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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   *
1   Pharmacological Institute
,
Shiow-Lin Pan   *
1   Pharmacological Institute
,
Jih-Hwa Guh
2   School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
,
Yi-Nan Liu
1   Pharmacological Institute
,
Ya-Ling Chang
1   Pharmacological Institute
,
Sheng-Chu Kuo
3   Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan
,
Fang-Yu Lee
4   Yung-Shin Pharmaceutical Industry Co, Ltd, Taichung, Taiwan
,
Che-Ming Teng
1   Pharmacological Institute
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Publikationsverlauf

Received 05. April 2004

Accepted after resubmission 10. September 2004

Publikationsdatum:
02. Dezember 2017 (online)

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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

* Chieh-Yu Peng and Shiow-Lin Pan contributed equally to this work


 

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