title: Direct Evidence that Myocardial Insulin Resistance following Myocardial Ischemia Contributes to Post-Ischemic Heart Failure.
abstract: A close link between heart failure (HF) and systemic insulin resistance has been well documented, whereas myocardial insulin resistance and its association with HF are inadequately investigated. This study aims to determine the role of myocardial insulin resistance in ischemic HF and its underlying mechanisms. Male Sprague-Dawley rats subjected to myocardial infarction (MI) developed progressive left ventricular dilation with dysfunction and HF at 4 wk post-MI. Of note, myocardial insulin sensitivity was decreased as early as 1 wk after MI, which was accompanied by increased production of myocardial TNF-α. Overexpression of TNF-α in heart mimicked impaired insulin signaling and cardiac dysfunction leading to HF observed after MI. Treatment of rats with a specific TNF-α inhibitor improved myocardial insulin signaling post-MI. Insulin treatment given immediately following MI suppressed myocardial TNF-α production and improved cardiac insulin sensitivity and opposed cardiac dysfunction/remodeling. Moreover, tamoxifen-induced cardiomyocyte-specific insulin receptor knockout mice exhibited aggravated post-ischemic ventricular remodeling and dysfunction compared with controls. In conclusion, MI induces myocardial insulin resistance (without systemic insulin resistance) mediated partly by ischemia-induced myocardial TNF-α overproduction and promotes the development of HF. Our findings underscore the direct and essential role of myocardial insulin signaling in protection against post-ischemic HF.
authors.affiliation: Department of Aerospace Medicine, The Fourth Military Medical University, Xi'an 710032, China.|Department of Physiology, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Fu
authors.affiliation: Department of Cardiac Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Department of Aerospace Medicine, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Aerospace Medicine, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Aerospace Medicine, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Aerospace Medicine, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Chengfeng
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Nuclear Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Gao
authors.affiliation: Department of Aerospace Medicine, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Aerospace Medicine, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cardiac Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Cui
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Haichang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Tao
authors.affiliation: Department of Nuclear Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Quon
authors.affiliation: Department of Aerospace Medicine, The Fourth Military Medical University, Xi'an 710032, China.|Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D004195:Disease Models, Animal; D004452:Echocardiography; D015870:Gene Expression; D006333:Heart Failure / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000150:complications* / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D011972:Receptor, Insulin / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling
chemical_list: D007328:Insulin; D014409:Tumor Necrosis Factor-alpha; D011972:Receptor, Insulin