Introduction: The asialoglycoprotein receptor-1 (ASGR-1) is known to be a hepatic receptor that clears desialylated glycoproteins from the circulation. A loss-of-function mutation in ASGR-1 was reported to associate with a 34% reduction in coronary artery disease (CAD) risk, suggesting a role for ASGR-1 in CAD.

Hypothesis: ASGR-1 is an important player in atherosclerosis and deletion of ASGR-1 will reduce atherosclerotic plaque via athero-protective mechanisms in macrophages.

Methods and Results: Using immunofluorescence, we detected ASGR-1 in aortic sinus plaques from apolipoprotein (Apo)e-/- mice fed a high cholesterol diet (HCD)-fed apolipoprotein (Apo)e-/- mice. Bone marrow-derived macrophages (BMDMs) from Asgr1-/- mice elicited greater cholesterol efflux (39%, P<0.05) and decreased oxLDL uptake (15%, P<0.05), compared to wildtype BMDMs. Plasma from Asgr-1-/- mice had lower total cholesterol (25%, P<0.05) and LDL cholesterol (36%, P<0.05) concentrations than wildtype control mice. Apoe-/- x Asgr-1-/+ mice fed HCD for 8 weeks developed less plaque in the aortic sinus (32.75%, P<0.001) than Apoe-/- controls, and had fewer circulating neutrophils (38%, P<0.05). In the tandem stenosis model of unstable plaque, Apoe-/- x Asgr-1-/- mice also developed smaller plaques in their carotid arteries (49%, P<0.05), than Apoe-/- controls. Furthermore, ASGR-1 was measured in peripheral blood mononuclear cells (PBMCs) isolated from patient samples (n=10-12/group). ASGR-1 protein levels were higher in PBMCs from patients with coronary plaque (61%, P<0.05), than those without plaque, as determined from coronary angiograms.

Conclusions: ASGR-1 plays an important role in atherosclerosis. Deletion of ASGR-1 causes athero-protective effects in macrophages in vitro and reduced plaque burden in vivo. Elevated ASGR-1 levels in PBMCs from clinical blood samples was also associated with the presence of coronary plaque. These studies have significant implications for the potential of ASGR-1 as a therapeutic target for the prevention of atherosclerosis.