Insulin signaling in endothelial cells (insulin receptor substrate) and atherosclerosis

我们以前证明，胰岛素受体底物（Irs）1敲除（KO）和Irs 2 KO小鼠表现出胰岛素抵抗，高血压和高胆固醇血症的程度相似。然而，Irs 2 KO小鼠对袖套损伤的反应比Irs 1 KO小鼠表现出更大的新生内膜形成。Irs 2主要在内皮细胞中表达。为了更精确地确定Irs 2在血管内皮细胞中的作用，我们产生了内皮细胞特异性Irs 2敲低（ETIrs 2KO）小鼠。ETIrs 2KO小鼠对胰岛素反应的内皮依赖性血管舒张功能显著受损。ETIrs 2KO小鼠也表现出轻度高血压和受损的胰岛素刺激的eNOS磷酸化。ETIrs 2KO小鼠具有生育能力和正常的代谢参数。有趣的是，在ETIrs 2KO小鼠中观察到胰岛素抵抗和葡萄糖耐受不良。在高胰岛素-正葡萄糖钳夹试验中，ETIrs 2KO小鼠的葡萄糖输注速率（GIR）和葡萄糖消失速率（Rd）显著低于野生型小鼠，而内源性葡萄糖产生（EGP）在ETIrs 2KO和野生型小鼠之间没有差异。这些数据表明ETIrs 2KO小鼠在骨骼肌中显示胰岛素抵抗。与此一致，ETIrs 2KO小鼠在高胰岛素-正葡萄糖钳夹后显示骨骼肌中胰岛素刺激的Akt磷酸化受损。ETIrs 2KO小鼠在高胰岛素-正葡萄糖钳夹后也显示骨骼肌血流量减少。这些数据表明，在ETIrs 2KO小鼠中观察到的骨骼肌胰岛素抵抗可能至少部分由骨骼肌血流量减少引起。为了阐明内皮细胞Irs 2在动脉粥样硬化中的作用，我们希望在将来检测ETIrs 2KO小鼠对袖状损伤的新生内膜形成反应。

We previously demonstrated that both insulin receptor substrate (Irs) 1 knockout (KO) and Irs2 KO mice showed insulin resistance, hypertension, and hypercholesterolemia to a similar degree. Irs2 KO mice, however, exhibited much greater neointimal formation in response to cuff-injury than Irs1 KO mice. Irs2 is mainly expressed in endothelial cells. To more precisely determine the roles of Irs2 in vascular endothelial cells, we generated endothelial cell-specific Irs2 knockdown (ETIrs2KO) mice. Endothelial-dependent vascular relaxation in response to insulin was significantly impaired in ETIrs2KO mice. ETIrs2KO mice also showed mild hypertension and impaired insulin-stimulated phosphorylation of eNOS. ETIrs2KO mice were fertile and normal metabolic parameter. Interestingly, insulin resistance and glucose intolerance were observed in ETIrs2KO mice. In hyperinsulinemic-euglycemic clamp, glucose infusion rate (GIR) and rate of glucose disappearance (Rd) were significantly lower in ETIrs2KO mice than wild-type mice, whereas endogenous glucose production (EGP) did not differ between ETIrs2KO and wild-type mice. These data indicate that ETIrs2KO mice showed insulin resistance in skeletal muscle. Consistent with this, ETIrs2KO mice showed impaired insulin-stimulated phosphorylation of Akt in skeletal muscle after hyperinsulinemic-euglycemic clamp. ETIrs2KO mice also showed decreased blood flow in skeletal muscle after hyperinsulinemic-euglycemic clamp. These data suggest that the skeletal muscle insulin resistance observed in the ETIrs2KO mice may, at least in part, be caused by the decrease in skeletal muscle blood flow. To clarify the role of Irs2 of endothelial cells in atherosclerosis, we would like to examine neointimal formation response to cuff-injury in ETIrs2KO mice in the future.