Titre :

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

Auteur(s) :

Perdomo, Liliana [Auteur]
Stress Oxydant et Pathologies Métaboliques [SOPAM]
Vidal-Gomez, Xavier [Auteur]
Stress Oxydant et Pathologies Métaboliques [SOPAM]
Soleti, Raffaella [Auteur]
Stress Oxydant et Pathologies Métaboliques [SOPAM]
Vergori, Luisa [Auteur]
Stress Oxydant et Pathologies Métaboliques [SOPAM]
Duluc, Lucie [Auteur]
Stress Oxydant et Pathologies Métaboliques [SOPAM]
Chwastyniak, Maggy [Auteur]
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE]
Bisserier, Malik [Auteur]
Institut des Maladies Métaboliques et Cardiovasculaires [I2MC]
Le Lay, Soazig [Auteur]
Stress Oxydant et Pathologies Métaboliques [SOPAM]
Villard, Alexandre [Auteur]
Stress Oxydant et Pathologies Métaboliques [SOPAM]
Simard, Gilles [Auteur]
Stress Oxydant et Pathologies Métaboliques [SOPAM]
Meilhac, Olivier [Auteur]
Diabète athérothrombose et thérapies Réunion Océan Indien [DéTROI]
Lezoualc'H, Frank [Auteur]
Institut des Maladies Métaboliques et Cardiovasculaires [I2MC]
Khantalin, Ilya [Auteur]
Centre Hospitalier Universitaire de La Réunion [CHU La Réunion]
Veerapen, Reuben [Auteur]
Clinique Sainte Clotilde
Dubois, Séverine [Auteur]
Centre Hospitalier Universitaire d'Angers [CHU Angers]
Stress Oxydant et Pathologies Métaboliques [SOPAM]
Boursier, Jérôme [Auteur]
Centre Hospitalier Universitaire d'Angers [CHU Angers]
Henni, Samir [Auteur]
Centre Hospitalier Universitaire d'Angers [CHU Angers]
Gagnadoux, Frédéric [Auteur]
Centre Hospitalier Universitaire d'Angers [CHU Angers]
Stress Oxydant et Pathologies Métaboliques [SOPAM]
PINET, FLORENCE [Auteur]
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE]
Andriantsitohaina, Ramaroson [Auteur]
Centre Hospitalier Universitaire d'Angers [CHU Angers]
Stress Oxydant et Pathologies Métaboliques [SOPAM]
Martinez, M Carmen [Auteur]
Centre Hospitalier Universitaire d'Angers [CHU Angers]
Stress Oxydant et Pathologies Métaboliques [SOPAM]

Titre de la revue :

Circulation Research

Pagination :

747 - 760

Éditeur :

American Heart Association

Date de publication :

2020-06-16

ISSN :

0009-7330

Mot(s)-clé(s) en anglais :

atherosclerosis
extracellular vesicles
inflammation
metabolic syndrome
muscle cells

Discipline(s) HAL :

Sciences du Vivant [q-bio]/Médecine humaine et pathologie/Cardiologie et système cardiovasculaire
Sciences du Vivant [q-bio]/Médecine humaine et pathologie/Endocrinologie et métabolisme

Résumé en anglais : [en]

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 ...
Lire la suite >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 Rap1dependent 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.Lire moins >

Langue :

Anglais

Comité de lecture :

Oui

Audience :

Internationale

Vulgarisation :

Non

Collections :

• Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement (RID-AGE) - U1167

Source :

Harvested from HAL