Up‐regulation of HDACs, a harbinger of uraemic endothelial dysfunction, is prevented by defibrotide

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.

Role of PI3K in the Progression and Regression of Atherosclerosis

“…However, total saponins inhibited these signaling pathways and were found to play a protective role in endothelial cells ( Zhou et al, 2018 ). Defibrotide may play a protective role in the endothelium by inhibiting the upregulation of histone deacetylase through the PI3K/AKT signaling pathway and hindering endothelial cell transformation into a proinflammatory phenotypes, thus reducing the expression of adhesion receptors and decreasing oxidative stress ( Shakespear et al, 2011 ; Palomo et al, 2020 ).…”

Is the Endothelium the Missing Link in the Pathophysiology and Treatment of COVID-19 Complications?

“…Studies by our group have previously characterized the ED associated with some of these pathological conditions, with alterations in hemostasis, accelerated atherothrombosis, enhanced inflammatory reaction, and an impaired immune response. Despite the causes differ among the mentioned pathological conditions, ED shares common characteristics, such as an increased expression of adhesion receptors at the cell surface, the production of a more thrombogenic extracellular matrix enriched with pro-adhesive proteins, such as von Willebrand factor (VWF) and tissue factor (TF), the activation of intracellular inflammation-related proteins, such as p38 MAPK and the nuclear factor kappa B (NFκB), and the development of oxidative stress [ 14 – 16 ]. These features coexist with the activation of monocytes, macrophages, and granulocytes, favoring the inflammatory phenotype.…”

Applying Proteomics and Integrative “Omics” Strategies to Decipher the Chronic Kidney Disease-Related Atherosclerosis

“…As a result, atherosclerosis and CVD accelerate. Translational proteomic studies have been used to demonstrate the changes occurring in endothelial cells under uremic serum exposure [ 85 , 86 ]. The mechanisms evoked by uremic factors on the endothelial dysfunction and thus atherosclerosis were closely linked to enhanced oxidative stress and induction of pro-thrombotic, pro-inflammatory, and pro-proliferative state.…”