.affiliation: Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Yi
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Xufeng
authors.initials: X
authors.lastname: Wei
authors.forename: Wayne Bond
authors.initials: WB
authors.lastname: Lau
authors.forename: Qijun
authors.initials: Q
authors.lastname: Zheng
authors.forename: Yajing
authors.initials: Y
authors.lastname: Wang
authors.forename: Yuexing
authors.initials: Y
authors.lastname: Yuan
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Wang
authors.forename: Ling
authors.initials: L
authors.lastname: Tao
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.forename: Walter
authors.initials: W
authors.lastname: Koch
authors.forename: Xin-Liang
authors.initials: XL
authors.lastname: Ma
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D052242:Adiponectin / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D059305:Diet, High-Fat / Q000009:adverse effects; D004789:Enzyme Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging / Q000209:etiology / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000473:pathology
chemical_list: D052242:Adiponectin; D000975:Antioxidants; D002316:Cardiotonic Agents; D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D000263:Adenylate Kinase; D000103:Acetyl-CoA Carboxylase