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Prepublished online as a Blood First Edition Paper on February 6, 2003; DOI 10.1182/blood-2002-08-2428. This Article Full Text (PDF) All Versions of this Article: 2002-08-2428v1 101/12/4765    most recent Alert me when this article is cited Alert me if a correction is posted 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ishii, H. Articles by Horie, S. Search for Related Content PubMed PubMed Citation Articles by Ishii, H. Articles by Horie, S. Social Bookmarking                   What's this? Submitted August 9, 2002 Accepted January 28, 2003 Oxidized phospholipids in oxidized low-density lipoprotein downregulate thrombomodulin transcription in vascular endothelial cells through a decrease in the binding of RAR-RXR heterodimers and Sp1 and 3 to their binding sequences in the TM promoter Hidemi Ishii*, Tsuyoshi Tezuka, Hiroyuki Ishikawa, Kimihiko Takada, Koji Oida, and Shuichi Horie Department of Public Health, Showa Pharmaceutical University, Tokyo, Japan Third Depertment of Internal Medicine, Fukui Medical University, Fukui, Japan Department of Clinical Biochemistry, Teikyo University, Faculty of Pharmaceutical Sciences, Tsukui, Kanagawa, Japan * Corresponding author; email: H-ishii{at}ac.shoyaku.ac.jp. The present work investigated the mechanism for down-regulation of thrombomodulin (TM), an anticoagulant glycoprotein, on cultured umbilical vein endothelial cells (HUVECs) exposed to lipid extracts from oxidized low density lipoprotein (ox-LDL). HUVECs exposed to phospholipid extracts, but not to free cholesterol, triglyceride, or cholesterol ester, isolated from ox-LDL reduced TM mRNA levels to nearly the same extent as native ox-LDL. Oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine (ox-PAPC), but not native PAPC or a reduced form of ox-PAPC, markedly decreased TM mRNA levels. The apparent half-life (t 1/2=2.7 h) of TM mRNA in control cells was not significantly different from that in cells exposed to ox-LDL or ox-PAPC. TM mRNA levels was regulated by transcriptional activation via a retinoid receptor (RAR). The binding activities of nuclear proteins from HUVECs treated with ox-LDL or ox-PAPC to the DR4 or Sp1 sequence in the TM promoter was significantly reduced with decreased expression of RAR, retinoid X receptor (RXR), Sp1 and Sp3 in the nuclei. The promoter activity in HUVECs transfected with a reporter plasmid expressing the TM promoter with targeted deletions in the DR4 and Sp1 binding elements was decreased to about 20 % of that with the wild type construct. Treatment of the cells with ox-PAPC had no additional effect on the promoter activity. These results suggest that oxidized phospholipids in ox-LDL inhibit transcription of the TM gene in HUVECs by inhibiting the binding of RAR-RXR heterodimer and Sp including Sp1 and Sp3 to the DR4 element and Sp1 binding element, respectively, in the TM promoter with reduced expression of RAR, RXR and Sp1 and 3 in the nuclei. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: N. Takeda, K. Maemura, S. Horie, K. Oishi, Y. Imai, T. Harada, T. Saito, T. Shiga, E. Amiya, I. Manabe, et al. Thrombomodulin Is a Clock-controlled Gene in Vascular Endothelial Cells J. Biol. Chem., November 9, 2007; 282(45): 32561 - 32567. [Abstract] [Full Text] [PDF] M. V. de Wouwer, D. Collen, and E. M. Conway Thrombomodulin-Protein C-EPCR System: Integrated to Regulate Coagulation and Inflammation Arterioscler. Thromb. Vasc. Biol., August 1, 2004; 24(8): 1374 - 1383. [Abstract] [Full Text] [PDF]

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