Book of Abstracts - New Frontiers 2022

Abstracts of oral presentations

EXTRACELLULAR VESICLES AS BIOMARKERS AND TARGETS IN VASCULAR CONSEQUENCES OF METABOLIC SYNDROME

R. Andriantsitohaina

PhyMedExp, INSERM U1046 - UMR CNRS 9214 - Université de Montpellier, Montpellier, France

Metabolic syndrome (MetS) is a worldwide public health problem, characterized by a cluster of risk factors including hyperglycemia, dyslipidemia, hypertension and obesity, leading to an increased risk of cardiovascular events. Endothelial dysfunction participates in the development of cardiovascular diseases associated with MetS. Extracellular vesicles (EVs) are involved in the pathogenesis and maintenance of cardiovascular and metabolic diseases.1,2 Two types of EVs have been described: microvesicles or large EVs (lEVs), and exosomes or small EVs (sEVs). Regarding MetS, we have described that circulating lEVs from MetS (MetS-lEVs) patients induced endothelial dysfunction characterized by a decrease of nitric oxide (NO) production associated with the inhibition of endothelial NO-synthase, and an increase in oxidative and nitrative stresses. Furthermore, MetS-lEVs carry Fas-ligand and interacted with Fas in endothelial cells. This induced a temporal crosstalk between endoplasmic reticulum and mitochondria with respect to spatial regulation of reactive oxygen species (ROS) production via the neutral sphingomyelinase. These events led to a reduction of NO bioavailability accounting for the subsequent impairment of endothelium-dependent vasorelaxation.3 Proteomic analysis revealed that the small GTPase, Rap1 is overexpressed in lEVs from MetS patients. Rap1-lEV levels correlated with increased cardiovascular risks. MetS-lEVs promoted migration and proliferation of human aortic smooth muscle cells, and increased expression of pro-inflammatory molecules. Neutralization of Rap1 completely prevented the effects of lEVs from MetS patients. High fat diet-fed ApoE-/- mice displayed an increased expression of Rap1 in aortas, circulating lEVs and lEVs from plaque atherosclerotic lesions. Human atherosclerotic lesions were enriched in lEVs expressing Rap1. Thus, Rap1 carried by MetS-lEVs is a novel determinant of diagnostic value for cardiometabolic risk factors and a potential therapeutic target against the development of atherosclerosis.4 Regarding sEVs, circulating concentration and size of sEVs were, positively or negatively respectively, correlated with visceral obesity, hypertension, insulin resistance and dyslipidemia. Furthermore, sEVs fromMetS patients decreased in vitro NO production in endothelial cells and impaired ex vivo endothelium-dependent relaxation. The decreased NO bioavailability induced by MetS-sEVs was associated with an increase of cytosolic and mitochondrial ROS production. Activation of TLR4 by LPS carried by MetS-sEVs account for the increased oxidative stress.5. In conclusion, we demonstrate that lEVs and sEVs are biomarkers and key players of both atherosclerosis, inflammation and metabolic disorders in MetS. 1-Martinez MC, Andriantsitohaina R Circ Res 2017; 2-Malloci M et al. Antioxid Red Signal 2019; 3 Safiedeen Z et al. Antioxid Redox Signal 2017; 4-Perdomo L et al. Circ Res 2020; 5-Ali S et al. Metabolism 2021

Keywords: extracellular vesicles, metabolic syndrome, vascular dysfunction, biomarkers, atherosclerosis

Funding:Fondation pour la Recherche Médicale (SPF201809006985), Institut National de la Santé et de la Recherche Médicale, Université d'Angers, Centre Hospitalo -Universitaire d'Angers.

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