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.