Pharmacological activation of the melanocortin system limits plaque inflammation and ameliorates vascular dysfunction in atherosclerotic mice.
OBJECTIVE
Melanocortin peptides have been shown to elicit anti-inflammatory actions and to promote vascular endothelial function by activating type 1 and 3 melanocortin receptors. Here, we addressed whether these favorable properties of melanocortins could reduce atherosclerotic plaque inflammation and improve vasoreactivity in atherosclerotic mice.


RESULTS
Low-density lipoprotein receptor-deficient mice expressing only apolipoprotein B100 were fed a high-fat diet for 8 or 16 weeks and treated with either vehicle or a stable melanocortin analog, melanotan II (MT-II, 0.3 mg/kg per day, 4 weeks). We determined plaque uptake of fluorine-18-labeled fluorodeoxyglucose as a surrogate marker for atherosclerotic plaque inflammation and vascular function of the aorta by ex vivo analyses. MT-II had no effect on body weight or composition, or plasma cholesterol levels in atherosclerotic mice. Without attenuating atherosclerotic lesion size or lesional macrophage accumulation, MT-II treatment reduced fluorine-18-labeled fluorodeoxyglucose uptake in the atherosclerotic plaques. Resident macrophages in the lesions of MT-II-treated mice were polarized toward the anti-inflammatory M2 phenotype. Systemic inflammation was also attenuated by MT-II intervention as evidenced by decreased plasma levels of proinflammatory cytokines. In terms of aortic vasoreactivity, MT-II-treated mice showed enhanced endothelium-dependent relaxations, as well as promotion of vascular sensitivity to nitric oxide-mediated vasodilation, which were markedly impaired in control mice after prolonged duration of diet exposure.


CONCLUSIONS
The present study demonstrates that pharmacological activation of the melanocortin system has therapeutic benefits in pre-established atherosclerosis by limiting plaque inflammation and promoting vascular endothelial function, which may provide a novel therapeutic approach for atherosclerosis.
From the Department of Pharmacology, Drug Development and Therapeutics (P.R., H.S., E.K., S.N., E.S.), Turku Center for Disease Modeling (H.L., A.R., E.S.), Department of Forensic Medicine (P.S.), Turku Heart Center (A.S.), Turku PET Centre (P.R., J.M.U.S., S.H., M.S., H.L., J.K., A.S., A.R.), University of Turku, Turku, Finland; and Unit of Clinical Pharmacology (E.S.), Turku University Hospital, Turku, Finland. pperin@utu.fi.
Petteri
P
Rinne
From the Department of Pharmacology, Drug Development and Therapeutics (P.R., H.S., E.K., S.N., E.S.), Turku Center for Disease Modeling (H.L., A.R., E.S.), Department of Forensic Medicine (P.S.), Turku Heart Center (A.S.), Turku PET Centre (P.R., J.M.U.S., S.H., M.S., H.L., J.K., A.S., A.R.), University of Turku, Turku, Finland; and Unit of Clinical Pharmacology (E.S.), Turku University Hospital, Turku, Finland.
Johanna M U
JM
Silvola
From the Department of Pharmacology, Drug Development and Therapeutics (P.R., H.S., E.K., S.N., E.S.), Turku Center for Disease Modeling (H.L., A.R., E.S.), Department of Forensic Medicine (P.S.), Turku Heart Center (A.S.), Turku PET Centre (P.R., J.M.U.S., S.H., M.S., H.L., J.K., A.S., A.R.), University of Turku, Turku, Finland; and Unit of Clinical Pharmacology (E.S.), Turku University Hospital, Turku, Finland.
Sanna
S
Hellberg
From the Department of Pharmacology, Drug Development and Therapeutics (P.R., H.S., E.K., S.N., E.S.), Turku Center for Disease Modeling (H.L., A.R., E.S.), Department of Forensic Medicine (P.S.), Turku Heart Center (A.S.), Turku PET Centre (P.R., J.M.U.S., S.H., M.S., H.L., J.K., A.S., A.R.), University of Turku, Turku, Finland; and Unit of Clinical Pharmacology (E.S.), Turku University Hospital, Turku, Finland.
Mia
M
Ståhle
From the Department of Pharmacology, Drug Development and Therapeutics (P.R., H.S., E.K., S.N., E.S.), Turku Center for Disease Modeling (H.L., A.R., E.S.), Department of Forensic Medicine (P.S.), Turku Heart Center (A.S.), Turku PET Centre (P.R., J.M.U.S., S.H., M.S., H.L., J.K., A.S., A.R.), University of Turku, Turku, Finland; and Unit of Clinical Pharmacology (E.S.), Turku University Hospital, Turku, Finland.
Heidi
H
Liljenbäck
From the Department of Pharmacology, Drug Development and Therapeutics (P.R., H.S., E.K., S.N., E.S.), Turku Center for Disease Modeling (H.L., A.R., E.S.), Department of Forensic Medicine (P.S.), Turku Heart Center (A.S.), Turku PET Centre (P.R., J.M.U.S., S.H., M.S., H.L., J.K., A.S., A.R.), University of Turku, Turku, Finland; and Unit of Clinical Pharmacology (E.S.), Turku University Hospital, Turku, Finland.
Henriikka
H
Salomäki
From the Department of Pharmacology, Drug Development and Therapeutics (P.R., H.S., E.K., S.N., E.S.), Turku Center for Disease Modeling (H.L., A.R., E.S.), Department of Forensic Medicine (P.S.), Turku Heart Center (A.S.), Turku PET Centre (P.R., J.M.U.S., S.H., M.S., H.L., J.K., A.S., A.R.), University of Turku, Turku, Finland; and Unit of Clinical Pharmacology (E.S.), Turku University Hospital, Turku, Finland.
Emilia
E
Koskinen
From the Department of Pharmacology, Drug Development and Therapeutics (P.R., H.S., E.K., S.N., E.S.), Turku Center for Disease Modeling (H.L., A.R., E.S.), Department of Forensic Medicine (P.S.), Turku Heart Center (A.S.), Turku PET Centre (P.R., J.M.U.S., S.H., M.S., H.L., J.K., A.S., A.R.), University of Turku, Turku, Finland; and Unit of Clinical Pharmacology (E.S.), Turku University Hospital, Turku, Finland.
Salla
S
Nuutinen
From the Department of Pharmacology, Drug Development and Therapeutics (P.R., H.S., E.K., S.N., E.S.), Turku Center for Disease Modeling (H.L., A.R., E.S.), Department of Forensic Medicine (P.S.), Turku Heart Center (A.S.), Turku PET Centre (P.R., J.M.U.S., S.H., M.S., H.L., J.K., A.S., A.R.), University of Turku, Turku, Finland; and Unit of Clinical Pharmacology (E.S.), Turku University Hospital, Turku, Finland.
Pekka
P
Saukko
From the Department of Pharmacology, Drug Development and Therapeutics (P.R., H.S., E.K., S.N., E.S.), Turku Center for Disease Modeling (H.L., A.R., E.S.), Department of Forensic Medicine (P.S.), Turku Heart Center (A.S.), Turku PET Centre (P.R., J.M.U.S., S.H., M.S., H.L., J.K., A.S., A.R.), University of Turku, Turku, Finland; and Unit of Clinical Pharmacology (E.S.), Turku University Hospital, Turku, Finland.
Juhani
J
Knuuti
From the Department of Pharmacology, Drug Development and Therapeutics (P.R., H.S., E.K., S.N., E.S.), Turku Center for Disease Modeling (H.L., A.R., E.S.), Department of Forensic Medicine (P.S.), Turku Heart Center (A.S.), Turku PET Centre (P.R., J.M.U.S., S.H., M.S., H.L., J.K., A.S., A.R.), University of Turku, Turku, Finland; and Unit of Clinical Pharmacology (E.S.), Turku University Hospital, Turku, Finland.
Antti
A
Saraste
From the Department of Pharmacology, Drug Development and Therapeutics (P.R., H.S., E.K., S.N., E.S.), Turku Center for Disease Modeling (H.L., A.R., E.S.), Department of Forensic Medicine (P.S.), Turku Heart Center (A.S.), Turku PET Centre (P.R., J.M.U.S., S.H., M.S., H.L., J.K., A.S., A.R.), University of Turku, Turku, Finland; and Unit of Clinical Pharmacology (E.S.), Turku University Hospital, Turku, Finland.
Anne
A
Roivainen
From the Department of Pharmacology, Drug Development and Therapeutics (P.R., H.S., E.K., S.N., E.S.), Turku Center for Disease Modeling (H.L., A.R., E.S.), Department of Forensic Medicine (P.S.), Turku Heart Center (A.S.), Turku PET Centre (P.R., J.M.U.S., S.H., M.S., H.L., J.K., A.S., A.R.), University of Turku, Turku, Finland; and Unit of Clinical Pharmacology (E.S.), Turku University Hospital, Turku, Finland.
Eriika
E
Savontaus
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001011:Aorta / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood / Q000175:diagnosis / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D015415:Biomarkers / Q000097:blood; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D007249:Inflammation / Q000097:blood / Q000175:diagnosis / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000097:blood; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D011877:Radionuclide Imaging; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D044101:Receptors, Melanocortin / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D001055:Apolipoproteins B; D015415:Biomarkers; D018836:Inflammation Mediators; D008055:Lipids; D010456:Peptides, Cyclic; D011973:Receptors, LDL; D044101:Receptors, Melanocortin; D014665:Vasodilator Agents; C079282:melanotan-II; D000521:alpha-MSH
atherosclerosis; inflammation; melanocortins