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Cardiac Insulin Resistance and MicroRNA Modulators

机译:心脏胰岛素抵抗和MicroRNA调节剂

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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.
机译:心脏胰岛素抵抗是一种代谢和功能性疾病,通常与肥胖症和/或心肾代谢综合征(CRS)有关,并且长期饮酒可能加剧这种疾病。在营养过度的情况下,增加的胰岛素(INS)和血管紧张素II(Ang II)会激活哺乳动物对雷帕霉素(mTOR)/ p70 S6激酶(S6K1)信号的靶标,而长期饮酒会抑制心脏组织中的mTOR / S6K1激活。尽管mTOR / S6K1的过度激活通过INS受体底物的丝氨酸磷酸化诱导心脏INS抵抗(IRS-1 / 2),但它也通过增加的Ang II受体2(AT2R)上调和适应性肥大来提供心脏保护作用。在INS耐药和高胰岛素的Zucker肥胖(ZO)大鼠中,CRS的啮齿动物模型是通过涉及mTOR↔AT2R信号回路和靶向S6K1的microRNA的分布变化的保护性反馈机制来调节心脏组织中mTOR / S6K1信号的激活。 。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,INS受体和生长抑制性mir-200家族的下调,以及促进胎儿基因程序的mir-212的上调,可能会加剧CRS相关的心肌病。

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