beta-Migrating very low density lipoprotein (beta VLDL) activates smooth muscle cell mitogen-activated protein (MAP) kinase via G protein-coupled receptor-mediated transactivation of the epidermal growth factor (EGF) receptor: effect of MAP kinase activation on beta VLDL plus EGF-induced cell proliferation.
This study examined the premise that the atherogenic lipoprotein, beta-migrating very low density lipoprotein (betaVLDL), might activate the mitogen-activated protein (MAP) kinases ERK1/ERK2, thereby contributing to the induction of smooth muscle cell proliferation in atherosclerosis. The data show that betaVLDL activates rabbit smooth muscle cell ERK1/ERK2. Interestingly, ERK1/ERK2 activation is mediated by G protein-coupled receptors that transactivate the epidermal growth factor (EGF) receptor. betaVLDL-induced MAP kinase activation depends on Ras and Src activity as well as protein kinase C. The inhibition of lysosomal degradation of betaVLDL has no effect on ERK1/ERK2 activation. The contribution of betaVLDL-induced activation of ERK1/ERK2 to smooth muscle cell proliferation was also explored. betaVLDL induces expression of egr-1 and c-fos mRNA. Despite its ability to stimulate early gene expression, betaVLDL alone is unable to inspire quiescent cells into S phase. When added in conjunction with EGF, however, stimulation of [(3)H]thymidine incorporation into DNA and an increase in histone gene expression are observed. Moreover, betaVLDL plus EGF synergistically induce cyclin D1 expression and down-regulate p27(KIP1) expression. The addition of either betaVLDL or EGF stimulates a robust activation of ERK1/ERK2, but the addition of both agents simultaneously sustains the activation for a longer time period. Inhibition of MAP kinase kinase, pertussis toxin-sensitive G proteins, the EGF receptor, or protein kinase C blocks betaVLDL plus EGF-induced proliferation, demonstrating that activation of the betaVLDL-induced signaling pathway results in smooth muscle cell proliferation.
Zhao
D
D
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Letterman
J
J
Schreiber
B M
BM
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008079:Lipoproteins, VLDL / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009130:Muscle, Smooth / Q000166:cytology / Q000201:enzymology*; D011493:Protein Kinase C / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D016760:Proto-Oncogene Proteins c-fos; D011956:Receptors, Cell Surface; D014157:Transcription Factors; C099252:oxidized low density lipoprotein; D019938:Cyclin D1; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins