Melanocortin 1 Receptor Signaling Regulates Cholesterol Transport in Macrophages

Author:

Rinne Petteri1,Rami Martina1,Nuutinen Salla1,Santovito Donato1,van der Vorst Emiel P.C.1,Guillamat-Prats Raquel1,Lyytikäinen Leo-Pekka1,Raitoharju Emma1,Oksala Niku1,Ring Larisa1,Cai Minying1,Hruby Victor J.1,Lehtimäki Terho1,Weber Christian1,Steffens Sabine1

Affiliation:

1. From Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Germany (P.R., M.R., D.S., E.P.C.v.d.V., R.Q.-P., L.R., C.W., S.S.); Department of Pharmacology, Drug Development and Therapeutics, University of Turku and Turku University Hospital, Finland (P.R., S.N.); Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center, Tampere, Faculty of Medicine and Life Sciences, University of Tampere (L.-P.L., E.R., N.O., T.L.); Department of...

Abstract

Background: The melanocortin 1 receptor (MC1-R) is expressed by monocytes and macrophages, where it exerts anti-inflammatory actions on stimulation with its natural ligand α-melanocyte–stimulating hormone. The present study was designed to investigate the specific role of MC1-R in the context of atherosclerosis and possible regulatory pathways of MC1-R beyond anti-inflammation. Methods: Human and mouse atherosclerotic samples and primary mouse macrophages were used to study the regulatory functions of MC1-R. The impact of pharmacological MC1-R activation on atherosclerosis was assessed in apolipoprotein E–deficient mice. Results: Characterization of human and mouse atherosclerotic plaques revealed that MC1-R expression localizes in lesional macrophages and is significantly associated with the ATP-binding cassette transporters ABCA1 and ABCG1, which are responsible for initiating reverse cholesterol transport. Using bone marrow–derived macrophages, we observed that α-melanocyte–stimulating hormone and selective MC1-R agonists similarly promoted cholesterol efflux, which is a counterregulatory mechanism against foam cell formation. Mechanistically, MC1-R activation upregulated the levels of ABCA1 and ABCG1. These effects were accompanied by a reduction in cell surface CD36 expression and in cholesterol uptake, further protecting macrophages from excessive lipid accumulation. Conversely, macrophages deficient in functional MC1-R displayed a phenotype with impaired efflux and enhanced uptake of cholesterol. Pharmacological targeting of MC1-R in atherosclerotic apolipoprotein E–deficient mice reduced plasma cholesterol levels and aortic CD36 expression and increased plaque ABCG1 expression and signs of plaque stability. Conclusions: Our findings identify a novel role for MC1-R in macrophage cholesterol transport. Activation of MC1-R confers protection against macrophage foam cell formation through a dual mechanism: It prevents cholesterol uptake while concomitantly promoting ABCA1- and ABCG1-mediated reverse cholesterol transport.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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