Effect of pitavastatin on transactivation of human serum paraoxonase 1 gene
Effect of pitavastatin on transactivation of human serum paraoxonase 1 gene
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DOI：
10.1016/j.metabol.2004.06.018
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发表时间：
2005-02-01
影响因子：
9.8
通讯作者：
Hashimoto, K
中科院分区：
文献类型：
--
作者：
Ota, K;Suehiro, T;Hashimoto, K
肝羟甲基戊二酰辅酶A HMG-CoA还原酶抑制剂（他汀类药物）具有多种不依赖于胆固醇降低的抗动脉粥样硬化多效性作用。人血清对氧磷酶1（PON 1）与高密度脂蛋白（HDL）相关，并抑制低密度脂蛋白（LDL）的氧化修饰。我们研究了他汀类药物对PON 1基因转录的影响，使用报告基因分析。通过测量转染到人肝癌HepG 2细胞和人胚肾（HEK）293细胞中的具有PON 1启动子区的质粒的荧光素酶活性来估计PON 1基因的启动子活性。匹伐他汀、辛伐他汀和阿托伐他汀各自显著增加PON 1启动子活性，并且匹伐他汀的反式激活被甲羟戊酸和焦磷酸法呢酯（FPP）废除，但是，不被香叶基香叶基焦磷酸。此外，PON 1启动子活性增强法呢基转移酶抑制剂（FTI），但不是由香叶基香叶基转移酶抑制剂（GGTI）。据报道，PON 1基因转录依赖于Sp1，并且匹伐他汀的反式激活被Sp1的抑制剂光辉霉素完全废除。我们的研究结果表明，匹伐他汀通过FPP途径激活PON 1基因的转录，这可能在他汀类药物的抗动脉粥样硬化作用中发挥重要作用。(C)2005年爱思唯尔公司All rights reserved.
Hepatic hydroxymethyl glutary coenzyme A HMG-CoA reductase inhibitors (statins) have various anti atherosclerosis pleiotropic effects that are independent of cholesterol reduction. Human serum paraoxonase 1 (PON1) is associated with high-density lipoprotein (HDL) and inhibits the oxidative modification of low-density lipoprotein (LDL). We investigated the effects of statins on PON1 gene transcription using a reporter gene assay. Promoter activity of the PON1 gene was estimated by measuring luciferase activity of plasmids with a PON1 promoter region transfected into human hepatoma HepG2 cells and human embryonic kidney (HEK) 293 cells. Pitavastatin, simvastatin, and atorvastatin each significantly increased PON1 promoter activity, and the transactivation by pitavastatin was abrogated by mevalonic acid and farnesyl pyrophosphate (FPP), however, not by geranylgeranyl pyrophosphate. Further, PON1 promoter activity was enhanced by farnesyl transferase inhibitor (FTI), but not by geranylgeranyl transferase inhibitor (GGTI). PON1 gene transcription has been reported to be dependent on Sp1 and the transactivation by pitavastatin was completely abrogated by mithramycin, an inhibitor of Sp1. Our results suggest that pitavastatin activates transcription of the PON1 gene through the FPP pathway, which may play an important role in the anti atherosclerotic effects of statins. (C) 2005 Elsevier Inc. All rights reserved.