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3 results on '"Xavier Vidal-Gómez"'

1. Faeces‐derived extracellular vesicles participate in the onset of barrier dysfunction leading to liver diseases

Author

Lionel Fizanne, Alexandre Villard, Nadia Benabbou, Sylvain Recoquillon, Raffaella Soleti, Erwan Delage, Mireille Wertheimer, Xavier Vidal‐Gómez, Thibauld Oullier, Samuel Chaffron, M. Carmen Martínez, Michel Neunlist, Jérôme Boursier, Ramaroson Andriantsitohaina, Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des Sciences du Numérique de Nantes (LS2N), Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École Centrale de Nantes (Nantes Univ - ECN), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes université - UFR des Sciences et des Techniques (Nantes univ - UFR ST), Nantes Université - pôle Sciences et technologie, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Sciences et technologie, Nantes Université (Nantes Univ), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), The Enteric Nervous System in gut and brain disorders [U1235] (TENS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université Bretagne Loire (UBL), Institut des Maladies de l'Appareil Digestif, and Université de Nantes (UN)

Subjects
Histology, gut microbiota, intestinal permeability, [SDV]Life Sciences [q-bio], non-alcoholic fatty liver disease, Cell Biology, extracellular vesicles
Abstract

International audience; The role of extracellular vesicles (EVs) from faeces (fEVs) and small circulating EVs (cEVs) in liver diseases such as non-alcoholic fatty diseases (NAFLD) and nonalcoholic steatohepatitis (NASH) has not been demonstrated. fEVs and cEVs of healthy donors, NAFLD and NASH patients were isolated and characterized. The effects of EVs were evaluated in intestinal, endothelial, Kupffer and stellate cells. Nonmuscular myosin light chain kinase (nmMLCK) deficient mice were used in vivo. Bacterial origins of fEVs were analysed by 16s rDNA gene sequencing. fEVs and small cEVs were composed of prokaryotic and eukaryotic origins. Only NASH-fEVs exerted deleterious effects. NASH-fEVs increased intestinal permeability and reduced expression of tight junction proteins that were prevented by nmMLCK inhibition, increased endothelial cell permeability and inflammatory cytokines and chemokines requiring TLR4/lipopolysaccharide pathway. NASH-fEVs and NASH-cEVs activated profibrotic and proinflammatory proteins of hepatic stellate cells. Treatment with NASH-fEVs evoked an increase in intestinal permeability in wild type but not in nmMLCK deficient mice. Bacterial origins of fEVs were different between NAFLD and NASH patients and 16 amplicon sequence variants were differentially abundant. We demonstrate that fEVs actively participate in barrier dysfunctions leading to liver injuries underscoring the role of nmMLCK and lipopolysaccharide carried by fEVs.

Published
2023
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2. LPS-enriched small extracellular vesicles from metabolic syndrome patients trigger endothelial dysfunction by activation of TLR4

Author

Gilles Simard, Zainab Safiedeen, Arnaud Chevrollier, Sakina Ali, Ramaroson Andriantsitohaina, Luisa Vergori, M. Carmen Martinez, Soazig Le Lay, Xavier Vidal-Gómez, Frédéric Gagnadoux, Marine Malloci, Jérôme Boursier, Charlène Besnard, Raffaella Soleti, Séverine Dubois, Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Inserm, Université d'Angers, Centre Hospitalo-Universitaire d'Angers, BOURGEAIS, Véronique, and MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)

Subjects
Lipopolysaccharides, Male, 0301 basic medicine, Mitochondrial ROS, Endocrinology, Diabetes and Metabolism, viruses, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Exosomes, Cohort Studies, Mice, chemistry.chemical_compound, Cytosol, Endocrinology, 0302 clinical medicine, Medicine, 030212 general & internal medicine, Endothelial dysfunction, Cells, Cultured, chemistry.chemical_classification, Organelle Biogenesis, virus diseases, MESH: Toll-Like Receptor 4, Middle Aged, respiratory system, Metabolic syndrome, Mitochondria, [SDV] Life Sciences [q-bio], Female, MESH: Endothelium, Vascular, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, MESH: Metabolic Syndrome, 030209 endocrinology & metabolism, Nitric Oxide, Nitric oxide, Extracellular Vesicles, 03 medical and health sciences, Insulin resistance, Internal medicine, Animals, Humans, MESH: Extracellular Vesicles, Reactive oxygen species, business.industry, medicine.disease, Toll-Like Receptor 4, Oxidative Stress, 030104 developmental biology, chemistry, Mitochondrial biogenesis, TLR4, Endothelium, Vascular, MESH: Lipopolysaccharides, Reactive Oxygen Species, business, Dyslipidemia
Abstract

Background Metabolic syndrome (MetS) is characterized by a cluster of interconnected risk factors -hyperglycemia, dyslipidemia, hypertension and obesity- leading to an increased risk of cardiovascular events. Small extracellular vesicles (sEVs) can be considered as new biomarkers of different pathologies, and they are involved in intercellular communication. Here, we hypothesize that sEVs are implicated in MetS-associated endothelial dysfunction. Methods Circulating sEVs of non-MetS (nMetS) subjects and MetS patients were isolated from plasma and characterized. Thereafter, sEV effects on endothelial function were analyzed by measuring nitric oxide (NO) and reactive oxygen species (ROS) production, and mitochondrial dynamic proteins on human endothelial aortic cells (HAoECs). Results Circulating levels of sEVs positively correlated with anthropometric and biochemical parameters including visceral obesity, glycaemia, insulinemia, and dyslipidemia. Treatment of HAoECs with sEVs from MetS patients decreased NO production through the inhibition of the endothelial NO-synthase activity. Injection of MetS-sEVs into mice impaired endothelium-dependent relaxation induced by acetylcholine. Furthermore, MetS-sEVs increased DHE and MitoSox-associated fluorescence in HAoECs, reflecting enhanced cytosolic and mitochondrial ROS production which was not associated with mitochondrial biogenesis or dynamic changes. MetS patients displayed elevated circulating levels of LPS in plasma, and, at least in part, it was associated to circulating sEVs. Pharmacological inhibition and down-regulation of TLR4, as well as sEV-carried LPS neutralization, results in a substantial decrease of ROS production induced by MetS-sEVs. Conclusion These results evidence sEVs from MetS patients as potential new biomarkers for this syndrome, and TLR4 pathway activation by sEVs provides a link between the endothelial dysfunction and metabolic disturbances described in MetS.

Published
2021
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3. Large Extracellular Vesicle-Associated Rap1 Accumulates in Atherosclerotic Plaques, Correlates with Vascular Risks and Is Involved in Atherosclerosis

Author

Séverine Dubois, Liliana Perdomo, Gilles Simard, M. Carmen Martinez, Lucie Duluc, Olivier Meilhac, Alexandre Villard, Ramaroson Andriantsitohaina, Samir Henni, Jérôme Boursier, Florence Pinet, Raffaella Soleti, Soazig Le Lay, Maggy Chwastyniak, Frédéric Gagnadoux, Xavier Vidal-Gómez, Frank Lezoualc'h, Luisa Vergori, Ilya Khantalin, Malik Bisserier, Reuben Veerapen, Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Clinique Sainte Clotilde, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), This work was supported by INSERM, Université d’Angers and CHU Angers, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Martinez, M. Carmen

Subjects
Male, Proteomics, Apolipoprotein E, Vascular smooth muscle, Mice, Knockout, ApoE, Physiology, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, p38 Mitogen-Activated Protein Kinases, Muscle, Smooth, Vascular, 0302 clinical medicine, Cell Movement, Risk Factors, Phosphorylation, Endothelial dysfunction, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, [SDV.BA]Life Sciences [q-bio]/Animal biology, rap1 GTP-Binding Proteins, Extracellular vesicle, Middle Aged, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Prognosis, Plaque, Atherosclerotic, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Endothelial stem cell, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, extracellular vesicles, Signal Transduction, Adult, medicine.medical_specialty, endocrine system, Myocytes, Smooth Muscle, Inflammation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Risk Assessment, Article, Permeability, metabolic syndrome, Proinflammatory cytokine, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Extracellular, Animals, Humans, Mitogen-Activated Protein Kinase 7, Aged, Cell Proliferation, 030304 developmental biology, business.industry, Endothelial Cells, muscle cells, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, enzymes and coenzymes (carbohydrates), rap GTP-Binding Proteins, Endocrinology, inflammation, Case-Control Studies, atherosclerosis, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Rationale:Metabolic syndrome (MetS) is a cluster of interrelated risk factors for cardiovascular diseases and atherosclerosis. Circulating levels of large extracellular vesicles (lEVs), submicrometer-sized vesicles released from plasma membrane, from MetS patients were shown to induce endothelial dysfunction, but their role in early stage of atherosclerosis and on vascular smooth muscle cells (SMC) remain to be fully elucidated.Objective:To determine the mechanisms by which lEVs lead to the progression of atherosclerosis in the setting of MetS.Methods and Results:Proteomic analysis revealed that the small GTPase, Rap1 was overexpressed in lEVs from MetS patients compared with those from non-MetS subjects. Rap1 was in GTP-associated active state in both types of lEVs, and Rap1-lEVs levels correlated with increased cardiovascular risks, including stenosis. MetS-lEVs, but not non-MetS-lEVs, increased Rap1-dependent endothelial cell permeability. MetS-lEVs significantly promoted migration and proliferation of human aortic SMC and increased expression of proinflammatory molecules and activation of ERK (extracellular signal-regulated kinase) 5/p38 pathways. Neutralization of Rap1 by specific antibody or pharmacological inhibition of Rap1 completely prevented the effects of lEVs from MetS patients. High-fat diet-fed ApoE−/−mice displayed an increased expression of Rap1 both in aortas and circulating lEVs. lEVs accumulated in plaque atherosclerotic lesions depending on the progression of atherosclerosis. lEVs from high-fat diet-fed ApoE−/−mice, but not those from mice fed with a standard diet, enhanced SMC proliferation. Human atherosclerotic lesions were enriched in lEVs expressing Rap1.Conclusions:These data demonstrate that Rap1 carried by MetS-lEVs participates in the enhanced SMC proliferation, migration, proinflammatory profile, and activation of ERK5/p38 pathways leading to vascular inflammation and remodeling, and atherosclerosis. These results highlight that Rap1 carried by MetS-lEVs may be a novel determinant of diagnostic value for cardiometabolic risk factors and suggest Rap1 as a promising therapeutic target against the development of atherosclerosis.Graphical Abstract:A graphical abstract is available for this article.

Published
2020
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