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Submitted on May 31, 2005
Accepted on November 21, 2005
Department of Pharmacology, Graduate School of Medical Sciences and Department of Clinical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto, Tokushima 770-8503, Japan
* To whom correspondence should be addressed. E-mail: fujita56{at}ri.ncvc.go.jp.
Lysophosphatidylcholine (LPC), a major lipid component of oxidized low density lipoprotein (oxLDL), is a bioactive lipid molecule involved in numerous biological processes including the progression of atherosclerosis. Recently, orphan G protein-coupled receptors (GPCRs) were identified as high-affinity receptors for LPC. Although several GPCR ligands transactivate receptor tyrosine kinases (RTKs), LPC-stimulated transactivation of RTK has not yet been reported. Here we observed for the first time that LPC treatment of human umbilical vein endothelial cells (HUVEC) induces tyrosyl phosphorylation of vascular endothelial growth factor (VEGF) receptor 2 (fetal liver kinase-1/kinase-insert domain-containing receptor, Flk-1/KDR). Flk-1/KDR transactivation by LPC was inhibited by VEGF receptor tyrosine kinase inhibitors, SU1498 and VTKi in immunoprecipitation. Furthermore, we examined the effects of the Src family kinases inhibitors, Herbimycin A and PP2 on LPC-induced Flk-1/KDR transactivation. Results from Western blots, c-Src is involved in LPC-induced Flk-1/KDR transactivation because Herbimycin A and PP2 inhibited this transactivation. Kinase-inactive (KI) Src transfection also inhibited LPC-induced Flk-1/KDR transactivation. In addition, results from Western blots, extracellular signal-regulated kinase 1/2 and Akt, which are downstream effectors of Flk-1/KDR, were also activated by LPC and this was inhibited by SU1498, VTKi, Herbimycin A, PP2 and KI Src transfection in HUVEC. LPC-induced stimulation of HUVEC proliferation was shown to be secondary to transactivation because it was suppressed by SU1498, VTKi, Herbimycin A, PP2 and KI Src transfection in MTT assay. These findings suggest that LPC-induced Flk-1/KDR transactivation via c-Src may have important implications for the progression of atherosclerosis.
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