1,25-Dihydroxyvitamin D3 suppresses inflammation-induced expression of plasminogen activator inhibitor-1 by blocking nuclear factor-κB activation

Yunzi Chen, Juan Kong, Tao Sun, George Li, Frances L. Szeto, Weicheng Liu, Dilip K. Deb, Youli Wang, Qun Zhao, Ravi Thadhani, Yan Chun Li

Research output: Contribution to journalArticle

62 Scopus citations

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)2D 3-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.

Original languageEnglish (US)
Pages (from-to)241-247
Number of pages7
JournalArchives of Biochemistry and Biophysics
Volume507
Issue number2
DOIs
StatePublished - Mar 15 2011
Externally publishedYes

Keywords

  • Gene regulation
  • NF-κB
  • PAI-1
  • Vitamin D

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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