Urotensin Ⅱ and urantide exert opposite effects on the cellular components of atherosclerotic plaque in hypercholesterolemic rabbits  

作　　者：Qing-qing Yu Da-xin Cheng Li-ran Xu Yan-kui Li Xiao-ya Zheng Yi Liu Ya-feng Li Hao-le Liu Liang Bai Rong Wang Jiang-lin Fan En-qi Liu Si-hai Zhao 

机构地区：[1]Research Institute of Atherosclerotic Disease,Xi’an Jiaotong University Cardiovascular Research Center,Xi’an 710061,China [2]Department of Vascular Surgery,Stanford University School of Medicine,Stanford 94305 CA,USA [3]Department of Molecular Pathology,Interdisciplinary Graduate School of Medicine,University of Yamanashi,Yamanashi 409-3898,Japan [4]Laboratory Animal Center,Health Science Center of Xi’an Jiaotong University,Xi’an 710061,China

出　　处：《Acta Pharmacologica Sinica》2020年第4期546-553,共8页中国药理学报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(81370379 and 30900526 to SHZ);the Natural Science Foundation of Shaanxi Province(2017BSHQYXMZZ18 to YFL,2012KJXX-07,2014JQ4137 to SHZ and 2014FWPT07 to EQL);the Fundamental Research Fund for the Central Universities(SHZ).

摘　　要：Increasing levels of plasma urotensin II(UII)are positively associated with atherosclerosis.In this study we investigated the role of macrophage-secreted UII in atherosclerosis progression,and evaluated the therapeutic value of urantide,a potent competitive UII receptor antagonist,in atherosclerosis treatment.Macrophage-speci?c human UII-transgenic rabbits and their nontransgenic littermates were fed a high cholesterol diet for 16 weeks to induce atherosclerosis.Immunohistochemical staining of the cellular components(macrophages and smooth muscle cells)of aortic atherosclerotic lesions revealed a signi?cant increase(52%)in the macrophage-positive area in only male transgenic rabbits compared with that in the nontransgenic littermates.However,both male and female transgenic rabbits showed a signi?cant decrease(45%in males and 31%in females)in the smooth muscle cell-positive area compared with that of their control littermates.The effects of macrophage-secreted UII on the plaque cellular components were independent of plasma lipid level.Meanwhile the wild-type rabbits were continuously subcutaneously infused with urantide(5.4μg·kg^?1·h^?1)using osmotic mini-pumps.Infusion of urantide exerted effects opposite to those caused by UII,as it signi?cantly decreased the macrophage-positive area in male wild-type rabbits compared with that of control rabbits.In cultured human umbilical vein endothelial cells,treatment with UII dose-dependently increased the expression of the adhesion molecules VCAM-1 and ICAM-1,and this effect was partially reversed by urantide.The current study provides direct evidence that macrophage-secreted UII plays a key role in atherogenesis.Targeting UII with urantide may promote plaque stability by decreasing macrophage-derived foam cell formation,which is an indicator of unstable plaque.

关 键 词：UROTENSIN II URANTIDE atherosclerosis PLAQUE MACROPHAGE 

分 类 号：R36[医药卫生—病理学]