|
|
Prepublished online as a Blood First Edition Paper on February 6, 2003; DOI 10.1182/blood-2002-08-2428.
 Previous Article | Table of Contents | Next Article 
Blood, 15 June 2003, Vol. 101, No. 12, pp. 4765-4774
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Oxidized phospholipids in oxidized low-density lipoprotein down-regulate thrombomodulin transcription in vascular endothelial cells through a decrease in the binding of RAR -RXR heterodimers and Sp1 and Sp3 to their binding sequences in the TM promoter
Hidemi Ishii,
Tsuyoshi Tezuka,
Hiroyuki Ishikawa,
Kimihiko Takada,
Koji Oida, and
Shuichi Horie
From the Department of Public Health, Showa Pharmaceutical University, Machida, Tokyo, Japan; the Third Department of Internal Medicine, Fukui Medical University, Fukui, Japan; and the Department of Clinical Biochemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Suarashi, Tsukui, Kanagawa, Japan.
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 hours) of TM mRNA in control cells was not significantly different from that in cells exposed to ox-LDL or ox-PAPC. TM mRNA levels were 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 stimulatory protein 1 (Sp1) sequence in the TM promoter were 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 Sp3 in the nuclei.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
T. Yoshida, Q. Gan, and G. K. Owens
Kruppel-like factor 4, Elk-1, and histone deacetylases cooperatively suppress smooth muscle cell differentiation markers in response to oxidized phospholipids
Am J Physiol Cell Physiol,
November 1, 2008;
295(5):
C1175 - C1182.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
