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Thromb Haemost 2012; 108(01): 74-85
DOI: 10.1160/TH12-02-0101
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Peroxisome proliferator-activated receptor-alpha agonists repress expression of thrombin-activatable fibrinolysis inhibitor by decreasing transcript stability

Yutaka Masuda
1   Laboratory of Molecular and Cellular Pathophysiology, Showa Pharmaceutical University, Machida, Tokyo, Japan
2   High Technology Research Center, Showa Pharmaceutical University, Machida, Tokyo, Japan
,
Dan Saotome
1   Laboratory of Molecular and Cellular Pathophysiology, Showa Pharmaceutical University, Machida, Tokyo, Japan
,
Kimihiko Takada
1   Laboratory of Molecular and Cellular Pathophysiology, Showa Pharmaceutical University, Machida, Tokyo, Japan
2   High Technology Research Center, Showa Pharmaceutical University, Machida, Tokyo, Japan
,
Katsuyoshi Sugimoto
2   High Technology Research Center, Showa Pharmaceutical University, Machida, Tokyo, Japan
,
Tomoyuki Sasaki
2   High Technology Research Center, Showa Pharmaceutical University, Machida, Tokyo, Japan
,
Hidemi Ishii
1   Laboratory of Molecular and Cellular Pathophysiology, Showa Pharmaceutical University, Machida, Tokyo, Japan
2   High Technology Research Center, Showa Pharmaceutical University, Machida, Tokyo, Japan
› Author Affiliations
Further Information

Publication History

Received: 27 February 2012

Accepted after minor revision: 13 April 2012

Publication Date:
22 November 2017 (online)

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Summary

Thrombin-activatable fibrinolysis inhibitor (TAFI) (carboxypeptidase B2) is a plasma zymogen that is biosynthesised in the liver and released into the circulation. Activated TAFI is a prothrombotic factor which inhibits fibrin clot lysis. Cultured human hepatoma HepG2 cells were treated with peroxisome proliferator-activated receptor (PPAR)α, β or γ agonists, and the levels of TAFI antigen and mRNA (here, termed CPB2 mRNA) were measured. HepG2 cells treated with the PPARα agonist WY14643, but not agonists for PPARβ or PPARγ, decreased their release of TAFI antigen into the conditioned medium. In parallel, there were decreased levels of CPB2 mRNA and TAFI antigen in the cells. The WY14643-mediated decrease in CPB2 mRNA levels was accelerated by overexpression of PPARα and abolished by RNA interference of PPARA mRNA. CPB2 gene promoter activity was not influenced by treatment of the cells with WY14643. The half-life of the CPB2 transcript was shortened by treatment with WY14643 as compared with that of the control, and the decreased half-life of mRNA returned to control levels by treatment with a PPARα antagonist MK886 or transfection of PPARΑ-specific siRNA to WY14643-treated HepG2 cells. The present results suggest that PPARα agonists not only play a hypolipidaemic role, but also decrease the expression of TAFI, a prothrombotic factor, by decreasing stability of CPB2 transcripts.

Keywords

Thrombin-activatable fibrinolysis inhibitor (TAFI) - peroxisome proliferator-activated receptor (PPAR)-alpha - WY14643 - HepG2 cells
 

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