LDL stimulates mitogen-activated protein kinase phosphatase-1 expression, independent of LDL receptors, in vascular smooth muscle cells.
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.
Metzler
B
B
Institute for Biomedical Aging Research, Austrian Academy of Sciences, Division of Cardiology, University Hospital of Innsbruck, Austria.
Li
C
C
Hu
Y
Y
Sturm
G
G
Ghaffari-Tabrizi
N
N
Xu
Q
Q
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D017874:Immediate-Early Proteins / Q000235:genetics*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D037342:Pertussis Toxin; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D011973:Receptors, LDL / Q000502:physiology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D011973:Receptors, LDL; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D017027:Protein Tyrosine Phosphatases