Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells
Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells
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胰岛素下调转录核心调节因子 CITED2（内皮细胞中促血管生成功能的抑制剂）
DOI：
10.2337/db16-0001
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发表时间：
2016-12-01
期刊：
影响因子：
7.7
通讯作者：
Rask-Madsen, Christian
中科院分区：
文献类型：
--
作者：
Wang, Xuanchun;Lockhart, Samuel M.;Rask-Madsen, Christian
在患有糖尿病动脉粥样硬化并发症的患者中，心肌和下肢中缺血组织的受损的新血管形成限制了这些组织补偿不良灌注的能力。我们确定了10个新的胰岛素调节基因，其中包括Adm、Cited 2和Ctgf，这些基因在内皮细胞中通过FoxO 1被胰岛素下调。CBP/p300-interacting transactivator with ED-rich tail 2（CITED 2）是缺氧诱导因子（HIF）的重要负调控因子，胰岛素可使其下调达54%。与血管胰岛素作用受损一致，饮食诱导的肥胖小鼠和db/db小鼠的心脏内皮细胞中CITED 2增加，2型糖尿病患者的动脉组织中CITED 2比对照组高3.8倍。CITED 2敲低促进内皮管形成和内皮细胞增殖，而CITED 2过表达在体外损害HIF活性。股动脉结扎后，诱导内皮特异性HIF靶基因在后肢肌肉中显着上调与内皮细胞缺失的CITED 2，表明CITED 2可以限制HIF活性在体内的小鼠。我们的结论是，2型糖尿病的血管胰岛素抵抗有助于CITED 2的上调，从而损害HIF信号传导和内皮促血管生成功能。
In patients with atherosclerotic complications of diabetes, impaired neovascularization of ischemic tissue in the myocardium and lower limb limits the ability of these tissues to compensate for poor perfusion. We identified 10 novel insulin-regulated genes, among themAdm,Cited2, andCtgf, which were downregulated in endothelial cells by insulin through FoxO1. CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2), which was downregulated by insulin by up to 54%, is an important negative regulator of hypoxia-inducible factor (HIF) and impaired HIF signaling is a key mechanism underlying the impairment of angiogenesis in diabetes. Consistent with impairment of vascular insulin action, CITED2 was increased in cardiac endothelial cells from mice with diet-induced obesity and fromdb/dbmice and was 3.8-fold higher in arterial tissue from patients with type 2 diabetes than control subjects without diabetes. CITED2 knockdown promoted endothelial tube formation and endothelial cell proliferation, whereas CITED2 overexpression impaired HIF activity in vitro. After femoral artery ligation, induction of an endothelial-specific HIF target gene in hind limb muscle was markedly upregulated in mice with endothelial cell deletion of CITED2, suggesting that CITED2 can limit HIF activity in vivo. We conclude that vascular insulin resistance in type 2 diabetes contributes to the upregulation of CITED2, which impairs HIF signaling and endothelial proangiogenic function.