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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-\u03b1. Overexpression of TNF-\u03b1 in heart mimicked impaired insulin signaling and cardiac dysfunction leading to HF observed after MI. Treatment of rats with a specific TNF-\u03b1 inhibitor improved myocardial insulin signaling post-MI. Insulin treatment given immediately following MI suppressed myocardial TNF-\u03b1 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-\u03b1 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.<\/jats:p>","DOI":"10.1038\/srep17927","type":"journal-article","created":{"date-parts":[[2015,12,14]],"date-time":"2015-12-14T10:16:19Z","timestamp":1450088179000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Direct Evidence that Myocardial Insulin Resistance following Myocardial Ischemia Contributes to Post-Ischemic Heart Failure"],"prefix":"10.1038","volume":"5","author":[{"given":"Feng","family":"Fu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengfeng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weidong","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haifeng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haichang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J","family":"Quon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,12,14]]},"reference":[{"key":"BFsrep17927_CR1","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/0002-9149(74)90089-7","volume":"34","author":"WB Kannel","year":"1974","unstructured":"Kannel, W. 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