Background and Purpose: GPR55 is a G protein-coupled receptor that
recognizes several lipid molecules. GPR55 expression in human monocytes
and its proinflammatory role lead us to investigate the role of GPR55 in
monocyte adhesion and atherosclerosis development. Experimental
Approach: We investigated monocyte adhesion in human THP-1 monocytes and
atherosclerosis development in ApoE-/- mice by using O-1602 (a potent
agonist of GPR55), CID16020046 (a specific GPR55 antagonist), and a
high-fat diet-induced atherosclerosis model. Key Results: In human THP-1
monocytes, treatment with O-1602 significantly increased monocyte
adhesion to human umbilical vein endothelial cells (HUVECs), 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. Furthermore, O-1602
induction of Mac-1 through AP-1 and NF-B was found to be dependent on
the signaling components of GPR55, that is, Gq protein, Ca2+, CaMKK, and
PI3K. In an in vivo study of high-fat diet-induced atherosclerosis in
ApoE-/- mice, administration of CID16020046 ameliorated atherosclerosis
development. These results suggest that high-fat diet-induced GPR55
activation leads to 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. Conclusions: This report suggests that GPR55 may be a
therapeutic target for atherosclerosis development.