Peroxisome proliferator-activated receptor-alp la agonists repress expression of thrombin-activatable fibrinolysis inhibitor by decreasing transcript stability
Peroxisome proliferator-activated receptor-alp la agonists repress expression of thrombin-activatable fibrinolysis inhibitor by decreasing transcript stability
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DOI：
10.1160/th12-02-0101
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发表时间：
2012-07-01
影响因子：
6.7
通讯作者：
Ishii, Hidemi
中科院分区：
文献类型：
--
作者：
Masuda, Yutaka;Saotome, Dan;Ishii, Hidemi
凝血酶活化纤维蛋白溶解抑制剂（TAFI）（羧肽酶82）是一种血浆酶原，在肝脏中生物合成并释放到血液循环中。活化的TAFI是一种抑制纤维蛋白凝块溶解的血栓形成因子。用过氧化物酶体增殖物激活受体(PPAR) α、β或γ激动剂处理培养的人肝癌HepG2细胞，测量TAFI抗原和mRNA（这里称为CPB2 mRNA）的水平。HepG2细胞用PPAR α激动剂WY14643处理，而不用PPAR β或PPAR γ激动剂处理，减少了它们向条件培养基中释放TAFI抗原。同时，细胞中CPB2 mRNA和TAFI抗原水平降低。PPARa的过表达加速了wy14643介导的CPB2 mRNA水平的下降，而PPARa mRNA的RNA干扰则使其消失。WY14643对CPB2基因启动子活性没有影响。与对照组相比，用WY14643处理CPB2转录物的半衰期缩短，用PPARa拮抗剂MK886处理或用PPARa特异性siRNA转染WY14643处理的HepG2细胞后，减少的mRNA半衰期恢复到对照水平。目前的研究结果表明，PPARa激动剂不仅具有降血脂作用，而且还通过降低CPB2转录本的稳定性来降低血栓形成因子TAFI的表达。
Thrombin-activatable fibrinolysis inhibitor (TAFI) (carboxypeptidase 82) 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)alpha, beta or gamma agonists, and the levels of TAFI antigen and mRNA (here, termed CPB2 mRNA) were measured. HepG2 cells treated with the PPAR alpha agonist WY14643, but not agonists for PPAR beta or PPAR gamma, 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 PPARa 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 PPARa antagonist MK886 or transfection of PPARA-specific siRNA to WY14643-treated HepG2 cells. The present results suggest that PPARa agonists not only play a hypolipidaemic role, but also decrease the expression of TAFI, a prothrombotic factor, by decreasing stability of CPB2 transcripts.