GPR182 promotes atherosclerosis via facilitating arterial lipid deposition

Elevated circulating low-density lipoprotein cholesterol (LDL-C) is a primary risk factor for atherosclerosis, but the molecular mechanisms driving lipid plaque formation within the artery wall remain poorly understood. This study identifies GPR182, a recently characterized lipoprotein receptor in the atypical chemokine receptor family, as a key mediator of lipid deposition in the aortic endothelium during atherosclerosis.

Genetic depletion of GPR182 protected against atherosclerosis across multiple mouse models without altering circulating cholesterol levels or immune cell recruitment to plaques. GPR182 is expressed by aortic endothelial cells (ECs) and is further upregulated during disease progression, and it mediates LDL uptake by aortic ECs both in vitro and in vivo.

Blockade of GPR182 with a monoclonal antibody reduced lipid uptake in the aorta and attenuated disease progression under hypercholesterolemic conditions. Collectively, the findings identify endothelial GPR182 as a critical regulator of aortic lipid deposition and atherosclerotic plaque formation and support GPR182 inhibition as a promising therapy for atherosclerotic cardiovascular disease.