Effect of pitavastatin on transactivation of human serum paraoxonase 1 gene.
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.
Ota
Kikuko
K
Department of Endocrinology, Metabolism and Nephrology, Mochi Medical School, Kochi University, Kochi 783-8505, Japan.
Suehiro
Tadashi
T
Arii
Kaoru
K
Ikeda
Yukio
Y
Kumon
Yoshitaka
Y
Osaki
Fumiaki
F
Hashimoto
Kozo
K
D019883:Alkyl and Aryl Transferases / Q000378:metabolism; D043303:Aryldialkylphosphatase / Q000235:genetics* / Q000378:metabolism*; D000069059:Atorvastatin; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D051231:Farnesyltranstransferase; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D008798:Mevalonic Acid / Q000378:metabolism / Q000494:pharmacology; D010957:Plasmids / Q000235:genetics; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D012717:Sesquiterpenes; D016329:Sp1 Transcription Factor; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D011758:Pyrroles; D011804:Quinolines; D012717:Sesquiterpenes; D016329:Sp1 Transcription Factor; C004808:farnesyl pyrophosphate; D004247:DNA; D000069059:Atorvastatin; D008156:Luciferases; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase; D043303:Aryldialkylphosphatase; C108475:pitavastatin; D008798:Mevalonic Acid