title: Lipophilic HMG-CoA reductase inhibitor has an anti-inflammatory effect: reduction of MRNA levels for interleukin-1beta, interleukin-6, cyclooxygenase-2, and p22phox by regulation of peroxisome proliferator-activated receptor alpha (PPARalpha) in primary endothelial cells.
abstract: We examined the effects of four 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (pravastatin, simvastatin, fluvastatin, and cerivastatin) on the production and expression of inflammatory cytokines and on enzyme expression involving prostaglandin and superoxide production in cultured human umbilical vein endothelial cells (HUVEC). All HMG-CoA reductase inhibitors significantly reduced interleukin-1beta and -6 mRNA expression and their protein levels in the culture medium, and also inhibited cyclooxygenase-2 mRNA expression and their protein levels. And these drugs induced peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma mRNA expression and their protein levels in HUVEC and hepatocyte. Moreover, the mRNA levels of p22phox, a 22-kD subunit and the protein levels of p47phox, a 47-kD subunit of nicotine adenine dinucleotide phosphate (NADPH) oxidase, was decreased by treatment with either simvastatin, fluvastatin or cerivastatin, and this effect was reversed by mevalonate, geranylgeraniol, farnesol, and cholesterol. The changes induced by HMG-CoA reductase inhibitors might be due to regulation of cellular cholesterol content level, cellular cholesterol metabolic pathway, and cellular PPARalpha activity, which was related with inflammation. This unique anti-inflammatory effect in addition to its hypolipidemic action, may be beneficial in preventing the vascular complications that are induced by hyperlipidemia.
authors.affiliation: Fourth Department of Internal Medicine, Saitama Medical School, Iruma-gun, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Inoue
authors.forename: S
authors.initials: S
authors.lastname: Goto
authors.forename: K
authors.initials: K
authors.lastname: Mizotani
authors.forename: T
authors.initials: T
authors.lastname: Awata
authors.forename: T
authors.initials: T
authors.lastname: Mastunaga
authors.forename: S
authors.initials: S
authors.lastname: Kawai
authors.forename: T
authors.initials: T
authors.lastname: Nakajima
authors.forename: S
authors.initials: S
authors.lastname: Hokari
authors.forename: T
authors.initials: T
authors.lastname: Komoda
authors.forename: S
authors.initials: S
authors.lastname: Katayama
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007375:Interleukin-1 / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics*; D007527:Isoenzymes / Q000235:genetics*; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009252:NADPH Dehydrogenase / Q000235:genetics*; D019255:NADPH Oxidases; D010750:Phosphoproteins / Q000235:genetics*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D000893:Anti-Inflammatory Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007375:Interleukin-1; D015850:Interleukin-6; D007527:Isoenzymes; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019255:NADPH Oxidases; C086986:CYBA protein, human; D009252:NADPH Dehydrogenase