Circulating extracellular vesicle-carried PTP1B and PP2A phosphatases as regulators of insulin resistance

We thank SCAHU staff of Angers University for taking care of animals, the SCIAM platform, especially Florence Manero, for technical assistance for electron microscopy imaging, and the staff of University Hospital Centre of Angers analysis of clinical data of NUMEVOX cohort. Also, we thank the Department of Pathology of University Hospital Centre of Angers for help on histological analysis.Peer reviewe

NLRP3, conveyed via extracellular vesicles from metabolic syndrome patients, is involved in atherosclerosis development

International audienceBackground: Inappropriate activation of the Nod-like receptor protein 3 (NLRP3)-inflammasome contributes to atherosclerosis progression and plaque instability in patients with cardiovascular events. However, its role in the atherosclerosis is not fully understood. We sought to uncover actionable targets that could help to refine the diagnostic values of metabolic syndrome (MetS) patients by taking advantage of extracellular vesicles (EVs) to support the inflammatory hypothesis of atherosclerosis.Methods: Circulating large (lEVs) and small (sEVs) EVs from non-MetS subjects and MetS patients were isolated and characterized. The involvement of NLRP3 in the effects of EVs on human aortic endothelial and smooth muscle cells (SMC) and macrophages were analyzed. The pathological relevance in human atherosclerotic lesions was investigated.Results: Circulating levels of lEVs carrying NLRP3 correlated with metabolic risk factors associated with obesity and insulin resistance. Both types of EVs from MetS patients increased endothelial permeability, monocyte transmigration, SMC migration and secretion of pro-inflammatory molecules by monocyte/macrophages. Interestingly, MetS-lEVs, but not MetS-sEVs, increased SMC proliferation and IL-1ß production. EVs isolated from advanced human plaques demonstrated an accumulation of EVs carrying NLRP3 and their implication in endothelial permeability increase. Pharmacological inhibition of NLRP3-inflammasome carried by MetS-EVs prevented all the effects leading to vascular inflammation and remodeling.Conclusions: Our data demonstrate that NLRP3-inflammasome, carried by EVs, is actively involved in vascular inflammation and atherosclerosis development in MetS. We highlight NLRP3 carried by EVs as potential biomarker and target for potential therapeutic strategies of atherosclerosis-related diseases leading to major adverse cardiovascular event