Gong Dong-Mei, Zhang Yan-Li, Chen Dan-Yang, Hong Ling-Juan, Han Feng, Liu Qi-Bing, Jiang Jian-Jun, Lu Ying-Mei
School of Medicine, Zhejiang University City College, Hangzhou, China.
Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Cell Physiol Biochem. 2018;45(2):547-557. doi: 10.1159/000487032. Epub 2018 Jan 25.
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.
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.
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.
The above results indicate that manipulating GPR124 in the endothelium may contribute to delayed pathological progression of atherosclerosis.
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亚家族中的一种孤儿受体，可促进大脑中的血管生成。在本研究中，我们探讨了内皮GPR124在成年小鼠动脉粥样硬化发生发展中的作用。
利用四环素诱导转基因系统，我们构建了在Tie-2启动子控制下特异性表达GPR124的小鼠。通过向四环素调控的小鼠静脉注射AAV-PCSK9DY并连续16周喂食高脂饮食，构建动脉粥样硬化动物模型。采用生化分析和免疫组化方法探讨GPR124在动脉粥样硬化病理过程中的作用及机制。
GPR124过表达的动脉粥样硬化小鼠血清中总胆固醇（TC）和低密度脂蛋白胆固醇（LDL-C）水平较高，主动脉窦脂质沉积增加，同时平滑肌细胞增殖升高。通过免疫荧光观察到该模型主动脉窦中过氧亚硝酸盐（ONOO-）升高，实验表明内皮中GPR124的特异性过表达诱导主动脉窦中CD68、NLRP3和半胱天冬酶-1水平上调。
上述结果表明，调控内皮中的GPR124可能有助于延缓动脉粥样硬化的病理进展。
