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Role of endothelial microvesicles released by p-cresol on endothelial dysfunction.

ABSTRACT: Protein bound uremic toxins, such as p-cresol, cannot be effectively removed by conventional dialysis techniques and are accumulated in plasma, thus contributing to progression of both chronic kidney disease (CKD) and cardiovascular disease (CVD). Pathological effects of uremic toxins include activation of inflammatory response, endothelial dysfunction and release of endothelial microvesicles. To date, the role of p-cresol in endothelial microvesicles formation has not been analyzed. The aim of the present study was evaluate the effects of endothelial microvesicles released by p-cresol (PcEMV) on endothelial dysfunction. An in vitro model of endothelial damage mediated by p-cresol was proposed to evaluate the functional effect of PcEMV on the endothelial repair process carried out by endothelial cells and microRNA (miRNA) that could be involved in this process. We observed that p-cresol induced a greater release of microvesicles in endothelial cells. These microvesicles altered regenerative capacity of endothelial cells, decreasing their capacity for cell migration and their potential to form vascular structures in vitro. Moreover, we observed increased cellular senescence and a deregulation of miRNA-146b-5p and miRNA-223-3p expression in endothelial cells treated with endothelial microvesicles released by p-cresol. In summary our data show that microvesicles generated in endothelial cells treated with p-cresol (PcEMV) interfere with the endothelial repair process by decreasing the migratory capacity, the ability to form new vessels and increasing the senescence of mature endothelial cells. These alterations could be mediated by the upregulation of miRNA-146b-5p and miRNA-223-3p.

SUBMITTER: Guerrero F

PROVIDER: S-EPMC7326964 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMicrovesicles are vesicles shed by plasma membranes following cell activation and apoptosis. The role of lymphocyte-derived microvesicles in endothelial function remains poorly understood.MethodsCD4+ T cells isolated from peripheral blood of healthy human donors were stimulated using anti-CD3/anti-CD28-coated beads. Proteomic profiling of microvesicles was performed using linear discriminant analysis (LDA) from activated T cells (MV.Act) and nonactivated T cells (MV.NAct). In addition, data processing analysis was performed using MaxQUANT workflow. Differentially expressed proteins found in MV.Act or MV.NAct samples with identification frequency = 100%, which were selected by both LDA (p < .01) and MaxQUANT (p < .01) workflows, were defined as "high-confidence" differentially expressed proteins. Functional effects of MV.Act on human primary microvascular endothelial cells were analysed.ResultsT cells released large amounts of microvesicles upon stimulation. Proteomic profiling of microvesicles using LDA identified 2279 proteins (n = 2110 and n = 851 proteins in MV.Act and MV.NAct, respectively). Protein-protein interaction network models reconstructed from both differentially expressed proteins (n = 594; LDA p ≤ .01) and "high-confidence" differentially expressed proteins (n = 98; p ≤ .01) revealed that MV.Act were enriched with proteins related to immune responses, protein translation, cytoskeleton organisation and TNFα-induced apoptosis. For instance, MV.Act were highly enriched with IFN-γ, a key proinflammatory pathway related to effector CD4+ T cells. Endothelial cell incubation with MV.Act induced superoxide generation, apoptosis, endothelial wound healing impairment and endothelial monolayer barrier disruption.ConclusionsT cell receptor-mediated activation of CD4+ T cells stimulates the release of microvesicles enriched with proteins involved in immune responses, inflammation and apoptosis. T cell-derived microvesicles alter microvascular endothelial function and barrier permeability, potentially promoting tissue inflammation.

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Role of endothelial microvesicles released by p-cresol on endothelial dysfunction.

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