Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
Sci Transl Med. 2024 Sep 4;16(763):eadn1507. doi: 10.1126/scitranslmed.adn1507.
Diabetic vascular disease is a major complication of diabetes mellitus (DM). Chemokine C-C motif ligand 7 (CCL7) attracts macrophages and monocytes, amplifying inflammatory processes in the vasculature. We hypothesized a causal role for CCL7 in diabetic vasculopathy. CCL7 concentrations were higher in the plasma of patients with type 2 DM, as well as in supernatants from their endothelial progenitor cells (EPCs). High-glucose stimulation increased the secretion of CCL7 from human dermal microvascular endothelial cells (HDMECs) through the c-Fos and c-Jun signaling pathways. CCL7 inhibition using knockdown or neutralization antibody treatment reversed the high glucose-induced impaired tube formation and migration abilities of EPCs, human aortic endothelial cells, human coronary artery endothelial cells, and HDMECs. Administration of recombinant human CCL7 protein impaired tube formation and migration abilities by down-regulating the AKT-endothelial nitric oxide synthase and AKT/nuclear factor erythroid 2-related factor 2/heme oxygenase-1/vascular endothelial growth factor/stromal cell-derived factor-1 pathways and by up-regulating ERK/phosphorylated p65/interleukin-1β/interleukin-6/tumor necrosis factor-α pathways through CC chemokine receptor 3 in endothelial cells. knockout in streptozotocin-treated mice showed improved neovasculogenesis in ischemic limbs and accelerated wound repair, with increased circulating EPCs and capillary density. CCL7 antibody treatment in mice and high-fat diet-induced hyperglycemia mice showed improved neovasculogenesis in ischemic limbs and wound areas, accompanied by up-regulation of angiogenic proteins and down-regulation of inflammatory proteins. Endothelial cell-specific -knockout mice showed ameliorated diabetic vasculopathy in streptozotocin-induced DM. This study highlights the potential of CCL7 as a therapeutic target for diabetic vasculopathy.
糖尿病血管疾病是糖尿病（DM）的主要并发症。趋化因子 C-C 基序配体 7（CCL7）吸引巨噬细胞和单核细胞，放大血管中的炎症过程。我们假设 CCL7 在糖尿病血管病变中起因果作用。2 型糖尿病患者的血浆以及其内皮祖细胞（EPC）的上清液中 CCL7 浓度较高。高葡萄糖刺激通过 c-Fos 和 c-Jun 信号通路增加人真皮微血管内皮细胞（HDMEC）中 CCL7 的分泌。使用敲低或中和抗体治疗 CCL7 抑制可逆转高葡萄糖诱导的 EPC、人主动脉内皮细胞、人冠状动脉内皮细胞和 HDMEC 的管形成和迁移能力受损。重组人 CCL7 蛋白的给药通过下调 AKT-内皮型一氧化氮合酶和 AKT/核因子红细胞 2 相关因子 2/血红素加氧酶-1/血管内皮生长因子/基质细胞衍生因子-1 途径，并通过上调 ERK/磷酸化 p65/白细胞介素-1β/白细胞介素-6/肿瘤坏死因子-α 途径通过内皮细胞中的 CC 趋化因子受体 3 来损害管形成和迁移能力。在链脲佐菌素处理的小鼠中敲除 显示缺血肢体的新血管生成得到改善，伤口愈合加快，循环 EPC 和毛细血管密度增加。在 小鼠和高脂肪饮食诱导的高血糖小鼠中进行 CCL7 抗体治疗显示缺血肢体和伤口区域的新血管生成得到改善，并伴有血管生成蛋白的上调和炎症蛋白的下调。内皮细胞特异性 - 敲除小鼠显示出链脲佐菌素诱导的 DM 中糖尿病血管病变的改善。这项研究强调了 CCL7 作为糖尿病血管病变治疗靶点的潜力。
