The indazole derivative YD-3 inhibits thrombin-induced vascular smooth muscle cell proliferation and attenuates intimal thickening after balloon injury

Chieh-Yu Peng; Shiow-Lin Pan; Jih-Hwa Guh; Yi-Nan Liu; Ya-Ling Chang; Sheng-Chu Kuo; Fang-Yu Lee; Che-Ming Teng

doi:10.1160/TH04-04-0216

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 92(06): 1232-1239
DOI: 10.1160/TH04-04-0216

Theme Issue Article

Schattauer GmbH

The indazole derivative YD-3 inhibits thrombin-induced vascular smooth muscle cell proliferation and attenuates intimal thickening after balloon injury

Chieh-Yu Peng^*

¹Pharmacological Institute

,

Shiow-Lin Pan^*

¹Pharmacological Institute

,

Jih-Hwa Guh

²School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan

,

Yi-Nan Liu

¹Pharmacological Institute

,

Ya-Ling Chang

¹Pharmacological Institute

,

Sheng-Chu Kuo

³Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan

,

Fang-Yu Lee

⁴Yung-Shin Pharmaceutical Industry Co, Ltd, Taichung, Taiwan

,

Che-Ming Teng

¹Pharmacological Institute

› Author Affiliations

Abstract

Summary

Proliferation of vascular smooth muscle cells (VSMCs) is postulated to be one of the key events in the pathogenesis of atherosclerosis and restenosis. We investigated whether YD-3, a lowmolecular weight, non-peptide compound, could modulate proliferation of VSMCs in vitro and restenosis after balloon angioplasty in vivo. We examined the effect of YD-3 on thrombininduced VSMC proliferation by [³H]thymidine incorporation assay. The data demonstrated that YD-3 inhibited VSMC proliferation in a concentration-dependent manner. To define the mechanisms of YD-3 action, we found that YD-3 showed a profound inhibition on thrombin-induced Ras and ERK1/2 activities by using Western blotting analysis. Furthermore, oral administration of YD-3 exhibited a marked reduction in neointimal thickness using the carotid injury model in rats. Using immunochemical detection, our experiments also revealed that YD-3 significantly suppressed expression of the PAR-1 receptor, and markedly inhibited PAR-1-activating peptide (SFLLRN)-induced VSMC proliferation in a concentration-dependent manner. These results suggest that YD-3 inhibits thrombin-induced VSMC growth via the Rasand ERK1/2-mediated signaling pathway. Moreover, YD-3 also shows a developmental potential in the treatment of atherosclerosis and restenosis after vascular injury.

Keywords

YD-3 - vascular smooth muscle cells - thrombin - restenosis - signal transduction

Full Text

References

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