Endothelial GPR124 Exaggerates the Pathogenesis of Atherosclerosis by Activating Inflammation.
Endothelial GPR124 Exaggerates the Pathogenesis of Atherosclerosis by Activating Inflammation.
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内皮 GPR124 通过激活炎症加剧动脉粥样硬化的发病机制
DOI：
10.1159/000487032
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Lu YM
中科院分区：
文献类型：
--
作者：
Gong DM;Zhang YL;Chen DY;Hong LJ;Han F;Liu QB;Jiang JJ;Lu YM
背景/目的：内皮细胞功能障碍是动脉粥样硬化性心血管疾病的主要病理过程。G蛋白偶联受体124 （GPR124）是粘附GPCR亚家族中的孤儿受体，可促进脑血管生成。在本研究中，我们探讨了内皮细胞GPR124在成年小鼠动脉粥样硬化发生和进展中的作用。方法：利用四环素诱导的转基因系统，在Tie-2启动子的控制下，产生特异性表达GPR124的小鼠。将AAV-PCSK9DY静脉注射四环素调节小鼠，连续16周喂高脂饮食，建立动脉粥样硬化动物模型。采用生化分析和免疫组织化学方法探讨GPR124在动脉粥样硬化病理过程中的作用及机制。结果：GPR124过表达的动脉粥样硬化小鼠血清TC（总胆固醇）和LDL-C（低密度脂蛋白胆固醇）水平升高，主动脉窦脂质沉积增加，与平滑肌细胞增殖增加一致。我们利用免疫荧光法观察到该模型主动脉窦ONOO-水平升高，实验表明内皮中特异性过表达GPR124可诱导主动脉窦内CD68、NLRP3和caspase-1水平上调。结论：调控内皮中GPR124可能有助于延缓动脉粥样硬化的病理进展。
Background/Aims: Endothelial cell dysfunction is the principal pathological process underlying atherosclerotic cardiovascular disease. G protein-coupled receptor 124 (GPR124), an orphan receptor in the adhesion GPCR subfamily, promotes angiogenesis in the brain. In the present study, we explored the role of endothelial GPR124 in the development and progression of atherosclerosis in adult mice. Methods: Using tetracycline-inducible transgenic systems, we generated mice expressing GPR124 specifically under control of the Tie-2 promoter. The animal model of atherosclerosis was constructed by intravenously injecting AAV-PCSK9DY into tetracycline-regulated mice and feeding the mice a high-fat diet for 16 consecutive weeks. Biochemical analysis and immunohistochemistry methods were used to address the role and mechanism of GPR124 in the pathological process of atherosclerosis. Results: Higher TC (total cholesterol) and LDL-C (low density lipoprotein cholesterol) levels in serum and greater lipid deposition in the aortic sinus were found in atherosclerotic mice with GPR124 overexpression, coincident with the elevated proliferation of smooth muscle cells. We observed an elevation of ONOO- in the aortic sinus in this model by using immunofluorescence, and the experiments showed that the specific overexpression of GPR124 in the endothelium induced the up-regulation of CD68, NLRP3 and caspase-1 levels in the aortic sinus. Conclusion: The above results indicate that manipulating GPR124 in the endothelium may contribute to delayed pathological progression of atherosclerosis.