Biomol Ther.  2016 Sep;24(5):523-528. 10.4062/biomolther.2015.142.

Blockade of Urotensin II Receptor Prevents Vascular Dysfunction

• Kim YA
• Lee DG
• Yi KY
• Lee BH
• Jung YS

• KMID: 2351677
• DOI: http://doi.org/10.4062/biomolther.2015.142

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.

Keyword

Urotensin II; Urotensin II receptor antagonist; KR-36676; ERK; Smooth muscle; Proliferation

MeSH Terms

Animals
Aorta
Carotid Arteries
Cell Proliferation
Humans
Ligation
Mice
Muscle, Smooth
Muscle, Smooth, Vascular
Neointima
Phosphorylation
Rats
Vasoconstriction