Pulakat Lakshmi, Aroor Annayya R, Gul Rukhsana, Sowers James R
Department of Internal Medicine, School of Medicine, University of Missouri, Columbia, MO 65212, USA.
Exp Diabetes Res. 2012;2012:654904. doi: 10.1155/2012/654904. Epub 2011 Jul 31.
Cardiac insulin resistance is a metabolic and functional disorder that is often associated with obesity and/or the cardiorenal metabolic syndrome (CRS), and this disorder may be accentuated by chronic alcohol consumption. In conditions of over-nutrition, increased insulin (INS) and angiotensin II (Ang II) activate mammalian target for rapamycin (mTOR)/p70 S6 kinase (S6K1) signaling, whereas chronic alcohol consumption inhibits mTOR/S6K1 activation in cardiac tissue. Although excessive activation of mTOR/S6K1 induces cardiac INS resistance via serine phosphorylation of INS receptor substrates (IRS-1/2), it also renders cardioprotection via increased Ang II receptor 2 (AT2R) upregulation and adaptive hypertrophy. In the INS-resistant and hyperinsulinemic Zucker obese (ZO) rat, a rodent model for CRS, activation of mTOR/S6K1signaling in cardiac tissue is regulated by protective feed-back mechanisms involving mTOR↔AT2R signaling loop and profile changes of microRNA that target S6K1. Such regulation may play a role in attenuating progressive heart failure. Conversely, alcohol-mediated inhibition of mTOR/S6K1, down-regulation of INS receptor and growth-inhibitory mir-200 family, and upregulation of mir-212 that promotes fetal gene program may exacerbate CRS-related cardiomyopathy.
心脏胰岛素抵抗是一种代谢和功能紊乱，常与肥胖和/或心肾代谢综合征（CRS）相关，这种紊乱可能因长期饮酒而加剧。在营养过剩的情况下，胰岛素（INS）和血管紧张素II（Ang II）增加会激活哺乳动物雷帕霉素靶蛋白（mTOR）/p70核糖体蛋白S6激酶（S6K1）信号通路，而长期饮酒会抑制心脏组织中mTOR/S6K1的激活。虽然mTOR/S6K1的过度激活通过胰岛素受体底物（IRS-1/2）的丝氨酸磷酸化诱导心脏胰岛素抵抗，但它也通过增加血管紧张素II受体2（AT2R）的上调和适应性肥大提供心脏保护作用。在胰岛素抵抗和高胰岛素血症的Zucker肥胖（ZO）大鼠（一种CRS的啮齿动物模型）中，心脏组织中mTOR/S6K1信号通路的激活受涉及mTOR↔AT2R信号环和靶向S6K1的微小RNA谱变化的保护性反馈机制调节。这种调节可能在减轻进行性心力衰竭中起作用。相反，酒精介导的mTOR/S6K1抑制、胰岛素受体下调和生长抑制性mir-200家族以及促进胎儿基因程序的mir-212上调可能会加重CRS相关的心肌病。
