ChemR23 prevents phenotypic switching of vascular smooth muscle cells into macrophage like foam cells in atherosclerosis.

In vitro, treatment of human aortic smooth muscle cells (HASMCs) with α-NETA, a small molecule inhibitor of ChemR23, increased synthetic gene expression but downregulated expression of TGFB, ABCA1, ABCG1 and SRB1. Further, α-NETA-treated HASMCs downregulated TGFB secretion, increased cholesterol uptake but decreased cholesterol efflux, and showed enhanced cell proliferation. Agonizing ChemR23 with its bona fide ligand chemerin 9 (C9) had no effect on synthetic gene expression but mitigated the effects of α-NETA on gene expression, cholesterol uptake, efflux, and cell proliferation.

In vivo, both α-NETA and C9 treatment of Apoe-/- mice over 4 weeks WD revealed therapeutic potential. C9 reduced general inflammatory burden while α-NETA promoted an atheroprotective M2 macrophage phenotype. Conclusions: These findings reveal a critical role of ChemR23 in regulating VSMC phenotype switching thereby affecting atherosclerosis and suggest ChemR23 as a therapeutic target to either modulate inflammation (C9) or macrophage polarization (α-NETA) in atherosclerotic disease.