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(Hypertension. 2004;44:944.)
© 2004 American Heart Association, Inc.

Scientific Contributions

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

Motohiro Kamimura; Florian Bea; Tadao Akizawa; Hugo A. Katus; Jörg Kreuzer; Christiane Viedt

From Innere Medizin III (M.K., F.B., H.A.K., J.K,. C.V.), Universität Heidelberg, Im Neuenheimer Feld, Heidelberg, Germany; and the Center of Blood Purification (T.A.), Wakayama Medical University, Kimiidera, Wakayama, Japan.

Correspondence to Christiane Viedt-Suelmann, MD, Innere Medizin III, Universität Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. E-mail Christiane_Viedt{at}med.uni-heidelberg.de

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.

Key Words: platelet-derived growth factor • atherosclerosis • gene regulation • signal transduction • transcription

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