Loss of insulin signaling in vascular endothelial cells accelerates atherosclerosis in apolipoprotein E null mice.
Loss of insulin signaling in vascular endothelial cells accelerates atherosclerosis in apolipoprotein E null mice.
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DOI：
10.1016/j.cmet.2010.03.013
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发表时间：
2010-05-05
期刊：
影响因子：
29
通讯作者：
King GL
中科院分区：
文献类型：
--
作者：
Rask-Madsen C;Li Q;Freund B;Feather D;Abramov R;Wu IH;Chen K;Yamamoto-Hiraoka J;Goldenbogen J;Sotiropoulos KB;Clermont A;Geraldes P;Dall'Osso C;Wagers AJ;Huang PL;Rekhter M;Scalia R;Kahn CR;King GL
为了确定胰岛素对内皮细胞的作用是否促进或保护动脉粥样硬化，我们产生了载脂蛋白E缺失小鼠，其中胰岛素受体基因在血管内皮细胞中是完整的或有条件地缺失。胰岛素敏感性、葡萄糖耐量、血脂和血压在两组之间没有差异，但缺乏内皮胰岛素信号传导的小鼠动脉粥样硬化病变大小高出2倍以上。内皮依赖性血管舒张功能受损，内皮细胞VCAM-1表达增加。与对照组相比，体内单核细胞与内皮细胞的粘附增加了4倍，但通过VCAM-1阻断抗体降低至低于对照值。这些结果提供了明确的证据，即在没有竞争性全身危险因素的情况下，内皮细胞中胰岛素信号的丢失加速了动脉粥样硬化。因此，改善胰岛素抵抗或2型糖尿病患者内皮细胞的胰岛素敏感性可能会预防心血管并发症。
To determine whether insulin action on endothelial cells promotes or protects against atherosclerosis, we generated apolipoprotein E null mice in which the insulin receptor gene was intact or conditionally deleted in vascular endothelial cells. Insulin sensitivity, glucose tolerance, plasma lipids, and blood pressure were not different between the two groups, but atherosclerotic lesion size was more than 2-fold higher in mice lacking endothelial insulin signaling. Endothelium-dependent vasodilation was impaired and endothelial cell VCAM-1 expression was increased in these animals. Adhesion of mononuclear cells to endothelium in vivo was increased 4-fold compared with controls, but reduced to below control values by a VCAM-1 blocking antibody. These results provide definitive evidence that loss of insulin signaling in endothelium, in the absence of competing systemic risk factors, accelerates atherosclerosis. Therefore, improving insulin sensitivity in the endothelium of patients with insulin resistance or type 2 diabetes may prevent cardiovascular complications.
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