Melanocortin 1 Receptor Deficiency Promotes Atherosclerosis in Apolipoprotein E Mice.

OBJECTIVE

The MC1-R (melanocortin 1 receptor) is expressed by monocytes and macrophages where it mediates anti-inflammatory actions. MC1-R also protects against macrophage foam cell formation primarily by promoting cholesterol efflux through the ABCA1 (ATP-binding cassette transporter subfamily A member 1) and ABCG1 (ATP-binding cassette transporter subfamily G member 1). In this study, we aimed to investigate whether global deficiency in MC1-R signaling affects the development of atherosclerosis.

APPROACH AND RESULTS

Apoe (apolipoprotein E deficient) mice were crossed with recessive yellow (Mc1r) mice carrying dysfunctional MC1-R and fed a high-fat diet to induce atherosclerosis. Apoe Mc1r mice developed significantly larger atherosclerotic lesions in the aortic sinus and in the whole aorta compared with Apoe controls. In terms of plaque composition, MC1-R deficiency was associated with less collagen and smooth muscle cells and increased necrotic core, indicative of more vulnerable lesions. These changes were accompanied by reduced and expression in the aorta. Furthermore, Apoe Mc1r mice showed a defect in bile acid metabolism that aggravated high-fat diet-induced hypercholesterolemia and hepatic lipid accumulation. Flow cytometric analysis of leukocyte profile revealed that dysfunctional MC1-R enhanced arterial accumulation of classical Ly6C monocytes and macrophages, effects that were evident in mice fed a normal chow diet but not under high-fat diet conditions. In support of enhanced arterial recruitment of Ly6C monocytes, these cells had increased expression of L-selectin and P-selectin glycoprotein ligand 1.

CONCLUSIONS

The present study highlights the importance of MC1-R in the development of atherosclerosis. Deficiency in MC1-R signaling exacerbates atherosclerosis by disturbing cholesterol handling and by increasing arterial monocyte accumulation.