Pitavastatin induces PON1 expression through p44/42 mitogen-activated protein kinase signaling cascade in Huh7 cells

被引:32
作者
Arii, Kaoru [1 ]
Suehiro, Tadashi [1 ]
Ota, Kikuko [1 ]
Ikeda, Yukio [1 ]
Kumon, Yoshitaka [2 ]
Osaki, Fumiaki [1 ]
Inoue, Mari [1 ]
Inada, Syojiro [1 ]
Ogami, Naoko [1 ]
Takata, Hiroshi [1 ]
Hashimoto, Kozo [1 ]
Terada, Yoshio [1 ]
机构
[1] Kochi Univ, Dept Endocrinol Metab & Nephrol, Kochi Med Sch, Nanko Ku, Kochi 7838505, Japan
[2] Kochi Univ, Dept Lab Med, Kochi Med Sch, Kochi 7838505, Japan
关键词
Paraoxonase; HMG-CoA reductase inhibitor; ERE; SREBP-2; Sp1; ELEMENT-BINDING PROTEIN-2; CORONARY HEART-DISEASE; SERUM PARAOXONASE; DENSITY-LIPOPROTEIN; MAP KINASE; GENE-EXPRESSION; OXIDATION; TRANSCRIPTION; POLYMORPHISM; MACROPHAGES;
D O I
10.1016/j.atherosclerosis.2008.05.013
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
It has been shown that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors have pleiotropic effects and that human serum paraoxonase (PON1) inhibits the oxidative modification of low-density lipoprotein. We investigated the effects of pitavastatin on PON1 gene promoter activity and PON1 protein expression through the activation of mitogen-activated protein (MAP) kinase signaling cascades in cultured Huh7 cells. Both PON1 gene promoter activity and PON1 protein expression were elevated by pitavastatin stimulation. Pitavastatin phosphorylated p44/42 MAP kinase. The effects of pitavastatin on PON1 promoter activity and PON1 protein expression were attenuated by PD98059. The cotransfection of Sp1 expression vector increased PON1 promoter activity, and mithramycin suppressed pitavastatin-enhanced PON1 promoter activity. The latter activity was attenuated by cotransfection with the expression vector of sterol regulatory element-binding protein-2 (SREBP-2) with mutated p44/42 MAP kinase specific phosphorylation sites. Pitavastatin increased the Sp1-PON1 DNA complex and this effect was attenuated by PD98059. These observations suggest that pitavastatin phosphorylates p44/42 MAP kinase and then activates the transcription of PON1 gene and increases the PON1 protein expression in Huh7 cells. Furthermore, we speculate that pitavastatin affects both the phosphorylation of SREBP-2 and the Sp1 binding to PON1 DNA through the activation of p44/42 MAP kinase signaling cascade. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码:439 / 445
页数:7
相关论文
共 27 条
[1]   Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions - A possible peroxidative role for paraoxonase [J].
Aviram, M ;
Rosenblat, M ;
Bisgaier, CL ;
Newton, RS ;
Primo-Parmo, SL ;
La Du, BN .
JOURNAL OF CLINICAL INVESTIGATION, 1998, 101 (08) :1581-1590
[2]   Atorvastatin and gemfibrozil metabolites, but not the parent drugs, are potent antioxidants against lipoprotein oxidation [J].
Aviram, M ;
Rosenblat, M ;
Bisgaier, CL ;
Newton, RS .
ATHEROSCLEROSIS, 1998, 138 (02) :271-280
[3]   Non-lipid-related effects of statins [J].
Bellosta, S ;
Ferri, N ;
Bernini, F ;
Paoletti, R ;
Corsini, A .
ANNALS OF MEDICINE, 2000, 32 (03) :164-176
[4]   IDENTIFICATION OF A DISTINCT HUMAN HIGH-DENSITY-LIPOPROTEIN SUBSPECIES DEFINED BY A LIPOPROTEIN-ASSOCIATED PROTEIN, K-45 - IDENTITY OF K-45 WITH PARAOXONASE [J].
BLATTER, MC ;
JAMES, RW ;
MESSMER, S ;
BARJA, F ;
POMETTA, D .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1993, 211 (03) :871-879
[5]   Mammalian MAP kinase signalling cascades [J].
Chang, LF ;
Karin, M .
NATURE, 2001, 410 (6824) :37-40
[6]   HMG-CoA reductase inhibitors induce COX-2 gene expression in murine macrophages:: role of MAPK cascades and promoter elements for CREB and C/EBPβ [J].
Chen, JC ;
Huang, KC ;
Wingerd, B ;
Wu, WT ;
Lin, WW .
EXPERIMENTAL CELL RESEARCH, 2004, 301 (02) :305-319
[7]   Paraoxonase-1 promoter haplotypes and serum paraoxonase: a predominant role for polymorphic position-107, implicating the Sp1 transcription factor [J].
Deakin, S ;
Leviev, I ;
Brulhart-Meynet, MC ;
James, RW .
BIOCHEMICAL JOURNAL, 2003, 372 (372) :643-649
[8]   Simvastatin modulates expression of the PON1 gene and increases serum paraoxonase -: A role for sterol regulatory element-binding protein-2 [J].
Deakin, S ;
Leviev, I ;
Guernier, S ;
James, RW .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2003, 23 (11) :2083-2089
[9]   SIMVASTATIN INHIBITS THE OXIDATION OF LOW-DENSITY LIPOPROTEINS BY ACTIVATED HUMAN MONOCYTE-DERIVED MACROPHAGES [J].
GIROUX, LM ;
DAVIGNON, J ;
NARUSZEWICZ, M .
BIOCHIMICA ET BIOPHYSICA ACTA, 1993, 1165 (03) :335-338
[10]   Serum paraoxonase activity and its relationship to diabetic complications in patients with non-insulin-dependent diabetes mellitus [J].
Ikeda, Y ;
Suehiro, T ;
Inoue, M ;
Nakauchi, Y ;
Morita, T ;
Arii, K ;
Ito, H ;
Kumon, Y ;
Hashimoto, K .
METABOLISM-CLINICAL AND EXPERIMENTAL, 1998, 47 (05) :598-602