A Novel Urotensin II Receptor Antagonist, KR-36996 Inhibits Smooth Muscle Proliferation through ERK/ROS Pathway

Abstract

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.

The Red Algae Compound 3-Bromo-4,5-dihydroxybenzaldehyde Protects Human Keratinocytes on Oxidative Stress-Related Molecules and Pathways Activated by UVB Irradiation

“…Cells were seeded in a 96-well plate at a density of 0.5 × 10 5 cells/well. Sixteen hours after plating, cells were treated with BDB at various concentrations and after 1 h, cells were exposed to UVB light and incubated for 24 h. After the addition of DCF-DA (25 μM) (Sigma-Aldrich Co., St. Louis, MO, USA), the fluorescence of 2′,7′-dichlorofluorescein was detected using a spectrofluorometer [ 34 ]. The ROS detection was repeated three times.…”

Geranylgeranyl Transferase-I Knockout Inhibits Oxidative Injury of Vascular Smooth Muscle Cells and Attenuates Diabetes-Accelerated Atherosclerosis

“…As is well known, the MAPK family is composed of ERK1/2, JNK, and p38. A growing body of evidence has demonstrated that ROS-ERK1/2 cascades participate in the regulation of VSMC proliferation in vitro and neointima formation in vivo [35][36][37]. Previous studies also showed that JNK, p38, and ERK1/2 phosphorylation acted a critical role in high-glucose-induced oxidative injury and VSMC proliferation [38,39].…”

The network map of urotensin-II mediated signaling pathway in physiological and pathological conditions

“…In THP‐1 monocytes, MAPK1/3 induces activation of the IL‐1ß pathway, which in turn downregulates expression of ABCA1, which speeds up foam cell formation leads to atherosclerotic lesions (Kim et al 2017a). Kim et al (2017a, b) reported that UTR activation by urotensin‐II induces ROS generation and MAPK1/3 activation in vascular smooth muscle cells, which are associated with atherosclerosis and restenosis (Kim et al 2017b). urotensin‐II stimulates UTR and induces the overexpression of 5‐lipoxygenase (ALOX5) protein and release of leukotriene B4 (LTB4) via ROS/AKT pathways, which initiates macrophage activation and promotes atherosclerosis in mouse RAW264.7 macrophages (Lu et al 2019).…”