title: 1,25-Dihydroxyvitamin D₃ suppresses inflammation-induced expression of plasminogen activator inhibitor-1 by blocking nuclear factor-κB activation.
abstract: Plasminogen activator inhibitor (PAI)-1 is a major fibrinolytic inhibitor. High PAI-1 is associated with increased renal and cardiovascular disease risk. Previous studies demonstrated PAI-1 down-regulation by 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), but the molecular mechanism remains unknown. Here we show that exposure of mouse embryonic fibroblasts to TNFα or LPS led to a marked induction of PAI-1, which was blunted by 1,25(OH)₂D₃, NF-κB inhibitor or p65 siRNA, suggesting the involvement of NF-κB in 1,25(OH)₂D₃-induced repression. In mouse Pai-1 promoter a putative cis-κB element was identified at -299. EMSA and ChIP assays showed that TNF-α increased p50/p65 binding to this κB site, which was disrupted by 1,25(OH)₂D₃. Luciferase reporter assays showed that PAI-1 promoter activity was induced by TNFα or LPS, and the induction was blocked by 1,25(OH)₂D₃. Mutation of the κB site blunted TNFα, LPS or 1,25(OH)₂D₃ effects. 1,25(OH)₂D₃ blocked IκBα degradation and arrested p50/p65 nuclear translocation. In mice LPS stimulated PAI-1 expression in the heart and macrophages, and the stimulation was blunted by pre-treatment with a vitamin D analog. Together these data demonstrate that 1,25(OH)₂D₃ down-regulates PAI-1 by blocking NF-κB activation. Inhibition of PAI-1 production may contribute to the reno- and cardio-protective effects of vitamin D.
authors.affiliation: Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL, USA.
authors.forename: Yunzi
authors.initials: Y
authors.lastname: Chen
authors.forename: Juan
authors.initials: J
authors.lastname: Kong
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.forename: George
authors.initials: G
authors.lastname: Li
authors.forename: Frances L
authors.initials: FL
authors.lastname: Szeto
authors.forename: Weicheng
authors.initials: W
authors.lastname: Liu
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Deb
authors.forename: Youli
authors.initials: Y
authors.lastname: Wang
authors.forename: Qun
authors.initials: Q
authors.lastname: Zhao
authors.forename: Ravi
authors.initials: R
authors.lastname: Thadhani
authors.forename: Yan Chun
authors.initials: YC
authors.lastname: Li
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001483:Base Sequence; D002117:Calcitriol / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D017395:Plasminogen Activator Inhibitor 1; D014409:Tumor Necrosis Factor-alpha; D002117:Calcitriol