Urotensin-II (UII) is a vasoactive peptide that promotes vascular smooth muscle cell proliferation and is involved in the pathogenesis of atherosclerosis, restenosis and vascular remodeling. In this study, effects of KR-36676 and KR-36996, a novel selective urotensin receptor (UT) antagonist, on smooth muscle cell proliferation was examined. UII-induced proliferation of human aortic smooth muscle cells (hAoSMCs), was found to be significantly inhibited by KR-36676 and KR-36996 (1, 10, and 100 nM) in dose-dependent manner. UII-induced proliferation of hAoSMCs cells was also inhibited by U0126, an ERK1/2 inhibitor, but not by SP600125 and SB202190, inhibitors of JNK and p38 MAPK, respectively. UII increased the phosphorylation of ERK1/2, but this increase was significantly inhibited by KR-36676 and KR-36996. In addition, the UII-induced proliferation was also inhibited by trolox, a scavenger of reactive oxygen species (ROS), while the UII-induced ROS was also decreased in response to KR-36676 and KR-36996 treatment. Moreover, in a carotid artery ligation mouse model, intimal thickening was dramatically suppressed by oral treatment with KR-36676 and KR-36996 (30 mg/kg). Taken together, KR-36676 and KR-36996 attenuated UII-induced proliferation of hAoSMCs cells, at least partially, through blocking ERK1/2 activation and ROS generation.
