CITED2通过调控IRS2介导的内皮胰岛素信号通路在糖尿病血管病变发生过程中的作用研究

Endothelial insulin signaling plays an important role in the pathogenesis of atherosclerosis which is a basic pathology of diabetic vascular diseases. Our group has identified CITED2 as a novel factor involving in the regulation of endothelial insulin signaling. The research article regarding previous CITED2 data has been published in Diabetes in which the applicant is listed as the first author. We successfully established a mouse model with endothelial-specific knockout of Cited2 gene. It was observed that CITED2 was significantly increased in vascular endothelial cells from both mouse models and patients with type 2 diabetes accompanying with insulin resistance. It was also found that ablation of CITED2 resulted in a significant enhancement of IRS2-mediated insulin/Akt signaling in mouse endothelial cells, in turn significantly potentiating the impacts of insulin on acceleration of cell proliferation and VEGF production as well as inhibition of VCAM-1 expression. These data imply that CITED2 increased in vascular endothelial cells of type 2 diabetes is capable of promoting atherosclerosis. So we are eager to get financial support from NSFC to elucidate the role and molecular mechanism of CITED2 in the pathogenesis of atherosclerosis in ApoE-/- mouse with endothelial-specific knockout of Cited2 gene.

内皮胰岛素信号通路在动脉粥样硬化（AS）发病过程中发挥重要作用，AS是糖尿病血管病变的重要病理基础。课题组发现了一个新的调控内皮胰岛素信号通路的因子-CITED2，有关CITED2前期的研究论文已经发表在《Diabetes》杂志上（申请人为第一作者）。课题组建立了Cited2基因在血管内皮细胞特异剔除的小鼠模型，后续研究发现，CITED2在伴有胰岛素抵抗的2型糖尿病病人和小鼠模型的血管内皮细胞中表达显著升高，CITED2缺失导致小鼠血管内皮细胞IRS2介导的胰岛素/Akt信号通路显著增强，胰岛素促细胞增殖、促VEGF表达以及抑制VCAM-1的作用显著增强，上述结果提示2型糖尿病血管内皮细胞中高表达的CITED2能够促进AS的发生，课题组期望得到国家自然科学基金的资助，以内皮Cited2基因特异剔除的ApoE-/-小鼠为研究对象，阐明CITED2在AS发生过程中的作用和分子机制。

内皮胰岛素抵抗能够促进动脉粥样硬化（AS）的发生，而胰岛素信号通路的激活则能够抑制AS的发生和进展，课题组在本项目中研究了一个新型血管内皮胰岛素信号通路调控因子-CITED2在AS发生中的作用。细胞水平的研究显示，Cited2基因缺失能够激活，而过表达则能够抑制血管内皮细胞Akt介导的胰岛素信号通路，这得益于CITED2对胰岛素受体底物2（IRS2）的负调控作用。荧光素酶分析显示过表达CITED2显著抑制HIF-2α对IRS2基因的转录激活，染色质免疫沉淀（ChIP）技术证实，CITED2敲除的内皮细胞中缺氧反应元件调节的IRS2启动子区上p300的结合率显著增加，提示CITED2直接参与了HIF-2α对IRS2基因的转录调控。动物模型层面上，剔除血管内皮细胞的Cited2基因能够显著抑制小鼠动脉粥样硬化的形成。本项目阐明了血管内皮细胞中一条新的信号通路CITED2-HIF2α/IRS2-Akt-eNOS在AS发生中的作用，为AS研究提供了新的分子机制，为开发治疗动脉粥样硬化心血管疾病提供了一个新型潜在的药物靶点-CITED2。受本项目资助，共发表SCI论文5篇（包括发表在《Nature Communications》1篇），培养2位硕士研究生和1位博士研究生毕业。