Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Metzler, B; Li, C; Hu, Y; Sturm, G; Ghaffari-Tabrizi, N; Xu, Q.
LDL stimulates mitogen-activated protein kinase phosphatase-1 expression, independent of LDL receptors, in vascular smooth muscle cells.
Arterioscler Thromb Vasc Biol. 1999; 19(8):1862-1871
Doi: 10.1161/01.ATV.19.8.1862
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- Co-Autor*innen der Med Uni Graz
- Ghaffari Tabrizi-Wizsy Nassim
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- Abstract:
- Low density lipoprotein (LDL) is a well-established risk factor for atherosclerosis, stimulating vascular smooth muscle cell (SMC) differentiation and proliferation, but the signal transduction pathways between LDL stimulation and cell proliferation are poorly understood. Because mitogen-activated protein kinases (MAPKs) play a crucial role in mediating cell growth, we studied the effect of LDL on the induction of MAPK phosphatase-1 (MKP-1) in human SMCs and found that LDL stimulated induction of MKP-1 mRNA and proteins in a time- and dose-dependent manner. Heparin, inhibiting LDL-receptor binding, did not influence LDL-stimulated MKP-1 mRNA expression, and human LDL also induced MKP-1 expression in rat SMCs and fibroblasts derived from LDL receptor-deficient mice, indicating an LDL receptor-independent process. Pretreatment of SMCs with pertussis toxin markedly inhibited LDL-induced MKP-1 expression. Depletion of protein kinase C (PKC) by phorbol 12-myristate 13 acetate or inhibition of PKC by calphostin C blocked MKP-1 induction, but the phospholipase C inhibitor U73122 had no effect. Pretreatment of SMCs with genistein or herbimycin A abrogated LDL-stimulated MKP-1 induction. The MAPK kinase inhibitor PD98059 abolished LDL-stimulated activation of extracellular signal-regulated protein kinases (ERKs) but not MKP-1 induction. Furthermore, constitutive expression of MKP-1 in vivo reduced LDL-induced expression of Elk-1-dependent reporter genes, and SMC lines overexpressing recombinant MKP-1 exhibited decreased ERK activities and retarded proliferation in response to LDL. Our findings demonstrate that LDL induces MKP-1 expression in SMCs via activation of PKC and tyrosine kinases, independent of LDL receptors and ERK-MAPKs, and that MKP-1 plays an important role in the regulation of LDL-initiated signal transductions leading to SMC proliferation.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Calcium-Calmodulin-Dependent Protein Kinases - physiology
- Cell Cycle Proteins - physiology
- Cell Division - drug effects
- Dual Specificity Phosphatase 1 - drug effects
- Enzyme Activation - drug effects
- Enzyme Induction - drug effects
- Gene Expression - drug effects
- Immediate-Early Proteins - genetics
- Lipoproteins, LDL - pharmacology
- Muscle, Smooth, Vascular - cytology
- Pertussis Toxin - cytology
- Phosphoprotein Phosphatases - cytology
- Protein Phosphatase 1 - cytology
- Protein Tyrosine Phosphatases - genetics
- Protein-Tyrosine Kinases - metabolism
- RNA, Messenger - metabolism
- Rats - metabolism
- Receptors, LDL - physiology
- Virulence Factors, Bordetella - pharmacology
- Find related publications in this database (Keywords)
- LDL
- mitogen-activated protein kinase phosphatase-1 signaling
- mitogen-activated protein kinases
- smooth muscle cells