Petteri Rinne1, Martina Rami2, Salla Nuutinen2, Donato Santovito2, Emiel P C van der Vorst2, Raquel Guillamat-Prats2, Leo-Pekka Lyytikäinen2, Emma Raitoharju2, Niku Oksala2, Larisa Ring2, Minying Cai2, Victor J Hruby2, Terho Lehtimäki2, Christian Weber2, Sabine Steffens2. 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 Surgery, Tampere University Hospital, Finland (N.O.); Department of Chemistry and Biochemistry, University of Arizona, Tucson (M.C., V.J.H.); and German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany (C.W., S.S.). pperin@utu.fi. 2. 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 Surgery, Tampere University Hospital, Finland (N.O.); Department of Chemistry and Biochemistry, University of Arizona, Tucson (M.C., V.J.H.); and German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany (C.W., S.S.).
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.
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.
Authors: Niku Oksala; Jenita Pärssinen; Ilkka Seppälä; Emma Raitoharju; Ivana Kholova; Kholova Ivana; Jussi Hernesniemi; Leo-Pekka Lyytikäinen; Mari Levula; Kari-Matti Mäkelä; Thanos Sioris; Mika Kähönen; Reijo Laaksonen; Vesa Hytönen; Terho Lehtimäki Journal: Circ Cardiovasc Genet Date: 2013-10-11
Authors: Robert S Rosenson; H Bryan Brewer; W Sean Davidson; Zahi A Fayad; Valentin Fuster; James Goldstein; Marc Hellerstein; Xian-Cheng Jiang; Michael C Phillips; Daniel J Rader; Alan T Remaley; George H Rothblat; Alan R Tall; Laurent Yvan-Charvet Journal: Circulation Date: 2012-04-17 Impact factor: 29.690
Authors: James J Kadiri; Sina Tadayon; Keshav Thapa; Anni Suominen; Maija Hollmén; Petteri Rinne Journal: Front Immunol Date: 2021-11-19 Impact factor: 7.561