Trapidil inhibits platelet-derived growth factor-stimulated mitogen- activated protein kinase cascade

Makiko Hoshiya, Midori Awazu

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Trapidil, an antiplatelet drug, has been shown to reduce restenosis after angioplasty. It exerts its action, at least in part, by inhibiting vascular smooth muscle cell proliferation, antagonizing platelet-derived growth factor (PDGF). We examined its site of action on PDGF cellular signaling. Exposure of cultured rat vascular smooth muscle cells to increasing concentrations of trapidil for 18 hours resulted in a dose- dependent reduction in PDGF-BB-stimulated [3H] thymidine incorporation. Trapidil (400 μg/mL) increased PDGF β-receptor protein by 28±8%, whereas PDGF-induced tyrosine phosphorylation of PDGF β-receptor remained unchanged PDGF-induced tyrosine phosphorylation of phospholipase Cγ, the p85 regulatory subunit of phosphatidyl-inositol 3 kinase, Ras GTPase-activating protein, and an adaptor molecule Shc were also not altered. On the other hand, trapidil inhibited PDGF-stimulated mitogen-activated protein kinase (MAP kinase) activity by 35± 7% at 10 minutes and by 32± 10% at 6 hours. Activation of Raf-1, an upstream activator of MAP kinase, by PDGF was also attenuated by trapidil. Moreover, protein content of MAP kinase phosphatase- 1, which inactivates MAP kinase, was elevated in trapidil-treated cells. These actions of trapidil may be mediated by cAMP. Thus, there was a 1.9- fold increase in cellular cAMP generation in trapidil-treated cells. The present results demonstrate that trapidil antagonizes PDGF-induced mitogenesis and MAP kinase activation in vascular smooth muscle cells, probably through cAMP.

Original languageEnglish
Pages (from-to)665-671
Number of pages7
JournalHypertension
Volume31
Issue number2
DOIs
Publication statusPublished - 1998 Feb

Keywords

  • Cyclic AMP
  • Growth factors, platelet- derived
  • Kinases
  • Mitogenesis
  • Restenosis
  • Trapidil

ASJC Scopus subject areas

  • Internal Medicine

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