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  2. Melanocortin 3 receptor activation with [D-Trp8]-γ-MSH suppresses inflammation in apolipoprotein E deficient mice

Melanocortin 3 receptor activation with [D-Trp8]-γ-MSH suppresses inflammation in apolipoprotein E deficient mice

  • Eur J Pharmacol. 2020 Aug 5;880:173186. doi: 10.1016/j.ejphar.2020.173186.
James J Kadiri 1 Keshav Thapa 1 Katja Kaipio 2 Minying Cai 3 Victor J Hruby 3 Petteri Rinne 4
Affiliations

Affiliations

  • 1 Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Finland; Turku Center for Disease Modeling, University of Turku, Turku, Finland.
  • 2 Department of Pathology, University of Turku, Turku, Finland.
  • 3 Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA.
  • 4 Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Finland; Turku Center for Disease Modeling, University of Turku, Turku, Finland. Electronic address: pperin@utu.fi.
Abstract

The melanocortin MC1 and MC3 receptors elicit anti-inflammatory actions in leukocytes and activation of these receptors has been shown to alleviate arterial inflammation in experimental atherosclerosis. Thus, we aimed to investigate whether selective targeting of melanocortin MC3 receptor protects against atherosclerosis. Apolipoprotein E deficient (ApoE-/-) mice were fed high-fat diet for 12 weeks and randomly assigned to receive either vehicle (n = 11) or the selective melanocortin MC3 receptor agonist [D-Trp(8)]-gamma-melanocyte-stimulating hormone ([D-Trp8]-γ-MSH; 15 μg/day, n = 10) for the last 4 weeks. Lesion size as well as macrophage and collagen content in the aortic root plaques were determined. Furthermore, leukocyte counts in the blood and aorta and cytokine mRNA expression levels in the spleen, liver and aorta were quantified. No effect was observed in the body weight development or plasma Cholesterol level between the two treatment groups. However, [D-Trp8]-γ-MSH treatment significantly reduced plasma levels of chemokine (C-C motif) ligands 2, 4 and 5. Likewise, cytokine and adhesion molecule expression levels were reduced in the spleen and liver of γ-MSH-treated mice, but not substantially in the aorta. In line with these findings, [D-Trp8]-γ-MSH treatment reduced leukocyte counts in the blood and aorta. Despite reduced inflammation, [D-Trp8]-γ-MSH did not change lesion size, macrophage content or collagen deposition of aortic root plaques. In conclusion, the findings indicate that selective activation of melanocortin MC3 receptor by [D-Trp8]-γ-MSH suppresses systemic and local inflammation and thereby also limits leukocyte accumulation in the aorta. However, the treatment was ineffective in reducing atherosclerotic plaque size.

Keywords

ApoE(-/-) mice; Atherosclerosis; Inflammation; Macrophage; Melanocortin; [D-Trp8]-γ-MSH.

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