Endothelial GPR124 Exaggerates the Pathogenesis of Atherosclerosis by Activating Inflammation

Abstract

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-PCSK9^DY 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.

Dare to Compare. Development of Atherosclerotic Lesions in Human, Mouse, and Zebrafish

“…One recent example is the use of PCSK9 DY -injections into mice expressing GPR124 under control of the Tie-2 promoter. Gong et al found that GPR124, a receptor known to increase angiogenesis in the brain, influences the pathogenesis of atherosclerosis by activating nitrosative stress and NLRP3 inflammasome signaling (50). Nevertheless, while PCSK9 DY itself is suitable to create atherosclerosis models user errors and gender-dependent susceptibility to PCSK9 DY could lead to great variations of study outcomes between laboratories (64,65).…”

MicroRNA-495 Ameliorates Cardiac Microvascular Endothelial Cell Injury and Inflammatory Reaction by Suppressing the NLRP3 Inflammasome Signaling Pathway

“…The repression of the NLRP3 inflammasome is a critical factor in I/R or inflammation by correlation with SIRT1, which was proved to be involved in both preventing cells from injury induced by various stress and improving endothelial precursor cell function [39,40]. Activating the NLRP3 inflammasome signaling can promote atherosclerosis pathogenesis via the overexpression of inducible endothelial-specific GPR124 [41]. In a previous study of ischemic acute kidney injury (AKI), the deficiency of NLRP3 served as a protective factor against mortality, renal dysfunction, and neutrophil influx of mice [42].…”

GPR124 facilitates pericyte polarization and migration by regulating the formation of filopodia during ischemic injury

“…Surprisingly, postnatal or adult GPR124 deletion does not affect BBB integrity 12. Recent studies have highlighted some essential yet long ignored roles played by GPR124 in various pathophysiological processes of cerebrocardiovascular diseases 12,13. For instance, GPR124 receptors are involved in the development of high blood pressure 14,15.…”