Laboratory for Signal Transduction, Department of Biomedicine, Basel University Hospital, Hebelstrasse 20, CH 4031 Basel, Switzerland.
Cardiovasc Res. 2012 Mar 1;93(3):498-507. doi: 10.1093/cvr/cvs004. Epub 2012 Jan 10.
T-cadherin (T-cad) is a glycosylphosphatidylinositol-anchored cadherin family member. Experimental, clinical, and genomic studies suggest a role for T-cad in vascular disorders such as atherosclerosis and hypertension, which are associated with endothelial dysfunction and insulin resistance (InsRes). In endothelial cells (EC), T-cad and insulin activate similar signalling pathways [e.g. PI3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR)] and processes (e.g. angiogenesis). We hypothesize that T-cad is a regulatory component of insulin signalling in EC and therefore a determinant of the development of endothelial InsRes.
We investigated T-cad-dependent effects on insulin sensitivity using human EC stably transduced with respect to T-cad overexpression or T-cad silencing. Responsiveness to insulin was examined at the level of effectors of the insulin signalling cascade, EC nitric oxide synthase (eNOS) activation, and angiogenic behaviour. Overexpression and ligation of T-cad on EC attenuates insulin-dependent activation of the PI3K/Akt/mTOR signalling axis, eNOS, EC migration, and angiogenesis. Conversely, T-cad silencing enhances these actions of insulin. Attenuation of EC responsiveness to insulin results from T-cad-mediated chronic activation of the Akt/mTOR-dependent negative feedback loop of the insulin cascade and enhanced degradation of the insulin receptor (IR) substrate. Co-immunoprecipitation experiments revealed an association between T-cad and IR. Filipin abrogated inhibitory effects of T-cad on insulin signalling, demonstrating localization of T-cad-insulin cross-talk to lipid raft plasma membrane domains. Hyperinsulinaemia up-regulates T-cad mRNA and protein levels in EC.
T-cad expression modulates signalling and functional responses of EC to insulin. We have identified a novel signalling mechanism regulating insulin function in the endothelium and attribute a role for T-cad up-regulation in the pathogenesis of endothelial InsRes.
T-钙黏蛋白（T-cad）是一种糖基磷脂酰肌醇锚定的钙黏蛋白家族成员。实验、临床和基因组研究表明，T-cad 在血管疾病（如动脉粥样硬化和高血压）中发挥作用，这些疾病与内皮功能障碍和胰岛素抵抗（InsRes）有关。在内皮细胞（EC）中，T-cad 和胰岛素激活相似的信号通路[例如，磷脂酰肌醇 3-激酶（PI3K）/Akt/哺乳动物雷帕霉素靶蛋白（mTOR）]和过程（例如，血管生成）。我们假设 T-cad 是 EC 中胰岛素信号的调节成分，因此是内皮细胞 InsRes 发展的决定因素。
我们使用稳定转染 T-cad 过表达或 T-cad 沉默的人 EC 研究了 T-cad 依赖性对胰岛素敏感性的影响。在胰岛素信号级联的效应物、EC 一氧化氮合酶（eNOS）激活和血管生成行为水平上检查了对胰岛素的反应性。T-cad 在 EC 上的过表达和连接会减弱胰岛素依赖性激活 PI3K/Akt/mTOR 信号轴、eNOS、EC 迁移和血管生成。相反，T-cad 沉默增强了胰岛素的这些作用。EC 对胰岛素反应性的减弱归因于 T-cad 介导的胰岛素级联 Akt/mTOR 依赖性负反馈回路的慢性激活和胰岛素受体（IR）底物的降解增强。共免疫沉淀实验显示 T-cad 与 IR 之间存在关联。Filipin 消除了 T-cad 对胰岛素信号的抑制作用，证明 T-cad-胰岛素相互作用定位于质膜脂筏区。高胰岛素血症上调 EC 中的 T-cad mRNA 和蛋白水平。
T-cad 表达调节 EC 对胰岛素的信号和功能反应。我们已经确定了一种新的信号机制来调节内皮细胞中的胰岛素功能，并将 T-cad 的上调归因于内皮细胞 InsRes 发病机制中的作用。
