Urotensin II (UII) is a mitogenic and hypertrophic agent that can induce the proliferation of vascular cells. UII inhibition has been considered as beneficial strategy for
atherosclerosis and restenosis. However, currently there is no
therapeutics clinically available for
atherosclerosis or restenosis. In this study, we evaluated the effects of a newly synthesized UII receptor (UT) antagonist, KR- 36996, on the proliferation of SMCs in vitro and
neointima formation in vivo in comparison with
GSK-1440115, a known potent UT antagonist. In primary human aortic SMCs (HASMCs), UII (50 nM) induced proliferation was significantly inhibited by
KR-36996 at 1, 10, and 100 nM which showed greater potency (IC₅₀: 3.5 nM) than
GSK-1440115 (IC₅₀: 82.3 nM). UII-induced proliferation of HASMC cells was inhibited by
U0126, an ERK1/2 inhibitor, but not by
SP600125 (inhibitor of JNK) or
SB202190 (inhibitor of
p38 MAPK). UII increased the phosphorylation level of ERK1/2. Such increase was significantly inhibited by
KR-36996. UII-induced proliferation was also inhibited by
trolox, a scavenger for
reactive oxygen species (ROS). UII-induced ROS generation was also decreased by
KR-36996 treatment. In a carotid artery
ligation mouse model, intimal thickening was dramatically suppressed by oral treatment with
KR-36996 (30 mg/kg) which showed better efficacy than
GSK-1440115. These results suggest that
KR-36996 is a better candidate than
GSK-1440115 in preventing vascular proliferation in the pathogenesis of
atherosclerosis and restenosis.