Inhibitory mechanism of tranilast in human coronary artery smooth muscle cells proliferation, due to blockade of PDGF-BB-receptors

Shinji Watanabe, Akihisa Matsuda, Yasuhiro Suzuki, Kazunao Kondo, Yasuhiko Ikeda, Hisakuni Hashimoto, Kazuo Umemura

研究成果: Article査読

17 被引用数 (Scopus)

抄録

1. We have previously reported that tranilast, an anti-allergic drug, prevented the experimental intimal thickening in the rat and mouse femoral arteries and its effect may be exerted through the inhibition of vascular smooth muscle cell proliferation. However, its inhibitory mechanism has yet to be understood. 2. In this study, we investigated the inhibitory effect of tranilast on platelet-derived growth factor BB-homodimer (PDGF-BB) mediated signal transduction pathways in cultured human coronary artery smooth muscle cells (CASMCs). 3. Growth responses to PDGF-BB were measured by [3H]-thymidine incorporation or cell counting. Activation of DNA synthesis and augmentation of cell proliferation stimulated by PDGF-BB in quiescent cultures of CASMCs were inhibited by tranilast in a concentration-dependent manner. 4. Western blot analysis of lysates from CASMCs with an anti-activated mitogen-activated protein (MAP) kinase antibody revealed that tranilast (10-300 μM) inhibited MAP kinase activation by PDGF-BB in a concentration-dependent manner. Tranilast also reduced PDGF-BB-stimulated tyrosine phosphorylation of a 180 kDa band, corresponding in mass to the PDGF β-receptor, as shown by immunoblots using an anti-phosphotyrosine antibody. 5. Receptor-binding study with [125I]-PDGF-BB on CASMCs showed that tranilast (10-1000 μM) inhibited the specific binding of PDGF-BB to cell surface receptors in a concentration-dependent manner. Scatchard analysis revealed that pretreatment with 300 μM tranilast decreased the maximum binding capacity (B(max)) from 27.6 to 18.0 fmol 106 cells-1 without affecting binding affinity (K(d) approximate 0.15 nM), indicating a non-competitive inhibition of the receptor binding. 6. These results suggest that the suppression of human CASMC growth by tranilast might be at least partly due to blockade of PDGF-BB-receptor binding.

本文言語English
ページ(範囲)307-314
ページ数8
ジャーナルBritish Journal of Pharmacology
130
2
DOI
出版ステータスPublished - 2000
外部発表はい

All Science Journal Classification (ASJC) codes

  • 薬理学

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