Adiponectin induces vascular smooth muscle cell differentiation via repression of mammalian target of rapamycin complex 1 and FoxO4.
Adiponectin induces vascular smooth muscle cell differentiation via repression of mammalian target of rapamycin complex 1 and FoxO4.
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DOI：
10.1161/atvbaha.110.216804
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发表时间：
2011-06
期刊：
影响因子：
--
通讯作者：
Martin KA
中科院分区：
文献类型：
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作者：
Ding M;Xie Y;Wagner RJ;Jin Y;Carrao AC;Liu LS;Guzman AK;Powell RJ;Hwa J;Rzucidlo EM;Martin KA
脂肪细胞分泌的激素脂联素发挥重要的心脏保护和抗糖尿病作用。关于其对血管平滑肌细胞（VSMC）的作用知之甚少，VSMC是再狭窄、高血压和动脉粥样硬化的关键细胞。使用人冠状动脉VSMC，我们报告了重组脂联素在HMW或三聚体，但不是球状形式诱导VSMC分化通过一种类似于经典的反馈信号雷帕霉素，一种药物，已知有效地抑制药物洗脱支架（DES）再狭窄的机制。使用药理学试剂、siRNA和过表达方法的组合，我们证明脂联素激活5′ AMP活化蛋白激酶（AMPKα2），导致抑制哺乳动物雷帕霉素复合物1靶蛋白（mTORC 1）和S6 K1。这反过来又稳定IRS-1，驱动Akt 2介导的FoxO 4抑制和随后的收缩蛋白诱导。虽然脂联素和雷帕霉素在细胞和器官培养中对VSMC表型具有类似的有益作用，但雷帕霉素与脂联素对内皮细胞（EC）的作用的直接比较揭示了明显的差异：雷帕霉素抑制Akt磷酸化，而脂联素维持Akt磷酸化。重要的是，Akt活性保持内皮功能。脂联素促进VSMC分化并保留EC Akt信号传导，这表明在开发新的DES疗法中，靶向脂联素途径可能比雷帕霉素具有优势。
The adipocyte-secreted hormone adiponectin exerts important cardioprotective and anti-diabetic effects. Little is known about its effect on vascular smooth muscle cells (VSMC), key cells in restenosis, hypertension, and atherosclerosis. Using human coronary artery VSMC, we report that recombinant adiponectin in the HMW or trimeric, but not globular forms induces VSMC differentiation through a mechanism similar to the classic feedback signaling employed by rapamycin, a drug known to effectively inhibit restenosis on drug-eluting stents (DES). Using a combination of pharmacologic agents, siRNA, and overexpression approaches, we demonstrate that adiponectin activates 5′ AMP-activated protein kinase (AMPKα2), leading to inhibition of mammalian target of rapamycin complex 1 (mTORC1) and S6K1. This in turn stabilizes IRS-1, driving Akt2 -mediated inhibition of FoxO4 and subsequent contractile protein induction. While adiponectin and rapamycin have similarly beneficial effects on VSMC phenotype in both cell and organ culture, a direct comparison of the effects of rapamycin versus adiponectin on endothelial cells (EC) revealed distinct differences: rapamycin inhibited, while adiponectin maintained, Akt phosphorylation. Importantly, Akt activity preserves endothelial function. Adiponectin promotes VSMC differentiation and preserves EC Akt signaling, suggesting that targeting the adiponectin pathway may have advantages over rapamycin in developing new DES therapeutics.