Platelet-derived growth factor induces tissue factor expression in vascular smooth muscle cells via activation of Egr-1.
Activation of vascular smooth muscle cells (SMCs) by platelet-derived growth factor (PDGF) is a seminal event in the initiation and progression of the atherosclerotic lesion and may contribute to atherosclerotic plaque instability with plaque rupture and thrombus formation. Tissue factor (TF), a prothrombotic molecule expressed by various cell types within atherosclerotic plaques, is thought to play a major role in thrombus formation after plaque rupture. This study examined intracellular signaling pathways leading to TF expression and Egr-1 activation, a key element in tissue factor transcription, by PDGF-BB in rat SMCs. PDGF-BB induced TF mRNA and protein expression in a time-dependent manner. Early growth response factor-1 (Egr-1) binding activity was also induced by PDGF-BB, as well as phosphorylation of extracellular signal-regulated kinase. PDGF-BB-induced Egr-1 activation was suppressed by inhibitors of 2 upstream activators of Egr-1, extracellular signal-regulated kinase (ERK) and Src family kinases, whereas antioxidants, phosphatidylinositol 3-phosphate kinase, and p38 MAPK inhibitors had no effect. PDGF-BB-stimulated expression of the transcriptional co-repressor NAB2 was time-dependent. Furthermore, transient transfections of SMCs with wild-type and mutated TF promoter constructs showed that the Egr-1 binding region is an important transcriptional regulator of PDGF-BB-induced TF expression. Taken together, the results suggest that PDGF-BB induces TF expression and activity in SMC by a Src family kinases/ERK/Egr-1 signaling pathway and may therefore contribute to thrombus formation in advanced atherosclerosis and restenosis.
Kamimura
Motohiro
M
Innere Medizin III, Universität Heidelberg, Im Neuenheimer Feld, Heidelberg, Germany.
Bea
Florian
F
Akizawa
Tadao
T
Katus
Hugo A
HA
Kreuzer
Jörg
J
Viedt
Christiane
C
D000818:Animals; D001161:Arteriosclerosis / Q000503:physiopathology*; D000077214:Becaplermin; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051766:Early Growth Response Protein 1; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013925:Thromboplastin / Q000378:metabolism*; D013927:Thrombosis / Q000503:physiopathology*; D014157:Transcription Factors / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology; D019061:src-Family Kinases / Q000502:physiology
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D014157:Transcription Factors; C075278:platelet-derived growth factor A; D000077214:Becaplermin; D013925:Thromboplastin; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases