Accéder au contenu
Merck

Downregulation of the glucocorticoid-induced leucine zipper (GILZ) promotes vascular inflammation.

Atherosclerosis (2014-04-22)
Rebecca T Hahn, Jessica Hoppstädter, Kerstin Hirschfelder, Nina Hachenthal, Britta Diesel, Sonja M Kessler, Hanno Huwer, Alexandra K Kiemer
RÉSUMÉ

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. 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. 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.

MATÉRIAUX
Référence du produit
Marque
Description du produit

Sigma-Aldrich
Acide acétique, glacial, ACS reagent, ≥99.7%
Sigma-Aldrich
Acide acétique, glacial, ReagentPlus®, ≥99%
Sigma-Aldrich
Acide acétique, glacial, ≥99.99% trace metals basis
Sigma-Aldrich
Acide acétique solution, suitable for HPLC
Sigma-Aldrich
Acide acétique, glacial, puriss., meets analytical specification of Ph. Eur., BP, USP, FCC, 99.8-100.5%
Sigma-Aldrich
Acide acétique, glacial, puriss. p.a., ACS reagent, reag. ISO, reag. Ph. Eur., ≥99.8%
Sigma-Aldrich
Anticorps monoclonal anti-α-tubuline antibody produced in mouse, clone DM1A, ascites fluid
Sigma-Aldrich
Acide acétique, for luminescence, BioUltra, ≥99.5% (GC)
USP
Acide acétique, United States Pharmacopeia (USP) Reference Standard
Sigma-Aldrich
Acide acétique, ≥99.5%, FCC, FG
Sigma-Aldrich
Acide acétique, natural, ≥99.5%, FG
Sigma-Aldrich
Acide acétique, glacial, puriss., 99-100%
Sigma-Aldrich
5α-Androstan-17β-ol-3-one, purum, ≥99.0% (TLC)
Supelco
Acide acétique, analytical standard
Sigma-Aldrich
Acetic acid-12C2, 99.9 atom % 12C
Sigma-Aldrich
Anti-TTP (N-terminal) antibody produced in rabbit, ~1.0 mg/mL, affinity isolated antibody, buffered aqueous solution
Supelco
5α-Androstan-17β-ol-3-one, VETRANAL®, analytical standard
Millipore
Acide acétique solution, suitable for microbiology