Platelet-Derived Growth Factor Induces Tissue Factor Expression in Vascular Smooth Muscle Cells via Activation of Egr-1

Abstract

Abstract-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.

Curcumin inhibits human colon cancer cell growth by suppressing gene expression of epidermal growth factor receptor through reducing the activity of the transcription factor Egr-1

“…The role of phosphorylation of Egr-1 remains controversial (Cao et al, 1993;Jain et al, 1996;Huang et al, 1998;Kamimura et al, 2004). We recently observed that curcumin reduced the level of phosphorylation of Egr-1, which was mimicked by a specific MEK inhibitor (data not shown here).…”

Oxymatrine suppresses MOVAS proliferation induced by platelet-derived growth factor via G0/G1 arrest

“…PDGF, mainly expressed in VSMCs and endothelial cells, promote mitosis and play an important role in the proliferation of VSMCs [6][7][8]37]. The binding of PDGF-BB, a subtype of PDGF released from injured vessels, to its receptor can trigger the activation of downstream and then contribute significantly to VSMCs proliferation [9][10][11][12]. In this paper, PDGF-BB could effectively induce MOVAS proliferation, which was consistent with the previous studies reported.…”

“…Platelet-Derived Growth Factor (PDGF) is an important regulator that stimulates the proliferation of VSMCs [6][7][8]. The binding of PDGF-BB, a subtype of PDGF, to its receptor triggers the activation of downstream signaling molecules such as Mitogen-Activated Protein Kinases (MAPKs) to promote VSMCs proliferation and growth [9][10][11][12][13]. Therefore, preventing the PDGF-BB induced VSMCs proliferation might be a promising strategy for treating the development of neointima in atherosclerosis and post-angioplasty restenosis in the future.…”

Tissue Factor in Cardiovascular Diseases

“…In human vascular smooth muscle cells, p38 and PI3-kinase mediate thrombin-induced TF expression. 26 In rat vascular smooth muscle cells, ERK is involved in TF expression to lysophosphatidic acid 28 and PDGF-BB, 25 whereas p38 and PI3-kinase do not play a role. Hence, the effect of MAP kinases and the PI3 kinase pathway appears to depend on the particular stimulus and/or the species involved.…”