Joslin Diabetes Center and Harvard Medical School, Boston, MA (T.R., B.K., C.T.C., X.W., S.M.L., J.C.P., Q.L., K.P., G.L.K., C.R.-M.).
Novo Nordisk A/S, Måløv, Denmark (T.R., H.W., G.S.O., G.K.P.).
Arterioscler Thromb Vasc Biol. 2022 Jul;42(7):e217-e227. doi: 10.1161/ATVBAHA.122.317476. Epub 2022 Jun 2.
An activated, proinflammatory endothelium is a key feature in the development of complications of obesity and type 2 diabetes and can be caused by insulin resistance in endothelial cells.
We analyzed primary human endothelial cells by RNA sequencing to discover novel insulin-regulated genes and used endothelial cell culture and animal models to characterize signaling through CXCR4 (C-X-C motif chemokine receptor 4) in endothelial cells.
CXCR4 was one of the genes most potently regulated by insulin, and this was mediated by PI3K (phosphatidylinositol 3-kinase), likely through FoxO1, which bound to the CXCR4 promoter. CXCR4 mRNA in CD31+ cells was 77% higher in mice with diet-induced obesity compared with lean controls and 37% higher in db/db mice than db/+ controls, consistent with upregulation of CXCR4 in endothelial cell insulin resistance. SDF-1 (stromal cell-derived factor-1)-the ligand for CXCR4-increased leukocyte adhesion to cultured endothelial cells. This effect was lost after deletion of CXCR4 by gene editing while 80% of the increase was prevented by treatment of endothelial cells with insulin. In vivo microscopy of mesenteric venules showed an increase in leukocyte rolling after intravenous injection of SDF-1, but most of this response was prevented in transgenic mice with endothelial overexpression of IRS-1 (insulin receptor substrate-1).
Endothelial cell insulin signaling limits leukocyte/endothelial cell interaction induced by SDF-1 through downregulation of CXCR4. Improving insulin signaling in endothelial cells or inhibiting endothelial CXCR4 may reduce immune cell recruitment to the vascular wall or tissue parenchyma in insulin resistance and thereby help prevent several vascular complications.
激活的、促炎的内皮细胞是肥胖和 2 型糖尿病并发症发展的一个关键特征，并且可能是由内皮细胞的胰岛素抵抗引起的。
我们通过 RNA 测序分析了原代人内皮细胞，以发现新的胰岛素调节基因，并使用内皮细胞培养和动物模型来描述内皮细胞中 CXCR4（C-X-C 基序趋化因子受体 4）的信号转导。
CXCR4 是受胰岛素调节最强烈的基因之一，这是通过 PI3K（磷脂酰肌醇 3-激酶）介导的，可能是通过 FoxO1 介导的，FoxO1 结合到 CXCR4 启动子上。与瘦对照组相比，饮食诱导肥胖的小鼠中 CD31+细胞中的 CXCR4 mRNA 高 77%，与 db/db 对照组相比，db/db 小鼠中的 CXCR4 mRNA 高 37%，这与内皮细胞胰岛素抵抗中 CXCR4 的上调一致。CXCR4 的配体 SDF-1（基质细胞衍生因子-1）增加了培养的内皮细胞上白细胞的黏附。通过基因编辑删除 CXCR4 后，这种作用消失，而内皮细胞用胰岛素处理后，这种作用增加了 80%。肠系膜静脉的体内显微镜检查显示，静脉内注射 SDF-1 后白细胞滚动增加，但在过表达胰岛素受体底物-1（IRS-1）的内皮细胞转基因小鼠中，这种反应大部分被阻止。
内皮细胞胰岛素信号通过下调 CXCR4 来限制 SDF-1 诱导的白细胞/内皮细胞相互作用。改善内皮细胞的胰岛素信号或抑制内皮 CXCR4 可能会减少免疫细胞在胰岛素抵抗时向血管壁或组织实质的募集，从而有助于预防几种血管并发症。
