1. Up-regulation of HDACs, a harbinger of uraemic endothelial dysfunction, is prevented by defibrotide.
- Author
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Palomo M, Vera M, Martin S, Torramadé-Moix S, Martinez-Sanchez J, Belen Moreno A, Carreras E, Escolar G, Cases A, and Díaz-Ricart M
- Subjects
- Case-Control Studies, Cell Nucleus drug effects, Cell Nucleus metabolism, Endothelium drug effects, Female, Human Umbilical Vein Endothelial Cells drug effects, Human Umbilical Vein Endothelial Cells metabolism, Humans, Intercellular Adhesion Molecule-1 metabolism, Male, Middle Aged, Phosphatidylinositol 3-Kinases metabolism, 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, Endothelium physiopathology, Histone Deacetylases metabolism, Polydeoxyribonucleotides pharmacology, Up-Regulation genetics, Uremia enzymology, Uremia pathology
- Abstract
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., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
- Published
- 2020
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