title: The protective effect of fenofibrate against TNF-α-induced CD40 expression through SIRT1-mediated deacetylation of NF-κB in endothelial cells.
abstract: Fenofibrate, as a lipid-lowering drug in clinic, participates in the regulation of inflammatory response. Recently, increasing studies have indicated that sirtuin1 (SIRT1), a NAD+-dependent deacetylase, has potential anti-inflammatory effect in endothelial cells. However, whether the regulatory effect of fenofibrate on inflammation response is mediated by SIRT1 remains unclear. The aim of this study was to investigate the effect of fenofibrate on the expressions of SIRT1 and pro-inflammatory cytokine CD40 in endothelial cells and explore the underlying mechanisms. The results showed that fenofibrate upregulated SIRT1 expression and inhibited CD40 expression in TNF-α-stimulated endothelial cells, but these effects were reversed by peroxisome proliferator-activated receptor-α (PPARα) antagonist GW6471. Furthermore, SIRT1 inhibitors sirtinol/nicotinamide (NAM) or SIRT1 knockdown could attenuate the effect of fenofibrate on CD40 expression in endothelial cells. Importantly, NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) augmented the effect of fenofibrate on CD40 expression. Further study found that fenofibrate decreased the expression of acetylated-NF-κB p65 (Ac-NF-κB p65) in TNF-α-stimulated endothelial cells, which was abolished by SIRT1 knockdown. These results indicate that fenofibrate has protective effect against TNF-α-induced CD40 expression through SIRT1-mediated deacetylation of the p65 subunit of NF-κB.
authors.forename: Weirong
authors.initials: W
authors.lastname: Wang
authors.forename: Ling
authors.initials: L
authors.lastname: Bai
authors.forename: Hu
authors.initials: H
authors.lastname: Qiao
authors.forename: Yanxiang
authors.initials: Y
authors.lastname: Lu
authors.forename: Lina
authors.initials: L
authors.lastname: Yang
authors.forename: Jiye
authors.initials: J
authors.lastname: Zhang
authors.forename: Rong
authors.initials: R
authors.lastname: Lin
authors.forename: Feng
authors.initials: F
authors.lastname: Ren
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhang
authors.forename: Meixi
authors.initials: M
authors.lastname: Ji
mesh_terms: D000107:Acetylation; D000975:Antioxidants / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D019013:CD40 Antigens / Q000096:biosynthesis*; D002478:Cells, Cultured; D011345:Fenofibrate / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy; D009284:Naphthols / Q000494:pharmacology; D009536:Niacinamide / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D047493:PPAR alpha / Q000037:antagonists & inhibitors; D011759:Pyrrolidines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D013859:Thiocarbamates / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000975:Antioxidants; D001549:Benzamides; D019013:CD40 Antigens; C449302:GW 6471; D000960:Hypolipidemic Agents; D009284:Naphthols; D010080:Oxazoles; D047493:PPAR alpha; D011759:Pyrrolidines; D034741:RNA, Small Interfering; D013859:Thiocarbamates; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C439060:sirtinol; C020972:pyrrolidine dithiocarbamic acid; D009536:Niacinamide; D014443:Tyrosine; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D011345:Fenofibrate
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