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

被引:37
作者
Kamimura, M
Bea, F
Akizawa, T
Katus, HA
Kreuzer, J
Viedt, C
机构
[1] Heidelberg Univ, D-69120 Heidelberg, Germany
[2] Wakayama Med Univ, Ctr Blood Purificat, Wakayama, Japan
关键词
platelet-derived growth factor; atherosclerosis; gene regulation; signal transduction; transcription;
D O I
10.1161/01.HYP.0000146908.75091.99
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
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.
引用
收藏
页码:944 / 951
页数:8
相关论文
共 34 条
[1]   MYC BUT NOT FOS RESCUE OF PDGF SIGNALING BLOCK CAUSED BY KINASE INACTIVE SRC [J].
BARONE, MV ;
COURTNEIDGE, S .
NATURE, 1995, 378 (6556) :509-512
[2]   Chlamydia pneumoniae induces tissue factor expression in mouse macrophages via activation of Egr-1 and the MEK-ERK1/2 pathway [J].
Bea, F ;
Puolakkainen, MH ;
McMillen, T ;
Hudson, FN ;
Mackman, N ;
Kuo, CC ;
Campbell, LA ;
Rosenfeld, ME .
CIRCULATION RESEARCH, 2003, 92 (04) :394-401
[3]   Platelet-derived-growth-factor stimulation of the p42/p44 mitogen-activated protein kinase pathway in airway smooth muscle: role of pertussis-toxinsensitive G-proteins, c-Src tyrosine kinases and phosphoinositide 3-kinase [J].
Conway, AM ;
Rakhit, S ;
Pyne, S ;
Pyne, NJ .
BIOCHEMICAL JOURNAL, 1999, 337 :171-177
[4]   Transcriptional regulation of the tissue factor gene in human epithelial cells is mediated by Sp1 and EGR-1 [J].
Cui, MZ ;
Parry, GCN ;
Oeth, P ;
Larson, H ;
Smith, M ;
Huang, RP ;
Adamson, ED ;
Mackman, N .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (05) :2731-2739
[5]   Multiple roles for Src in a PDGF-stimulated cell [J].
DeMali, KA ;
Godwin, SL ;
Soltoff, SP ;
Kazlauskas, A .
EXPERIMENTAL CELL RESEARCH, 1999, 253 (01) :271-279
[6]   INHIBITION OF NEOINTIMAL SMOOTH-MUSCLE ACCUMULATION AFTER ANGIOPLASTY BY AN ANTIBODY TO PDGF [J].
FERNS, GAA ;
RAINES, EW ;
SPRUGEL, KH ;
MOTANI, AS ;
REIDY, MA ;
ROSS, R .
SCIENCE, 1991, 253 (5024) :1129-1132
[7]   EARLY GROWTH-RESPONSE PROTEIN 1(EGR-1) - PROTOTYPE OF A ZINC-FINGER FAMILY OF TRANSCRIPTION FACTORS [J].
GASHLER, A ;
SUKHATME, VP .
PROGRESS IN NUCLEIC ACID RESEARCH AND MOLECULAR BIOLOGY, VOL 50, 1995, 50 :191-224
[8]   Early growth response-1 promotes atherogenesis - Mice deficient in early growth response-1 and apolipoprotein E display decreased atherosclerosis and vascular inflammation [J].
Harja, E ;
Bucciarelli, LG ;
Lu, Y ;
Stern, DM ;
Zou, YS ;
Schmidt, AM ;
Yan, SF .
CIRCULATION RESEARCH, 2004, 94 (03) :333-339
[9]   Platelet-derived growth factor and arterial response to injury [J].
Hart, CE ;
Clowes, AW .
CIRCULATION, 1997, 95 (03) :555-556
[10]   Mechanism of action and in vivo role of platelet-derived growth factor [J].
Heldin, CH ;
Westermark, B .
PHYSIOLOGICAL REVIEWS, 1999, 79 (04) :1283-1316