Front Cardiovasc Med. 2026 Aug 7;13:1808833. doi: 10.3389/fcvm.2026.1808833. eCollection 2026.
ABSTRACT
BACKGROUND: Atherosclerotic plaque instability is a major determinant of acute cardiovascular events; however, reliable blood-based indicators reflecting plaque stability remain limited. Cholesin, a recently identified endogenous ligand of G protein-coupled receptor 146 (GPR146), has been implicated in cholesterol metabolism, but its potential relevance to human atherosclerosis and plaque stability remains largely unknown.
METHODS: We used real-time quantitative PCR (RT-qPCR) to measure Cholesin expression in peripheral blood mononuclear cells (PBMCs) from 60 participants, including patients with stable plaques, patients with unstable plaques, and controls. Public transcriptomic datasets (GSE100927, GSE28829, and GSE163154) were analyzed to characterize the expression patterns of Cholesin and GPR146 across plaque development and instability. Differential expression, co-expression, and functional enrichment analyses were performed. In vitro, THP-1 monocytes were stimulated with oxidized low-density lipoprotein (oxLDL), and the effects of GPR146 silencing on inflammatory responses were evaluated.
RESULTS: Cholesin mRNA expression in PBMCs was higher in patients with stable plaques than in those with unstable plaques. In contrast, Cholesin expression in plaque tissue was downregulated in atherosclerotic lesions compared with controls but did not differ significantly between disease stages or stable and unstable phenotypes. In the GSE28829 dataset, GPR146 expression was upregulated in advanced lesions, and in GSE163154, GPR146 expression was higher in unstable than in stable plaques. In THP-1 cells, oxLDL treatment increased GPR146 expression, whereas GPR146 silencing attenuated oxLDL-induced pro-inflammatory gene expression.
CONCLUSION: PBMC Cholesin mRNA was associated with plaque phenotype, whereas plaque-tissue Cholesin did not distinguish lesion stage or stability. In contrast, GPR146 expression was higher in advanced and vulnerable plaques, and GPR146 silencing attenuated oxLDL-induced pro-inflammatory gene expression in THP-1 monocytes. These findings identify GPR146 as a candidate molecule associated with plaque progression and instability, although its causal role requires further validation.
PMID:42630214 | PMC:PMC13493280 | DOI:10.3389/fcvm.2026.1808833