Platelet-derived growth factor induces tissue factor expression in vascular smooth muscle cells via activation of Egr-1

Autor: Christiane Viedt, Tadao Akizawa, Florian Bea, Hugo A. Katus, Jörg Kreuzer, Motohiro Kamimura
Rok vydání: 2004
Předmět:
MAPK/ERK pathway
medicine.medical_specialty
Platelet-derived growth factor
Arteriosclerosis
p38 mitogen-activated protein kinases
medicine.medical_treatment
Myocytes
Smooth Muscle
Becaplermin
Biology
p38 Mitogen-Activated Protein Kinases
Muscle
Smooth
Vascular
Immediate-Early Proteins
Thromboplastin
Rats
Sprague-Dawley
chemistry.chemical_compound
Tissue factor
Phosphatidylinositol 3-Kinases
Internal medicine
Internal Medicine
medicine
Animals
Humans
Extracellular Signal-Regulated MAP Kinases
Cells
Cultured
Early Growth Response Protein 1
Platelet-Derived Growth Factor
Kinase
Growth factor
Thrombosis
Proto-Oncogene Proteins c-sis
Cell biology
Rats
DNA-Binding Proteins
Endocrinology
src-Family Kinases
chemistry
Gene Expression Regulation
biology.protein
Signal transduction
Platelet-derived growth factor receptor
Signal Transduction
Transcription Factors
Zdroj: Hypertension (Dallas, Tex. : 1979). 44(6)
ISSN: 1524-4563
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: