高半胱氨酸通过激活代谢型谷氨酸受体 5 损害血管内皮细胞的伤口愈合。
Homocysteine impairs endothelial wound healing by activating metabotropic glutamate receptor 5.
机构信息
Department of Biological Sciences, Idaho State University, Pocatello, Idaho 83209-8007, USA.
出版信息
Microcirculation. 2012 May;19(4):285-95. doi: 10.1111/j.1549-8719.2012.00159.x.
OBJECTIVE
Hcy is an independent risk factor for cerebrovascular disease and cognitive impairment. The purpose of this study was to elucidate the role of mGluR5 in Hcy-mediated impairment of cerebral endothelial wound repair.
METHODS
Mouse CMVECs (bEnd.3) were used in conjunction with directed pharmacology and shRNA. AutoDock was used to simulate the docking of ligand-receptor interactions.
RESULTS
Hcy (20 μM) significantly increased Cx43-pS368 by mGluR5- and PKC-dependent mechanisms. Hcy attenuated wound repair by an mGluR5-dependent mechanism over the six-day study period but did not alter cell proliferation in a proliferation assay, suggesting that the attenuation of wound repair may be due to dysfunctional migration in HHcy. Hcy increased the expression of Cx43 and Cx43-pS368 at the wound edge by activating mGluR5. Direct activation of mGluR5, using the specific agonist CHPG, was sufficient to reproduce the results whereas KO of mGluR5 with shRNA, or inhibition with MPEP, blocked the response to Hcy.
CONCLUSIONS
Inhibition of mGluR5 activation could be a novel strategy for promoting endothelial wound repair in patients with HHcy. Activation of mGluR5 may be a viable strategy for disrupting angiogenesis.
目的
同型半胱氨酸（Hcy）是脑血管病和认知障碍的独立危险因素。本研究旨在阐明代谢型谷氨酸受体 5（mGluR5）在 Hcy 介导的脑内皮细胞伤口修复损伤中的作用。
方法
采用小鼠 CMVECs（bEnd.3），结合定向药理学和 shRNA。AutoDock 用于模拟配体-受体相互作用的对接。
结果
Hcy（20 μM）通过 mGluR5 和 PKC 依赖性机制显著增加 Cx43-pS368。Hcy 通过 mGluR5 依赖性机制在为期六天的研究期间减弱伤口修复，但在增殖试验中不改变细胞增殖，表明伤口修复的减弱可能是由于 HHcy 中迁移功能障碍。Hcy 通过激活 mGluR5 增加伤口边缘处的 Cx43 和 Cx43-pS368 的表达。用特异性激动剂 CHPG 直接激活 mGluR5 足以复制结果，而用 shRNA 敲除 mGluR5 或用 MPEP 抑制则阻断了对 Hcy 的反应。
结论
抑制 mGluR5 激活可能是促进 HHcy 患者内皮伤口修复的一种新策略。激活 mGluR5 可能是破坏血管生成的可行策略。
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