Syndecan-4 shedding impairs macrovascular angiogenesis in diabetes mellitus
Syndecan-4 shedding impairs macrovascular angiogenesis in diabetes mellitus
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Syndecan-4 脱落损害糖尿病患者的大血管生成
DOI：
10.1016/j.bbrc.2016.03.112
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发表时间：
2016-05-20
影响因子：
3.1
通讯作者：
Xu, Biao
中科院分区：
文献类型：
--
作者：
Li, Ran;Xie, Jun;Xu, Biao
目的：多配体蛋白聚糖 - 4（synd4）是一种普遍存在的硫酸乙酰肝素蛋白聚糖细胞表面受体，可调节细胞增殖、迁移、机械转导和内吞作用。在急性炎症中，synd4的细胞外结构域大量脱落，但在慢性炎症（如糖尿病（DM））中，synd4的脱落情况仍不明确。我们研究了糖尿病中synd4在内皮细胞表达的变化，以及synd4信号受损对人脐静脉内皮细胞（HUVECs）、糖尿病大鼠、synd4基因敲除小鼠和db/db小鼠血管生成的影响。
材料与方法：将HUVECs与晚期糖基化终末产物（AGES）一起孵育。采用蛋白质免疫印迹分析（Western blot analysis）测定synd4蛋白表达，采用酶联免疫吸附试验（ELISA）检测可溶性synd4片段。通过免疫组织化学染色检测糖尿病大鼠主动脉内皮中synd4的浓度。进行主动脉环试验，研究糖尿病大鼠以及synd4基因敲除小鼠和db/db小鼠的血管生成过程。构建含有synd4基因或空载体的重组腺病毒，以增强db/db小鼠主动脉中synd4的表达。
结果：蛋白质免疫印迹分析显示，HUVECs中synd4细胞外结构域的表达降低，ELISA检测到培养基中synd4可溶性片段增加。糖尿病大鼠主动脉中synd4的内皮表达降低。主动脉环试验表明，synd4基因敲除小鼠和db/db小鼠的血管生成受损，而在db/db小鼠中过表达synd4可部分逆转这种情况。
结论：血管内皮细胞中synd4的脱落在糖尿病相关的血管生成受损中起重要作用。（C）2016爱思唯尔公司版权所有。
Purpose: Syndecan-4 (synd4) is a ubiquitous heparan sulfate proteoglycan cell surface receptor that modulates cell proliferation, migration, mechanotransduction, and endocytosis. The extracellular domain of synd4 sheds heavily in acute inflammation, but the shedding of synd4 in chronic inflammation, such as diabetes mellitus (DM), is still undefined. We investigated the alterations of synd4 endothelial expression in DM and the influence of impaired synd4 signaling on angiogenesis in human umbilical vein endothelial cells (HUVECs), diabetic rats, synd4 null mice, and db/db mice.Material and methods: HUVECs were incubated with advanced glycation end products (AGES). Western blot analysis was used to determine synd4 protein expression and ELISA was used to detect soluble synd4 fragments. The concentration of synd4 in the aortic endothelia of diabetic rats was detected by immunohistochemical staining. Aortic ring assays were performed to study the process of angiogenesis in the diabetic rats and in synd4 null and dbidb mice. Recombinant adenoviruses containing the synd4 gene or null were constructed to enhance synd4 aortic expression in dbidb mice.Results: Western blot analysis showed decreased expression of the synd4 extracellular domain in HUVECs, and ELISA detected increased soluble fragments of synd4 in the media. Synd4 endothelial expression in the aortas of diabetic rats was decreased. Aortic ring assay indicated impaired angiogenesis in synd4 null and dbidb mice, which was partially reversed by synd4 overexpression in db/db mice.Conclusion: Synd4 shedding from vascular endothelial cells played an important role in the diabetes related impairment of angiogenesis. (C) 2016 Elsevier Inc. All rights reserved.