Up-regulation of HDACs, a harbinger of uraemic endothelial dysfunction, is prevented by defibrotide.
Case-Control Studies
Cell Nucleus
/ drug effects
Endothelium
/ drug effects
Female
Histone Deacetylases
/ metabolism
Human Umbilical Vein Endothelial Cells
/ drug effects
Humans
Intercellular Adhesion Molecule-1
/ metabolism
Male
Middle Aged
Phosphatidylinositol 3-Kinases
/ metabolism
Polydeoxyribonucleotides
/ pharmacology
Proto-Oncogene Proteins c-akt
/ metabolism
Reactive Oxygen Species
/ metabolism
Renal Insufficiency, Chronic
/ blood
Signal Transduction
Toll-Like Receptor 4
/ metabolism
Up-Regulation
/ drug effects
Uremia
/ blood
von Willebrand Factor
/ metabolism
HDAC
HDAC1
HDAC2
chronic kidney disease
defibrotide
endothelial dysfunction
inflammation
oxidative stress
Journal
Journal of cellular and molecular medicine
ISSN: 1582-4934
Titre abrégé: J Cell Mol Med
Pays: England
ID NLM: 101083777
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
15
09
2019
revised:
24
10
2019
accepted:
11
11
2019
pubmed:
30
11
2019
medline:
23
4
2021
entrez:
30
11
2019
Statut:
ppublish
Résumé
Endothelial dysfunction is an earlier contributor to the development of atherosclerosis in chronic kidney disease (CKD), in which the role of epigenetic triggers cannot be ruled out. Endothelial protective strategies, such as defibrotide (DF), may be useful in this scenario. We evaluated changes induced by CKD on endothelial cell proteome and explored the effect of DF and the mechanisms involved. Human umbilical cord vein endothelial cells were exposed to sera from healthy donors (n = 20) and patients with end-stage renal disease on haemodialysis (n = 20). Differential protein expression was investigated by using a proteomic approach, Western blot and immunofluorescence. HDAC1 and HDAC2 overexpression was detected. Increased HDAC1 expression occurred at both cytoplasm and nucleus. These effects were dose-dependently inhibited by DF. Both the HDACs inhibitor trichostatin A and DF prevented the up-regulation of the endothelial dysfunction markers induced by the uraemic milieu: intercellular adhesion molecule-1, surface Toll-like receptor-4, von Willebrand Factor and reactive oxygen species. Moreover, DF down-regulated HDACs expression through the PI3/AKT signalling pathway. HDACs appear as key modulators of the CKD-induced endothelial dysfunction as specific blockade by trichostatin A or by DF prevents endothelial dysfunction responses to the CKD insult. Moreover, DF exerts its endothelial protective effect by inhibiting HDAC up-regulation likely through PI3K/AKT.
Identifiants
pubmed: 31782253
doi: 10.1111/jcmm.14865
pmc: PMC6991634
doi:
Substances chimiques
Polydeoxyribonucleotides
0
Reactive Oxygen Species
0
Toll-Like Receptor 4
0
von Willebrand Factor
0
Intercellular Adhesion Molecule-1
126547-89-5
defibrotide
438HCF2X0M
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Histone Deacetylases
EC 3.5.1.98
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1713-1723Informations de copyright
© 2019 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
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