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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2017.1
- 수록면
- 308 - 314 (7page)
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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 ($IC_{50}$: 3.5 nM) than GSK-1440115 ($IC_{50}$: 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.
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참고문헌 (25)
참고문헌 신청
Ames, R. S. / 1999 / Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14 / Nature 401:282~286
Behm, D. J. / 2010 / GSK1562590, a slowly dissociating urotensin-II receptor antagonist, exhibits prolonged pharmacodynamic activity ex vivo / Br. J. Pharmacol 161:207~228
Behm, D. J. / 2008 / Palosuran inhibits binding to primate UT receptors in cell membranes but demonstrates differential activity in intact cells and vascular tissues / Br. J. Pharmacol 155:374~386
Chen, Y. L. / 2008 / Involvement of reactive oxygen species in urotensin II-induced proliferation of cardiac fibroblasts / Eur. J. Pharmacol 593:24~29
Djordjevic, T. / 2005 / Human urotensin II is a novel activator of NADPH oxidase in human pulmonary artery smooth muscle cells / Arterioscler. Thromb. Vasc. Biol 25:519~525
Behm, D. J. / 2010 / GSK1562590, a slowly dissociating urotensin-II receptor antagonist, exhibits prolonged pharmacodynamic activity ex vivo / Br. J. Pharmacol 161:207~228
Behm, D. J. / 2008 / Palosuran inhibits binding to primate UT receptors in cell membranes but demonstrates differential activity in intact cells and vascular tissues / Br. J. Pharmacol 155:374~386
Chen, Y. L. / 2008 / Involvement of reactive oxygen species in urotensin II-induced proliferation of cardiac fibroblasts / Eur. J. Pharmacol 593:24~29
Djordjevic, T. / 2005 / Human urotensin II is a novel activator of NADPH oxidase in human pulmonary artery smooth muscle cells / Arterioscler. Thromb. Vasc. Biol 25:519~525
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