GPR55 Antagonist CID16020046 Protects against Atherosclerosis Development in Mice by Inhibiting Monocyte Adhesion and Mac-1 Expression.

Seung-Jin Lee,Dong-Soon Im

doi:10.3390/ijms222313084

Seung-Jin Lee, Dong-Soon Im

Open Access

https://doi.org/10.3390/ijms222313084

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Abstract

GPR55 recognizes several lipid molecules such as lysophosphatidylinositol. GPR55 expression was reported in human monocytes. However, its role in monocyte adhesion and atherosclerosis development has not been studied. The role of GPR55 in monocyte adhesion and atherosclerosis development was investigated in human THP-1 monocytes and ApoE−/− mice using O-1602 (a potent agonist of GPR55) and CID16020046 (a specific GPR55 antagonist). O-1602 treatment significantly increased monocyte adhesion to human umbilical vein endothelial cells, and the O-1602-induced adhesion was inhibited by treatment with CID16020046. O-1602 induced the expression of Mac-1 adhesion molecules, whereas CID16020046 inhibited this induction. Analysis of the promoter region of Mac-1 elucidated the binding sites of AP-1 and NF-κB between nucleotides −750 and −503 as GPR55 responsive elements. O-1602 induction of Mac-1 was found to be dependent on the signaling components of GPR55, that is, Gq protein, Ca2+, CaMKK, and PI3K. In Apo−/− mice, administration of CID16020046 ameliorated high-fat diet-induced atherosclerosis development. These results suggest that high-fat diet-induced GPR55 activation leads to the adhesion of monocytes to endothelial cells via induction of Mac-1, and CID16020046 blockage of GPR55 could suppress monocyte adhesion to vascular endothelial cells through suppression of Mac-1 expression, leading to protection against the development of atherosclerosis.

Highlights

Atherosclerosis is a major contributor to cardiovascular diseases, including heart failure, myocardial infarction, stroke, and claudication [1,2]
We explored how GPR55 activation leads to monocyte adhesion to human umbilical vein endothelial cells (HUVEC)
We reported the following: (1) GPR55 activation by O-1602 induced monocyte adhesion to endothelial cells via macrophage-1 antigen (Mac-1) expression; (2) Mac-1 expression is regulated by binding of the transcription factors AP-1 and NF-κB to the nt −750 to −503 promoter region of Mac-1 in monocytes, (3) signaling cascades of GPR55 activation to

Summary

Introduction

Atherosclerosis is a major contributor to cardiovascular diseases, including heart failure, myocardial infarction, stroke, and claudication [1,2]. Monocyte adhesion to endothelium is an early event in atherosclerosis in blood vessels [3,4]. Adherent monocytes penetrate into the intima and differentiate into macrophages, which become foam cells by accumulating modified forms of low-density lipoproteins (LDL) [5]. Chronic inflammation caused by inflammatory stimuli, such as oxidized LDL (oxLDL), accelerates monocyte adhesion to endothelial cells [3,4,5]. Specific adhesion molecules on the surface of endothelial cells E-selectin) and monocytes (Mac-1, LFA1, VLA-4, and PSGL-1) mediate the initial loose contact and subsequent tight adhesion [6,7,8]. GPR55 is recognized as a receptor for lysophosphatidylinositols [9,10,11,12,13] and is known as an atypical cannabinoid receptor, because a range of endogenous, plant-derived, and synthetic cannabinoid ligands, such as 2-arachidonoylglycerol, palmitoylethanolamide,

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