Document Detail


Downregulation of the glucocorticoid-induced leucine zipper (GILZ) promotes vascular inflammation.
MedLine Citation:
PMID:  24747114     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
OBJECTIVE: Glucocorticoid-induced leucine zipper (GILZ) represents an anti-inflammatory mediator, whose downregulation has been described in various inflammatory processes. Aim of our study was to decipher the regulation of GILZ in vascular inflammation.
APPROACH AND RESULTS: Degenerated aortocoronary saphenous vein bypass grafts (n = 15), which exhibited inflammatory cell activation as determined by enhanced monocyte chemoattractrant protein 1 (MCP-1, CCL2) and Toll-like receptor 2 (TLR2) expression, showed significantly diminished GILZ protein and mRNA levels compared to healthy veins (n = 23). GILZ was also downregulated in human umbilical vein endothelial cells (HUVEC) and macrophages upon treatment with the inflammatory cytokine TNF-α in a tristetraprolin (ZFP36, TTP)- and p38 MAPK-dependent manner. To assess the functional implications of decreased GILZ expression, we determined NF-κB activation after GILZ knockdown by siRNA and found that NF-κB activity and inflammatory gene expression were significantly enhanced. Importantly, ZFP36 is induced in TNF-α-activated HUVEC as well as in degenerated vein bypasses. When atheroprotective laminar shear stress was employed, GILZ levels in HUVEC increased on mRNA and protein level. Laminar flow also counteracted TNF-α-induced ZFP36 expression and GILZ downregulation. MAP kinase phosphatase 1 (MKP-1, DUSP1), a negative regulator of ZFP36 expression, was distinctly upregulated under laminar shear stress conditions and downregulated in degenerated vein bypasses.
CONCLUSION: Our data show a diminished expression of the anti-inflammatory mediator GILZ in the inflamed vasculature and indicate that GILZ downregulation requires the mRNA binding protein ZFP36. We suggest that reduced GILZ levels play a role in cardiovascular disease.
Authors:
Rebecca T Hahn; Jessica Hoppstädter; Kerstin Hirschfelder; Nina Hachenthal; Britta Diesel; Sonja M Kessler; Hanno Huwer; Alexandra K Kiemer
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-4-5
Journal Detail:
Title:  Atherosclerosis     Volume:  234     ISSN:  1879-1484     ISO Abbreviation:  Atherosclerosis     Publication Date:  2014 Apr 
Date Detail:
Created Date:  2014-4-21     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0242543     Medline TA:  Atherosclerosis     Country:  -    
Other Details:
Languages:  ENG     Pagination:  391-400     Citation Subset:  -    
Copyright Information:
Copyright © 2014. Published by Elsevier Ireland Ltd.
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