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The Transcriptional Co-Regulator CITED2 Suppresses Expression of IRS-2 and Impairs Insulin Signaling in Endothelial Cells
American Journal of Physiology-Endocrinology and Metabolism ( IF 5.1 ) Pub Date : 2021-06-21 , DOI: 10.1152/ajpendo.00435.2020
Britta Kunkemoeller 1 , Kuangyang Chen 2 , Sam M Lockhart 1 , Xuanchun Wang 2 , Christian Rask-Madsen 1
Affiliation  

Endothelial cell insulin resistance contributes to the development of vascular complications in diabetes. Hypoxia-inducible factors (HIF) modulate insulin sensitivity, and we have previously shown that a negative regulator of HIF activity, CBP/p300 interacting transactivator-2 (CITED2), is increased in the vasculature of people with type 2 diabetes. Therefore, we examined whether CITED2 regulates endothelial insulin sensitivity. In endothelial cells isolated from mice with a "floxed" mutation in the Cited2 gene, loss of CITED2 markedly enhanced insulin-stimulated Akt phosphorylation without altering ERK1/2 phosphorylation. Similarly, insulin-stimulated Akt phosphorylation was increased in aortas of mice with endothelial-specific deletion of CITED2. Consistent with these observations, loss of CITED2 in endothelial cells increased insulin-stimulated endothelial nitric oxide synthase phosphorylation, Vegfa expression, and cell proliferation. Endothelial cells lacking CITED2 exhibited an increase in insulin receptor substrate (IRS)-2 protein, a key mediator of the insulin signaling cascade, while IRS-1 was unchanged. Conversely, overexpression of CITED2 in endothelial cells decreased IRS-2 protein by 55% without altering IRS-1, resulting in impaired insulin-stimulated Akt phosphorylation and Vegfa expression. Overexpression of HIF-2α significantly increased activity of the Irs2 promoter and co-expression of CITED2 abolished this increase. Moreover, ChIP showed that loss of CITED2 increased occupancy of p300, a key component of the HIF transcriptional complex, on the Irs2 promoter. Together, these results show that CITED2 selectively inhibits endothelial insulin signaling and action through the PI3K/Akt pathway via repression of HIF-dependent IRS-2 expression. CITED2 is thus a promising target to improve endothelial insulin sensitivity and prevent the vascular complications of diabetes.

中文翻译:

转录共调节因子 CITED2 抑制 IRS-2 的表达并损害内皮细胞中的胰岛素信号传导

内皮细胞胰岛素抵抗有助于糖尿病血管并发症的发展。缺氧诱导因子 (HIF) 调节胰岛素敏感性,我们之前已经表明,HIF 活性的负调节因子 CBP/p300 相互作用的反式激活因子 2 (CITED2) 在 2 型糖尿病患者的脉管系统中增加。因此,我们检查了 CITED2 是否调节内皮胰岛素敏感性。在从具有 Cited2 基因“floxed”突变的小鼠中分离的内皮细胞中,CITED2 的缺失显着增强了胰岛素刺激的 Akt 磷酸化,而不会改变 ERK1/2 磷酸化。同样,内皮特异性 CITED2 缺失的小鼠主动脉中胰岛素刺激的 Akt 磷酸化增加。与这些观察一致,内皮细胞中 CITED2 的缺失增加了胰岛素刺激的内皮一氧化氮合酶磷酸化、Vegfa 表达和细胞增殖。缺乏 CITED2 的内皮细胞表现出胰岛素受体底物 (IRS)-2 蛋白的增加,这是胰岛素信号级联反应的关键介质,而 IRS-1 没有变化。相反,内皮细胞中 CITED2 的过表达使 IRS-2 蛋白降低 55%,而不改变 IRS-1,导致胰岛素刺激的 Akt 磷酸化和 Vegfa 表达受损。HIF-2α 的过表达显着增加了 Irs2 启动子的活性,而 CITED2 的共表达消除了这种增加。此外,ChIP 表明 CITED2 的缺失增加了 P300(HIF 转录复合物的关键成分)在 Irs2 启动子上的占有率。一起,这些结果表明,CITED2 通过抑制 HIF 依赖性 IRS-2 表达,通过 PI3K/Akt 途径选择性地抑制内皮胰岛素信号传导和作用。因此,CITED2 是改善内皮胰岛素敏感性和预防糖尿病血管并发症的有希望的靶点。
更新日期:2021-06-21
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