Direct Evidence that Myocardial Insulin Resistance following Myocardial Ischemia Contributes to Post-Ischemic Heart Failure.
Direct Evidence that Myocardial Insulin Resistance following Myocardial Ischemia Contributes to Post-Ischemic Heart Failure.
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直接证据表明心肌缺血后的心肌胰岛素抵抗导致缺血后心力衰竭。
DOI：
10.1038/srep17927
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发表时间：
2015-12-14
影响因子：
4.6
通讯作者：
Gao F
中科院分区：
文献类型：
--
作者：
Fu F;Zhao K;Li J;Xu J;Zhang Y;Liu C;Yang W;Gao C;Li J;Zhang H;Li Y;Cui Q;Wang H;Tao L;Wang J;Quon MJ;Gao F
心力衰竭（HF）和全身胰岛素抵抗之间的密切联系已被充分证明，而心肌胰岛素抵抗及其与HF的关系尚未得到充分研究。本研究旨在探讨心肌胰岛素抵抗在缺血性心力衰竭中的作用及其机制。心肌梗死（MI）后4周，雄性Sprague-Dawley大鼠发生进行性左心室扩张伴功能障碍和HF。值得注意的是，心肌胰岛素敏感性早在MI后1周就降低，同时伴有心肌TNF-α产生增加。心脏中TNF-α的过度表达模拟了MI后观察到的导致HF的胰岛素信号传导受损和心功能不全。用特异性TNF-α抑制剂治疗大鼠可改善MI后心肌胰岛素信号传导。MI后立即给予胰岛素治疗可抑制心肌TNF-α的产生，改善心脏胰岛素敏感性，对抗心功能不全/重塑。此外，与对照组相比，他莫昔芬诱导的心肌细胞特异性胰岛素受体敲除小鼠表现出严重的缺血后心室重构和功能障碍。总之，MI诱导心肌胰岛素抵抗（无全身胰岛素抵抗），部分由缺血诱导的心肌TNF-α过度产生介导，并促进HF的发展。我们的研究结果强调了心肌胰岛素信号在缺血后HF保护中的直接和重要作用。
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.