Activation of mitogen-activated protein kinase by oxidized low-density lipoprotein in canine cultured vascular smooth muscle cells

Chuen Mao Yang, Chi Tso Chiu, Chuan Chawn Wang, Chin Sung Chien, Li Der Hsiao, Chih Chung Lin, Ming Tze Tu, Shiow Lin Pan

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Oxidized low-density lipoprotein (OX-LDL) contributes significantly to the development of atherosclerosis. However, the mechanisms of OX-LDL-induced vascular smooth muscle cell (VSMC) proliferation are not completely understood. Therefore, we investigated the effect of OX-LDL on cell proliferation associated with a specific pattern of mitogen-activated protein kinase (MAPK) by [3H]thymidine incorporation and p42/p44 MAPK phosphorylation in canine cultured VSMCs. OX-LDL-induced [3H]thymidine incorporation and p42/p44 MAPK phosphorylation in a time- and concentration-dependent manner in VSMCs. Pretreatment of these cells with pertussis toxin (PTX) for 24 hours attenuated the OX-LDL-induced [3H]thymidine incorporation and p42/p44 MAPK phosphorylation, indicating that these responses were mediated through a receptor coupled to a PTX-sensitive G protein. In cells pretreated with PMA for 24 h and with either the PKC inhibitor staurosporine or the tyrosine kinase inhibitor genistein for 1h, substantially reduced the [3H]thymidine incorporation and p42/p44 MAPK phosphorylation in response to OX-LDL. Removal of Ca2+ by addition of BAPTA/AM plus EGTA significantly inhibited OX-LDL-induced [3H]thymidine incorporation and p42/p44 MAPK phosphorylation, indicating the requirement of Ca2+ for these responses. OX-LDL-induced [3H]thymidine incorporation and p42/p44 MAPK phosphorylation was completely inhibited by PD98059 (an inhibitor of MEK1/2) and SB203580 (an inhibitor of p38 MAPK). Furthermore, we also showed that overexpression of dominant negative mutants of Ras (RasN17) and Raf (Raf-301) completely suppressed MEK1/2 and p42/p44 MAPK activation induced by OX-LDL and PDGF-BB, indicating that Ras and Raf may be required for activation of these kinases. Taken together, these results suggest that the mitogenic effect of OX-LDL is mediated through a PTX-sensitive G-protein-coupled receptor that involves the activation o Ras/Raf/MEK/MAPK pathway similar to those of PDGF-BB in canine cultured VSMCs. Copyright (C) 2000 Elsevier Science Inc.

Original languageEnglish
Pages (from-to)205-214
Number of pages10
JournalCellular Signalling
Volume12
Issue number4
DOIs
Publication statusPublished - Apr 2000
Externally publishedYes

Keywords

  • Ca
  • Mitogen-activated protein kinase (MAPK)
  • Oxidized low-density lipoprotein (OX-LDL)
  • Pertussis toxin (PTX)
  • Platelet-derived growth factor (PDGF)
  • Protein kinase C (PKC)
  • Tyrosine kinase
  • Vascular smooth muscle cells (VSMCs)

ASJC Scopus subject areas

  • Cell Biology

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