高胰岛素血症通过增加血管生成素-2的表达和释放促进内皮炎症,Atherosclerosis

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高胰岛素血症通过增加血管生成素-2的表达和释放促进内皮炎症
Atherosclerosis ( IF 4.9 ) Pub Date : 2020-08-01 , DOI: 10.1016/j.atherosclerosis.2020.06.016
Shivam Chandel ₁ , Anuradha Sathis ₂ , Monalisa Dhar ₁ , Hemant Giri ₁ , Abel Arul Nathan ₁ , Sai Kiran Reddy Samawar ₁ , Akshari Gupta ₁ , Jayashree Gopal ₃ , Ranjani Harish ₂ , Viswanathan Mohan ₂ , Madhulika Dixit ₁

Affiliation

背景和目的血管生成素-2 (ANG-2) 介导内皮炎症以引发动脉粥样硬化和血管生成。在这里，我们确定了高胰岛素血症受试者中 ANG-2 的血清水平以及胰岛素是否会增加其表达和释放。方法从 D-CLIP 和 CURES 研究中招募健康男性受试者，根据他们的空腹胰岛素水平，将其分为正常胰岛素 (n = 228) 和高胰岛素 (n = 32)。通过ELISA估计血清蛋白。内皮炎症作为粘附在 HUVEC 单层上的 THP-1 单核细胞的数量进行评分。基因表达通过启动子报告基因检测和半定量 RT-PCR 确定。蛋白质印迹用于评估蛋白质表达和激活的变化。免疫荧光成像和 ChIP 测定分别用于核定位和启动子结合研究。结果高胰岛素血症受试者的 ANG-2 和 sTIE2 水平较高。高胰岛素血清引发内皮炎症，而 ANG-2 阻滞剂抗体可消除这种炎症。胰岛素 (100 nM) 增加了 ANG-2 的 mRNA 和蛋白质表达，以及它从 HUVEC 中的释放。它诱导 p38 MAPK 的激活和 cFOS 蛋白水平和核定位的增加。cFOS 与 -640 至 -494 启动子区域的结合介导了胰岛素依赖性 ANG-2 转录。p38 MAPK 抑制剂 (25 μM) 可阻断胰岛素诱导的 cFOS 核定位、ANG-2 和 ICAM-1 的表达以及 ANG-2 向培养基中的释放。从胰岛素处理过的细胞中收集的废培养基增强了内皮炎症，它在 ANG-2 敲低和 p38 MAPK 抑制后丢失。结论高胰岛素血症受试者的 ANG-2 水平较高，胰岛素通过 p38 MAPK-cFOS 途径诱导 HUVEC 表达和释放 ANG-2，从而引发内皮炎症。

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Hyperinsulinemia promotes endothelial inflammation via increased expression and release of Angiopoietin-2

BACKGROUND AND AIMS Angiopoietin-2 (ANG-2) mediates endothelial inflammation to initiate atherosclerosis and angiogenesis. Here we determined the serum levels of ANG-2 in hyperinsulinemic subjects and whether insulin increases its expression and release. METHODS Healthy male subjects were recruited from the D-CLIP and CURES studies and, based on their fasting insulin levels, were classified as normoinsulinemic (n = 228) and hyperinsulinemic (n = 32). Serum proteins were estimated by ELISA. Endothelial inflammation was scored as the number of THP-1 monocytes adhered to HUVEC monolayer. Gene expression was determined with promoter reporter assays and semi-quantitative RT-PCR. Western blotting was used to assess changes in protein expression and activation. Immunofluorescence imaging and ChIP assay were used for nuclear localization and promoter binding studies, respectively. RESULTS ANG-2 and sTIE2 levels were higher in hyperinsulinemic subjects. Hyperinsulinemic serum elicited endothelial inflammation, which was abrogated by an ANG-2 blocker antibody. Insulin (100 nM) increased mRNA and protein expression of ANG-2, and its release from HUVECs. It induced activation of p38 MAPK and an increase in protein levels and nuclear localization of cFOS. Binding of cFOS to the -640 to -494 promoter region mediated insulin dependent ANG-2 transcription. p38 MAPK inhibitor (25 μM) blocked insulin-induced nuclear localization of cFOS, expression of ANG-2 and ICAM-1, and release of ANG-2 into the culture medium. Spent medium collected from insulin treated cells enhanced endothelial inflammation, which was lost upon ANG-2 knockdown as well as upon p38 MAPK inhibition. CONCLUSIONS ANG-2 levels are high in hyperinsulinemic subjects and insulin induces expression and release of ANG-2 from HUVECs through p38 MAPK-cFOS pathway to elicit endothelial inflammation.

更新日期：2020-08-01

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