Cardiovascular Pharmacology

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

Authors: Qing-qing Yu1, Da-xin Cheng1, Li-ran Xu1, Yan-kui Li2, Xiao-ya Zheng2, Yi Liu1, Ya-feng Li1, Hao-le Liu1, Liang Bai1, Rong Wang1, Jiang-lin Fan3, En-qi Liu1,4, Si-hai Zhao1,2,4
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
Correspondence to: En-qi Liu: liuenqi@xjtu.edu.cn, Si-hai Zhao: sihaizhao@xjtu.edu.cn,
DOI: 10.1038/s41401-019-0315-8
Received: 3 May 2019
Accepted: 30 September 2019
Advance online: 4 November 2019

Abstract

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-specific 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 significant 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 significant 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 (5.4 µg· kg−1·h−1) using osmotic mini-pumps. Infusion of urantide exerted effects opposite to those caused by UII, as it significantly 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.
Keywords: urotensin II; urantide; atherosclerosis; plaque; macrophage

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