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Lysophosphatidylcholine stimulates MAP kinase activity in rat vascular smooth muscle cells.

Abstract
Lysophosphatidylcholine (lyso-PC) has been implicated in atherogenesis and the inflammatory process. Although lyso-PC has been reported to contribute to the mitogenic effect of oxidized LDL on rat cultured vascular smooth muscle cells (VSMCs), the signaling mechanisms by which lyso-PC promotes its proliferation are poorly characterized. Mitogen-activated protein (MAP) kinases are important mediators involved in the intracellular network of interacting proteins that transduces extracellular cues to intracellular responses. We therefore examined the effect of lyso-PC on MAP kinase activation, proto-oncogene expression, and AP-1 binding activity using cultured rat VSMC. Marked activation of MAP kinase occurred within 10 minutes of lyso-PC treatment, whereupon rapid inactivation ensued. MAP kinase activation by lyso-PC was concentration-dependent (6.25 to 25 micromol/L). Pertussis toxin treatment did not affect lyso-PC-induced MAP kinase phosphorylation. Lyso-PC (25 micromol/L) also increased the mRNA expression of c-fos and c-jun genes. An electrophoretic mobility shift assay showed that AP-1 binding activity was enhanced by lyso-PC. To examine the upstream signaling of MAP kinase, we used several inhibitors on MAP kinase activation induced by lyso-PC. Although lyso-PC induced sustained increase in intracellular Ca2+ concentration, EGTA had no effect on MAP kinase activation induced by lyso-PC. However, protein kinase C inhibitor GF109203X and downregulation of protein kinase C activity by prolonged treatment with phorbol ester inhibited lyso-PC-induced MAP kinase activation. These data suggest that lyso-PC transmits its mitogenic activity through a MAP kinase-AP-1 pathway, which exists downstream of its protein kinase C activation in VSMCs.
AuthorsT Yamakawa, S Eguchi, Y Yamakawa, E D Motley, K Numaguchi, H Utsunomiya, T Inagami
JournalHypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 31 Issue 1 Pt 2 Pg. 248-53 (Jan 1998) ISSN: 0194-911X [Print] United States
PMID9453311 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Lysophosphatidylcholines
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Transcription Factor AP-1
  • Calcium-Calmodulin-Dependent Protein Kinases
Topics
  • Animals
  • Aorta, Thoracic (cytology, drug effects, metabolism)
  • Calcium-Calmodulin-Dependent Protein Kinases (metabolism)
  • Cell Nucleus (metabolism)
  • Cells, Cultured
  • Enzyme Activation
  • Genes, fos
  • Genes, jun
  • Lysophosphatidylcholines (pharmacology)
  • Muscle, Smooth, Vascular (cytology, drug effects, metabolism)
  • Proto-Oncogene Proteins c-fos (biosynthesis)
  • Proto-Oncogene Proteins c-jun (biosynthesis)
  • RNA, Messenger (biosynthesis)
  • Rats
  • Rats, Sprague-Dawley
  • Transcription Factor AP-1 (metabolism)
  • Transcription, Genetic (drug effects)

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