HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 23, 22172-22180, June 10, 2005

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 280/23/22172    most recent M500721200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McLaughlin, J. N. Articles by Hamm, H. E. Search for Related Content PubMed PubMed Citation Articles by McLaughlin, J. N. Articles by Hamm, H. E. Social Bookmarking                      What's this?

Thrombin Modulates the Expression of a Set of Genes Including Thrombospondin-1 in Human Microvascular Endothelial Cells^*

Joseph N. McLaughlin¶, Maria R. Mazzoni||, John H. Cleator**, Laurie Earls, Ana Luisa Perdigoto, Joshua D. Brooks, James A. S. Muldowney, III**, Douglas E. Vaughan**, and Heidi E. Hamm

From the Department of Pharmacology and ^**Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232 and ^||Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnology, University of Pisa, Pisa, 56126, Italy

Thrombospondin-1 (THBS1) is a large extracellular matrix glycoprotein that affects vasculature systems such as platelet activation, angiogenesis, and wound healing. Increases in THBS1 expression have been liked to disease states including tumor progression, atherosclerosis, and arthritis. The present study focuses on the effects of thrombin activation of the G-protein-coupled, protease-activated receptor-1 (PAR-1) on THBS1 gene expression in the microvascular endothelium. Thrombin-induced changes in gene expression were characterized by microarray analysis of 11,000 different human genes in human microvascular endothelial cells (HMEC-1). Thrombin induced the expression of a set of at least 65 genes including THBS1. Changes in THBS1 mRNA correlated with an increase in the extracellular THBS1 protein concentration. The PAR-1-specific agonist peptide (TFLLRNK-PDK) mimicked thrombin stimulation of THBS1 expression, suggesting that thrombin signaling is through PAR-1. Further studies showed THBS1 expression was sensitive to pertussis toxin and protein kinase C inhibition indicating G_i/o- and G_q-mediated pathways. THBS1 up-regulation was also confirmed in human umbilical vein endothelial cells stimulated with thrombin. Analysis of the promoter region of THBS1 and other genes of similar expression profile identified from the microarray predicted an EBOX/EGRF transcription model. Expression of members of each family, MYC and EGR1, respectively, correlated with THBS1 expression. These results suggest thrombin formed at sites of vascular injury increases THBS1 expression into the extracellular matrix via activation of a PAR-1, G_i/o, G_q, EBOX/EGRF-signaling cascade, elucidating regulatory points that may play a role in increased THBS1 expression in disease states.

Received for publication, January 20, 2005 , and in revised form, March 14, 2005.

^* This work was supported in part by the National Institutes of Health Grant 5 RO1 HL60906-04. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental material.

These authors contributed equally to this work.

Supported by American Medical Association Post-doctoral Award 0325373B.

Supported by National Institutes of Health Grant 5T32 HL07411-23 and The Stanley J. Sarnoff Endowment for Cardiovascular Research.

^¶ Supported by National Institutes of Health Grant 5T32 HL07751-11. To whom correspondence should be addressed: Dept. of Pharmacology, Vanderbilt University Medical Center, 444 Robinson Research Bldg., 23rd Ave. South at Pierce, Nashville, TN 37232-6600. Tel.: 615-936-0736; Fax: 615-322-5117; E-mail: joseph.mclaughlin{at}vanderbilt.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				P. Ghafoori, T. Yoshimura, B. Turpie, and S. Masli Increased I{kappa}B{alpha} expression is essential for the tolerogenic property of TGF-{beta}-exposed APCs FASEB J, July 1, 2009; 23(7): 2226 - 2234. [Abstract] [Full Text] [PDF]

				J. S. Blackburn and C. E. Brinckerhoff Matrix Metalloproteinase-1 and Thrombin Differentially Activate Gene Expression in Endothelial Cells via PAR-1 and Promote Angiogenesis Am. J. Pathol., December 1, 2008; 173(6): 1736 - 1746. [Abstract] [Full Text] [PDF]

				Y. Kai, K. Hirano, Y. Maeda, J. Nishimura, T. Sasaki, and H. Kanaide Prevention of the Hypercontractile Response to Thrombin by Proteinase-Activated Receptor-1 Antagonist in Subarachnoid Hemorrhage Stroke, December 1, 2007; 38(12): 3259 - 3265. [Abstract] [Full Text] [PDF]

				K. Urayama, C. Guilini, N. Messaddeq, K. Hu, M. Steenman, H. Kurose, G. Ert, and C. G. Nebigil The prokineticin receptor-1 (GPR73) promotes cardiomyocyte survival and angiogenesis FASEB J, September 1, 2007; 21(11): 2980 - 2993. [Abstract] [Full Text] [PDF]

				J. N. McLaughlin, M. M. Patterson, and A. B. Malik Protease-activated receptor-3 (PAR3) regulates PAR1 signaling by receptor dimerization PNAS, March 27, 2007; 104(13): 5662 - 5667. [Abstract] [Full Text] [PDF]

				K. Hirano The Roles of Proteinase-Activated Receptors in the Vascular Physiology and Pathophysiology Arterioscler. Thromb. Vasc. Biol., January 1, 2007; 27(1): 27 - 36. [Abstract] [Full Text] [PDF]

				J. P. Luyendyk, L. D. Lehman-McKeeman, D. M. Nelson, V. M. Bhaskaran, T. P. Reilly, B. D. Car, G. H. Cantor, X. Deng, J. F. Maddox, P. E. Ganey, et al. Coagulation-Dependent Gene Expression and Liver Injury in Rats Given Lipopolysaccharide with Ranitidine but Not with Famotidine J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 635 - 643. [Abstract] [Full Text] [PDF]

				R. Sood, S. Kalloway, A. E. Mast, C. J. Hillard, and H. Weiler Fetomaternal cross talk in the placental vascular bed: control of coagulation by trophoblast cells Blood, April 15, 2006; 107(8): 3173 - 3180. [Abstract] [Full Text] [PDF]