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

Yutaka Masuda; Dan Saotome; Kimihiko Takada; Katsuyoshi Sugimoto; Tomoyuki Sasaki; Hidemi Ishii

doi:10.1160/TH12-02-0101

Thrombosis and Haemostasis, Table of Contents

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

¹Laboratory of Molecular and Cellular Pathophysiology, Showa Pharmaceutical University, Machida, Tokyo, Japan

²High Technology Research Center, Showa Pharmaceutical University, Machida, Tokyo, Japan

,

Dan Saotome

¹Laboratory of Molecular and Cellular Pathophysiology, Showa Pharmaceutical University, Machida, Tokyo, Japan

,

Kimihiko Takada

¹Laboratory of Molecular and Cellular Pathophysiology, Showa Pharmaceutical University, Machida, Tokyo, Japan

²High Technology Research Center, Showa Pharmaceutical University, Machida, Tokyo, Japan

,

Katsuyoshi Sugimoto

²High Technology Research Center, Showa Pharmaceutical University, Machida, Tokyo, Japan

,

Tomoyuki Sasaki

²High Technology Research Center, Showa Pharmaceutical University, Machida, Tokyo, Japan

,

Hidemi Ishii

¹Laboratory of Molecular and Cellular Pathophysiology, Showa Pharmaceutical University, Machida, Tokyo, Japan

²High Technology Research Center, Showa Pharmaceutical University, Machida, Tokyo, Japan

› Author Affiliations

Abstract

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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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References

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