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.
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Acknowledgements
This study was 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) and the Fundamental Research Fund for the Central Universities (SHZ). We thank HZ and HLC for their technical assistance.
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QQY, DXC, LRX, YL, YFL, HLL, YKL, XYZ, and SHZ performed the experiments and analyzed the data. SHZ, EQL, QQY, and JLF Fan designed this project, analyzed the data, and wrote the paper. LB and RW helped to analyze the data and performed some of the experiments. SHZ, EQL, and JLF supervised the experiments and revised the paper. All of the authors have read and approved the final paper.
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Yu, Qq., Cheng, Dx., Xu, Lr. et al. Urotensin II and urantide exert opposite effects on the cellular components of atherosclerotic plaque in hypercholesterolemic rabbits. Acta Pharmacol Sin 41, 546–553 (2020). https://doi.org/10.1038/s41401-019-0315-8
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DOI: https://doi.org/10.1038/s41401-019-0315-8
