| First Author | Chen Y | Year | 2011 |
| Journal | Arch Biochem Biophys | Volume | 507 |
| Issue | 2 | Pages | 241-7 |
| PubMed ID | 21176770 | Mgi Jnum | J:169245 |
| Mgi Id | MGI:4940149 | Doi | 10.1016/j.abb.2010.12.020 |
| Citation | Chen Y, et al. (2011) 1,25-Dihydroxyvitamin D(3) suppresses inflammation-induced expression of plasminogen activator inhibitor-1 by blocking nuclear factor-kappaB activation. Arch Biochem Biophys 507(2):241-7 |
| abstractText | 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 D(3) (1,25(OH)(2)D(3)), but the molecular mechanism remains unknown. Here we show that exposure of mouse embryonic fibroblasts to TNFalpha or LPS led to a marked induction of PAI-1, which was blunted by 1,25(OH)(2)D(3), NF-kappaB inhibitor or p65 siRNA, suggesting the involvement of NF-kappaB in 1,25(OH)(2)D(3)-induced repression. In mouse Pai-1 promoter a putative cis-kappaB element was identified at -299. EMSA and ChIP assays showed that TNF-alpha increased p50/p65 binding to this kappaB site, which was disrupted by 1,25(OH)(2)D(3). Luciferase reporter assays showed that PAI-1 promoter activity was induced by TNFalpha or LPS, and the induction was blocked by 1,25(OH)(2)D(3). Mutation of the kappaB site blunted TNFalpha, LPS or 1,25(OH)(2)D(3) effects. 1,25(OH)(2)D(3) blocked IkappaBalpha 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)(2)D(3) down-regulates PAI-1 by blocking NF-kappaB activation. Inhibition of PAI-1 production may contribute to the reno- and cardio-protective effects of vitamin D. |
