QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.054346v1 307/3/987    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hamaguchi, E. Articles by Nagai, Y. Search for Related Content PubMed PubMed Citation Articles by Hamaguchi, E. Articles by Nagai, Y. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB 12-O-TETRADECANOYLPHORBOL-13-ACETATE

CELLULAR AND MOLECULAR

Tumor Necrosis Factor- and Troglitazone Regulate Plasminogen Activator Inhibitor Type 1 Production through Extracellular Signal-Regulated Kinase- and Nuclear Factor-B-Dependent Pathways in Cultured Human Umbilical Vein Endothelial Cells

Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan

Plasminogen activator inhibitor type 1 (PAI-1) plays a role in the development of atherosclerosis in diabetic patients. PAI-1 is produced by endothelial cells stimulated with various inflammatory cytokines, such as tumor necrosis factor (TNF)-, which induces insulin resistance. In diabetic patients, troglitazone, a thiazolidinedione, can lower the concentration of PAI-1. We investigated the TNF--induced signaling pathway that leads to PAI-1 synthesis and the target step of troglitazone in this pathway. TNF- induced PAI-1 mRNA expression and protein production in human umbilical vein endothelial cells (HUVECs). A specific inhibitor for p38 mitogen-activated protein kinase, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB 203580), and a protein kinase C inhibitor, calphostin C, had no inhibitory effects on TNF--induced PAI-1 secretion. A protein tyrosine kinase inhibitor, genistein, completely inhibited TNF--induced PAI-1 secretion, whereas an inhibitor of extracellular signal-regulated kinase (ERK) kinase, 2'-amino-3'-methoxyflavone (PD98059), and a nuclear factor-B (NF-B) inhibitor, emodin, partly inhibited TNF--induced PAI-1 secretion. Together, PD98059 and emodin completely inhibited TNF--induced PAI-1 secretion, suggesting that both NF-B-dependent and NF-B-independent pathways are involved in TNF--induced signal pathway to PAI-1 production and that the latter pathway is mediated by activation of ERK. Furthermore, we have shown that troglitazone inhibited both TNF--induced PAI-1 protein secretion and mRNA in HUVECs. Genistein, but neither PD98059 nor emodin, was additive to the inhibitory effect of troglitazone on TNF--induced PAI-1 secretion. These results indicate That ERK and NF-B are possible targets of TNF- and troglitazone in the regulation of PAI-1 production.

Address correspondence to: Dr. Toshinari Takamura, Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan. E-mail: tt{at}medf.m.kanazawa-u.ac.jp

This article has been cited by other articles:

				J. I. Beier, L. Guo, C. von Montfort, J. P. Kaiser, S. Joshi-Barve, and G. E. Arteel New Role of Resistin in Lipopolysaccharide-Induced Liver Damage in Mice J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 801 - 808. [Abstract] [Full Text] [PDF]

				C. E. Hafer-Macko, F. M. Ivey, J. D. Sorkin, and R. F. Macko Microvascular tissue plasminogen activator is reduced in diabetic neuropathy Neurology, July 17, 2007; 69(3): 268 - 274. [Abstract] [Full Text] [PDF]

				Y. Mukai, C.-Y. Wang, Y. Rikitake, and J. K. Liao Phosphatidylinositol 3-kinase/protein kinase Akt negatively regulates plasminogen activator inhibitor type 1 expression in vascular endothelial cells Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1937 - H1942. [Abstract] [Full Text] [PDF]

				H. Leipold, M. Knoefler, C. Gruber, K. Klein, P. Haslinger, and C. Worda Plasminogen activator inhibitor 1 gene polymorphism and gestational diabetes mellitus. Obstet. Gynecol., March 1, 2006; 107(3): 651 - 656. [Abstract] [Full Text] [PDF]

				R. H. Sohn, C. B. Deming, D. C. Johns, H. C. Champion, C. Bian, K. Gardner, and J. J. Rade Regulation of endothelial thrombomodulin expression by inflammatory cytokines is mediated by activation of nuclear factor-kappa B Blood, May 15, 2005; 105(10): 3910 - 3917. [Abstract] [Full Text] [PDF]

				J. P. Luyendyk, W. B. Mattes, L. D. Burgoon, T. R. Zacharewski, J. F. Maddox, G. N. Cosma, P. E. Ganey, and R. A. Roth Gene Expression Analysis Points to Hemostasis in Livers of Rats Cotreated with Lipopolysaccharide and Ranitidine Toxicol. Sci., July 1, 2004; 80(1): 203 - 213. [Abstract] [Full Text] [PDF]