A Novel Urotensin II Receptor Antagonist, KR-36996 Inhibits Smooth Muscle Proliferation through ERK/ROS Pathway.
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 SMCsin vitroand neointima formationin vivoin 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.
College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea.
Tae-Ho
TH
Kim
College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea.
Dong Gil
DG
Lee
College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea.
Young-Ae
YA
Kim
Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
Byung Ho
BH
Lee
Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
Kyu Yang
KY
Yi
College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea.|Research Institute of Pharmaceutical Sciences and Technology, Ajou University, Suwon 16499, Republic of Korea.
Yi-Sook
YS
Jung
Antagonist; GSK-1440115; KR-36996; Proliferation; Urotensin II; Vascular smooth muscle