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http://dx.doi.org/10.4062/biomolther.2015.142

Blockade of Urotensin II Receptor Prevents Vascular Dysfunction  

Kim, Young-Ae (College of Pharmacy, Ajou University)
Lee, Dong Gil (College of Pharmacy, Ajou University)
Yi, Kyu Yang (Research Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology)
Lee, Byung Ho (Research Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology)
Jung, Yi-Sook (College of Pharmacy, Ajou University)
Publication Information
Biomolecules & Therapeutics / v.24, no.5, 2016 , pp. 523-528 More about this Journal
Abstract
Urotensin II (UII) is a potent vasoactive peptide and mitogenic agent to induce proliferation of various cells including vascular smooth muscle cells (VSMCs). In this study, we examined the effects of a novel UII receptor (UT) antagonist, KR-36676, on vasoconstriction of aorta and proliferation of aortic SMCs. In rat aorta, UII-induced vasoconstriction was significantly inhibited by KR-36676 in a concentration-dependent manner. In primary human aortic SMCs (hAoSMCs), UII-induced cell proliferation was significantly inhibited by KR-36676 in a concentration-dependent manner. In addition, KR-36676 decreased UII-induced phosphorylation of ERK, and UII-induced cell proliferation was also significantly inhibited by a known ERK inhibitor U0126. In mouse carotid ligation model, intimal thickening of carotid artery was dramatically suppressed by oral treatment with KR-36676 (30 mg/kg/day) for 4 weeks compared to vehicle-treated group. From these results, it is indicated that KR-36676 suppress UII-induced proliferation of VSMCs at least partially through inhibition of ERK activation, and that it also attenuates UII-induced vasoconstriction and vascular neointima formation. Our study suggest that KR-36676 may be an attractive candidate for the pharmacological management of vascular dysfunction.
Keywords
Urotensin II; Urotensin II receptor antagonist; KR-36676; ERK; Smooth muscle; Proliferation;
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