Resistin impairs insulin-evoked vasodilation
Resistin impairs insulin-evoked vasodilation
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DOI：
10.2337/db07-0557
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发表时间：
2008-03-01
期刊：
影响因子：
7.7
通讯作者：
Lembo, Giuseppe
中科院分区：
文献类型：
--
作者：
Gentile, Maria Teresa;Vecchione, Carmine;Lembo, Giuseppe
目的 - 由于血管功能障碍是肥胖受试者的一个主要特征，因此在本研究中，我们评估了抵抗素（一种最近发现的在肥胖中显着增加的激素）对血管的影响。 研究设计和方法 - 我们对年轻和年老 C57BL/6 小鼠的主动脉和肠系膜段以及培养的内皮细胞进行了分析。在体外和体内评估了抵抗素诱导的血管效应。通过免疫沉淀和蛋白质印迹进行分子分析。结果-重组鼠抵抗素不会引起基础血管张力或去氧肾上腺素诱导的血管收缩的变化。相比之下，体内和体外施用抵抗素均通过降低内皮一氧化氮合酶（eNOS）酶活性而显着损害剂量依赖性胰岛素诱发的血管舒张。抵抗素的这种作用对于胰岛素血管作用是选择性的，因为由增加剂量的乙酰胆碱或硝酸甘油引起的血管舒张不受激素的影响。内皮细胞的分子分析通过显示暴露于抵抗素后胰岛素诱发的 AKT 和 eNOS 磷酸化受损，进一步详细说明了抵抗素诱导的血管阻力。即使后一种异常也是胰岛素信号传导的选择性，因为 AKT/eNOS 磷酸化通常在乙酰胆碱刺激期间被激活。更重要的是，抵抗素诱导的内皮功能障碍取决于抵抗素改变胰岛素受体底物（IRS）-1酪氨酸/丝氨酸磷酸化的能力及其随后与磷脂酰肌醇3-激酶的相互作用。结论-我们的结果表明，抵抗素能够诱导选择性血管胰岛素抵抗，损害内皮IRS-1信号通路，从而导致eNOS激活和血管舒张。
OBJECTIVE-Since vascular dysfunction is a main trait of obese subjects, in the present study we evaluated the vascular impact of resistin, a recently discovered hormone markedly increased in obesity.RESEARCH DESIGN AND METHODS-We performed our analysis on aortic and mesenteric segments from young and old C57BL/6 mice and on cultured endothelial cells. Resistin-induced vascular effect was evaluated in vitro and in vivo. Molecular analyses were performed by immunoprecipitation and Western blotting.RESULTS-Recombinant murine resistin did not induce changes in either basal vascular tone or phenylephrine-induced vascular contraction. In contrast, both in vivo and in vitro administration of resistin significantly impaired dose-dependent insulin-evoked vasodilation by reducing endothelial nitric oxide synthase (eNOS) enzymatic activity. This effect of resistin was selective for insulin vascular action, since vasodilatation induced by increasing doses of acetylcholine or nitroglycerin was not influenced by the hormone. Molecular analysis of endothelial cells further detailed resistin-induced vascular resistance by showing impairment of insulin-evoked AKT and eNOS phosphorylations after exposure to resistin. Even this latter abnormality is selective of insulin signaling since AKT/eNOS phosphorylations are normally activated during acetylcholine stimulation. More important, the resistin-induced endothelial dysfunction depends on resistin's ability to alter insulin receptor substrate (IRS)-1 tyrosine/serine phosphorylation and its consequent interaction with phosphatidylinositol 3-kinase.CONCLUSIONS-Our results demonstrate that resistin is able to induce a selective vascular insulin resistance-impairing endothelial IRS-1 signaling pathway that leads to eNOS activation and vasodilation.