Research Center for Integrative Physiology and Pharmacologyand Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.
Unit of Clinical PharmacologyTurku University Hospital, Turku, Finland.
J Endocrinol. 2018 Mar;236(3):111-123. doi: 10.1530/JOE-17-0636. Epub 2018 Jan 9.
Atherosclerosis is a chronic inflammatory disease of the arteries. The disease is initiated by endothelial dysfunction that allows the transport of leukocytes and low-density lipoprotein into the vessel wall forming atherosclerotic plaques. The melanocortin system is an endogenous peptide system that regulates, for example, energy homeostasis and cardiovascular function. Melanocortin treatment with endogenous or synthetic melanocortin peptides reduces body weight, protects the endothelium and alleviates vascular inflammation, but the long-term effects of melanocortin system activation on atheroprogression remain largely unknown. In this study, we evaluated the effects of transgenic melanocortin overexpression in a mouse model of atherosclerosis. Low-density lipoprotein receptor-deficient mice overexpressing alpha- and gamma-MSH (MSH-OE) and their wild-type littermates were fed either a regular chow or Western-style diet for 16 weeks. During this time, their metabolic parameters were monitored. The aortae were collected for functional analysis, and the plaques in the aortic root and arch were characterised by histological and immunohistochemical stainings. The aortic expression of inflammatory mediators was determined by quantitative PCR. We found that transgenic MSH-OE improved glucose tolerance and limited atherosclerotic plaque formation particularly in Western diet-fed mice. In terms of aortic vasoreactivity, MSH-OE blunted alpha-adrenoceptor-mediated vasoconstriction and enhanced relaxation response to acetylcholine, indicating improved endothelial function. In addition, MSH-OE markedly attenuated Western diet-induced upregulation of proinflammatory cytokines (, and ) that contribute to the pathogenesis of atherosclerosis. These results show that the activation of the melanocortin system improves glucose homeostasis and limits diet-induced vascular inflammation and atherosclerotic plaque formation.
动脉粥样硬化是一种动脉的慢性炎症性疾病。该疾病由内皮功能障碍引发，内皮功能障碍使白细胞和低密度脂蛋白转运到血管壁，形成动脉粥样硬化斑块。黑皮质素系统是一种内源性肽系统，调节能量稳态和心血管功能等。用内源性或合成的黑皮质素肽进行黑皮质素治疗可降低体重、保护内皮并减轻血管炎症，但黑皮质素系统激活对动脉粥样硬化进展的长期影响在很大程度上仍不清楚。在这项研究中，我们评估了在动脉粥样硬化小鼠模型中转基因黑皮质素过表达的作用。过表达α-和γ-MSH（MSH-OE）的低密度脂蛋白受体缺陷型小鼠及其野生型同窝仔鼠分别用普通饲料或西式饮食喂养 16 周。在此期间，监测其代谢参数。收集主动脉用于功能分析，并通过组织学和免疫组织化学染色对主动脉根部和弓部的斑块进行特征描述。通过定量 PCR 确定主动脉中炎症介质的表达。我们发现，转基因 MSH-OE 改善了葡萄糖耐量，并特别限制了西式饮食喂养小鼠的动脉粥样硬化斑块形成。就主动脉血管反应性而言，MSH-OE 减弱了α-肾上腺素能受体介导的血管收缩，并增强了对乙酰胆碱的舒张反应，表明内皮功能得到改善。此外，MSH-OE 显著减弱了西式饮食诱导的促炎细胞因子（、和）的上调，这些细胞因子有助于动脉粥样硬化的发病机制。这些结果表明，黑皮质素系统的激活可改善葡萄糖稳态并限制饮食诱导的血管炎症和动脉粥样硬化斑块形成。
