Large Extracellular Vesicle-Associated Rap1 Accumulates in Atherosclerotic Plaques, Correlates with Vascular Risks and Is Involved in Atherosclerosis
| العنوان: | Large Extracellular Vesicle-Associated Rap1 Accumulates in Atherosclerotic Plaques, Correlates with Vascular Risks and Is Involved in Atherosclerosis |
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| المؤلفون: | 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 |
| المساهمون: | 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), Martinez, M. Carmen |
| المصدر: | Circulation Research Circulation Research, American Heart Association, 2020, 127 (6), pp.747-760. ⟨10.1161/CIRCRESAHA.120.317086⟩ Circulation Research, 2020, 127 (6), pp.747-760. ⟨10.1161/CIRCRESAHA.120.317086⟩ Circulation Research, American Heart Association, 2020, ⟨10.1161/CIRCRESAHA.120.317086⟩ Circ Res |
| بيانات النشر: | HAL CCSD, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 0009-7330 1524-4571 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cc89d194640bc027eda1481439b06c17Test https://hal.archives-ouvertes.fr/hal-03048054/documentTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....cc89d194640bc027eda1481439b06c17 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00097330 15244571 |
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