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.
Highlights
Tumor necrosis factor-α (TNF-α ) is a pro-inflammatory cytokine that promotes ischemic myocardial injury and cardiac dysfunction[9]
We observed that myocardial insulin resistance occurred as early as 1 wk following surgically-induced myocardial infarction (MI) in rats, while systemic insulin sensitivity and glucose tolerance remained normal
Insulin treatment itself opposed myocardial insulin resistance caused by MI
Summary
Tumor necrosis factor-α (TNF-α ) is a pro-inflammatory cytokine that promotes ischemic myocardial injury and cardiac dysfunction[9]. TNF-α impairs insulin signaling and action, in part, by increasing serine phosphorylation of insulin receptor substrate-1 (IRS-1). Elevated local and/or circulating levels of TNF-α may contribute directly to myocardial insulin resistance. Our previous studies have demonstrated that insulin exerts cardioprotective effects via PI3K/Akt-dependent survival signaling pathways that promote metabolic, anti-apoptotic and anti-inflammatory actions in various animals, including canine model of myocardial ischemia/reperfusion[14,15,16]. Systemic insulin resistance (that likely includes myocardial insulin resistance) increases infarct size in ischemic hearts leading to reduced functional recovery. We developed a rodent model of MI to study the effects of local cardiac TNF-α overexpression (adenoviral) and blockade (etanercept), insulin treatment, and cardiac insulin receptor signaling with respect to post-MI heart structure/function and subsequent HF
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