on January 9, 2003
Published online before print January 9, 2003, doi: 10.1161/01.ATV.0000054660.61191.7D
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on November 12, 2002
Accepted on December 11, 2002
Lysophosphatidic Acid Induction of Tissue Factor Expression in Aortic Smooth Muscle Cells
Mei-Zhen Cui *;
From the Department of Pathology (M.-Z.C., G.Z., E.L., X.X.), University of Tennessee, Knoxville, and the Department of Cell Biology (A.L.W., J.R.B., M.S.P., G.M.C.), Cleveland Clinic Foundation, Cleveland, Ohio.
* To whom correspondence should be addressed. E-mail: cuim{at}utk.edu.
Objective--Tissue factor (TF), the initiator of the coagulation cascade, is expressed by cells in atherosclerotic lesions. Lysophosphatidic acid (LPA) is a component of oxidized lipoproteins and an agent released by activated platelets. The present study investigated whether and how TF expression is regulated by LPA.
Methods and Results--Northern blotting, Western blotting, and TF activity assays demonstrated that LPA markedly induced TF mRNA, protein, and activity in vascular smooth muscle cells. LPA-induced TF expression is primarily controlled at the transcriptional level. Phosphorylation of mitogen-activated protein kinase kinase (MEK) and extracellular signaling-regulated kinases (ERK1/2) was rapidly and markedly induced by LPA. MEK inhibitors U0126 and PD98059 blocked both ERK activation and the increase in TF mRNA. In contrast, the specific p38 MAP kinase inhibitor SB203580 had no effect on LPA-induced TF mRNA increase. The G
i protein inhibitor, pertussis toxin, abolished LPA-induced phosphorylation of MEKs and ERKs, as well as the induction of TF mRNA.
Conclusions--Our data demonstrate that a Gi protein and activation of MEKs and ERKs mediate LPA-induced TF expression. Our data suggest that elevated LPA could be a thrombogenic risk factor by upregulating TF expression. These results may have important implications in vascular remodeling and vascular diseases.
Key words: atherosclerosis • arterial thrombosis • lipid/lipoprotein metabolism • gene expression
This article has been cited by other articles:
 |
|
 |
|
  B. E. Stahli, A. Breitenstein, A. Akhmedov, G. G. Camici, K. Shojaati, N. Bogdanov, J. Steffel, D. Ringli, T. F. Luscher, and F. C. Tanner Cardiac Glycosides Regulate Endothelial Tissue Factor Expression in Culture Arterioscler. Thromb. Vasc. Biol., December 1, 2007; 27(12): 2769 - 2776. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. E. Stahli, G. G. Camici, J. Steffel, A. Akhmedov, K. Shojaati, M. Graber, T. F. Luscher, and F. C. Tanner Paclitaxel Enhances Thrombin-Induced Endothelial Tissue Factor Expression via c-Jun Terminal NH2 Kinase Activation Circ. Res., July 21, 2006; 99(2): 149 - 155. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-Z. Cui, E. Laag, L. Sun, M. Tan, G. Zhao, and X. Xu Lysophosphatidic Acid Induces Early Growth Response Gene 1 Expression in Vascular Smooth Muscle Cells: CRE and SRE Mediate the Transcription Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 1029 - 1035. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Steffel, T. F. Luscher, and F. C. Tanner Tissue Factor in Cardiovascular Diseases: Molecular Mechanisms and Clinical Implications Circulation, February 7, 2006; 113(5): 722 - 731. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Steffel, R. A. Latini, A. Akhmedov, D. Zimmermann, P. Zimmerling, T. F. Luscher, and F. C. Tanner Rapamycin, but Not FK-506, Increases Endothelial Tissue Factor Expression: Implications for Drug-Eluting Stent Design Circulation, September 27, 2005; 112(13): 2002 - 2011. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Steffel, A. Akhmedov, H. Greutert, T. F. Luscher, and F. C. Tanner Histamine Induces Tissue Factor Expression: Implications for Acute Coronary Syndromes Circulation, July 19, 2005; 112(3): 341 - 349. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. P. H. Leung, R. Y. K. Man, and C.-M. Tse D-Glucose upregulates adenosine transport in cultured human aortic smooth muscle cells Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2756 - H2762. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Mackman How Do Oxidized Phospholipids Inhibit LPS Signaling? Arterioscler. Thromb. Vasc. Biol., July 1, 2003; 23(7): 1133 - 1136. [Full Text] [PDF]
|
|