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.
Arterioscler Thromb Vasc Biol. 2014 Jul;34(7):1346-54. doi: 10.1161/ATVBAHA.113.302963. Epub 2014 May 1.
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.
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.
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.
已证实黑色素皮质素肽通过激活 1 型和 3 型黑色素皮质素受体发挥抗炎作用，并促进血管内皮功能。在此，我们探讨了黑色素皮质素的这些有利特性是否可以减少动脉粥样硬化斑块炎症并改善动脉粥样硬化小鼠的血管反应性。
表达仅载脂蛋白 B100 的低密度脂蛋白受体缺陷型小鼠接受高脂肪饮食 8 或 16 周，并接受载体或稳定的黑色素皮质素类似物黑素促黑激素 II（MT-II，0.3mg/kg/天，4 周）治疗。我们通过离体分析来确定氟-18 标记的氟脱氧葡萄糖的斑块摄取作为动脉粥样硬化斑块炎症和主动脉血管功能的替代标志物。MT-II 对动脉粥样硬化小鼠的体重或体重组成或血浆胆固醇水平没有影响。在不减轻动脉粥样硬化病变大小或病变中巨噬细胞积累的情况下，MT-II 治疗可减少动脉粥样硬化斑块中的氟-18 标记的氟脱氧葡萄糖摄取。MT-II 治疗小鼠的病变中常驻巨噬细胞向抗炎 M2 表型极化。MT-II 干预还减轻了全身炎症，这表现为促炎细胞因子的血浆水平降低。就主动脉血管反应性而言，与对照组相比，MT-II 治疗的小鼠表现出增强的内皮依赖性舒张作用，以及对一氧化氮介导的血管舒张的血管敏感性增强，而在长时间暴露于饮食后，对照组小鼠的这些作用明显受损。
本研究表明，黑色素皮质素系统的药理学激活在已建立的动脉粥样硬化中具有治疗益处，可限制斑块炎症并促进血管内皮功能，这可能为动脉粥样硬化提供一种新的治疗方法。
