The role of melanocortin-1 and -3 receptors in inflammation and atherosclerosis

Kadiri James Jamal

The melanocortin system comprises the endogenous melanocortin peptides, adrenocorticotropic hormone (ACTH) and melanocyte-stimulating hormones (a-, ß- & ?-MSH) as well as their five cognate receptors (MC1R – MC5R). These peptides mediate multiple biological processes including skin pigmentation, energy homeostasis and inflammation. Melanocortins mediate anti-inflammatory actions by activating MC1R and MC3R, which are widely expressed in different white blood cells.

Cardiovascular diseases (CVDs) are the leading cause of death (31%) in the world. Atherosclerosis accounts for the primary cause of most CVDs. Atherosclerosis is a chronic inflammatory disease caused by the build-up of lipids and white blood cells in blood vessel walls, which leads to the development of atherosclerotic plaques. Eventually, acute complications such as stroke and myocardial infarction may develop.

The primary aim of this thesis was to investigate the specific roles of MC1R and MC3R in experimental atherosclerosis since these receptors mediate anti-inflammatory processes.

To address this objective, the contribution of MC1R to the development of atherosclerosis was investigated in atherosclerotic (Apoe-/-) mice. In these Apoe-/- mice, MC1R function was silenced to better understand its role in the development of atherosclerosis. Remarkably, the lack of MC1R function in these mice accelerated the development of atherosclerosis. The atherosclerotic plaques in these mice were found to accommodate a larger number of white blood cells and less plaque-stabilizing smooth muscle cells and collagen. In addition, the absence of functional MC1R protein in these mice disturbed cholesterol handling, thereby increasing cholesterol concentration in the blood and escalating the propensity of plaque expansion within the artery.

Secondly, we found that when MC1R protein was deactivated specifically on white blood cells of atherosclerotic (Apoe-/-) mice, it resulted in an increased count of white blood cells, particularly the CD4 T-cell subtype in the spleen and blood. Thirdly, the therapeutic potential of the MC3R in atherosclerosis was explored in Apoe-/- mice. The treatment of these mice with melanocortin peptide, which activates MC3R, reduced white blood cell counts in the blood and aorta, thus suppressing inflammation.

In conclusion, this thesis work advances our understanding of the significant roles of MC1R and MC3R in regulating cholesterol, inflammatory responses and white blood cell behavior in the context of experimental atherosclerosis.

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