Erythrocyte-derived microvesicles induce arterial spasms in JAK2V617F myeloproliferative neoplasm.

Autor: Poisson J; Paris-Centre de recherche cardiovasculaire (PARCC), Université de Paris, Paris, France.; Centre de recherche sur l'inflammation, Inserm, Université de Paris, Paris, France.; Geriatrics Department, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France., Tanguy M; Paris-Centre de recherche cardiovasculaire (PARCC), Université de Paris, Paris, France.; Centre de recherche sur l'inflammation, Inserm, Université de Paris, Paris, France., Davy H; Paris-Centre de recherche cardiovasculaire (PARCC), Université de Paris, Paris, France., Camara F; Paris-Centre de recherche cardiovasculaire (PARCC), Université de Paris, Paris, France., El Mdawar MB; Paris-Centre de recherche cardiovasculaire (PARCC), Université de Paris, Paris, France., Kheloufi M; Paris-Centre de recherche cardiovasculaire (PARCC), Université de Paris, Paris, France., Dagher T; Inserm U1170, Institut Gustave Roussy, Université Paris XI, Villejuif, France., Devue C; Paris-Centre de recherche cardiovasculaire (PARCC), Université de Paris, Paris, France., Lasselin J; Paris-Centre de recherche cardiovasculaire (PARCC), Université de Paris, Paris, France., Plessier A; Service d'Hépatologie, Pôle des Maladies de l'Appareil Digestif, Hôpital Beaujon, Département Hospitalo-Universitaire (DHU Unity), AP-HP, Clichy, France.; Centre de Référence des Maladies Vasculaires du Foie, French Network for Rare Liver Diseases (FILFOIE), European Reference Network (ERN), Clichy, France., Merchant S; Inserm U1170, Institut Gustave Roussy, Université Paris XI, Villejuif, France., Blanc-Brude O; Paris-Centre de recherche cardiovasculaire (PARCC), Université de Paris, Paris, France., Souyri M; Inserm UMR S1131, University Hospital Institute (IHU), Université de Paris, Paris, France., Mougenot N; Inserm UMS 28, Phénotypage du petit animal, Plateforme d'expérimentations coeur-muscle-vaisseaux (PECMV), Sorbonne University, Paris, France., Dingli F; Laboratoire de Spectrométrie de Masse Protéomique, Institut Curie, Université de recherche PSL, Paris, France., Loew D; Laboratoire de Spectrométrie de Masse Protéomique, Institut Curie, Université de recherche PSL, Paris, France., Hatem SN; Inserm, UMR 1166, Institut de cardiométabolisme et nutrition (ICAN), Sorbonne University, Paris, France., James C; Inserm U1034, Biology of Cardiovascular, Pessac, France.; University of Bordeaux, Pessac, France.; Laboratory of Hematology, Bordeaux University Hospital Center, Pessac, France., Villeval JL; Inserm U1170, Institut Gustave Roussy, Université Paris XI, Villejuif, France., Boulanger CM; Paris-Centre de recherche cardiovasculaire (PARCC), Université de Paris, Paris, France., Rautou PE; Paris-Centre de recherche cardiovasculaire (PARCC), Université de Paris, Paris, France.; Centre de recherche sur l'inflammation, Inserm, Université de Paris, Paris, France.; Inserm U1170, Institut Gustave Roussy, Université Paris XI, Villejuif, France.; Service d'Hépatologie, Pôle des Maladies de l'Appareil Digestif, Hôpital Beaujon, Département Hospitalo-Universitaire (DHU Unity), AP-HP, Clichy, France.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2020 May 01; Vol. 130 (5), pp. 2630-2643.
DOI: 10.1172/JCI124566
Abstrakt: Arterial cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms (MPNs). However, their mechanisms are poorly understood. The high prevalence of myocardial infarction without significant coronary stenosis or atherosclerosis in patients with MPNs suggests that vascular function is altered. The consequences of JAK2V617F mutation on vascular reactivity are unknown. We observe here increased responses to vasoconstrictors in arteries from Jak2V617F mice resulting from a disturbed endothelial NO pathway and increased endothelial oxidative stress. This response was reproduced in WT mice by circulating microvesicles isolated from patients carrying JAK2V617F and by erythrocyte-derived microvesicles from transgenic mice. Microvesicles of other cellular origins had no effect. This effect was observed ex vivo on isolated aortas, but also in vivo on femoral arteries. Proteomic analysis of microvesicles derived from JAK2V617F erythrocytes identified increased expression of myeloperoxidase as the likely mechanism accounting for their effect. Myeloperoxidase inhibition in microvesicles derived from JAK2V617F erythrocytes suppressed their effect on oxidative stress. Antioxidants such as simvastatin and N-acetyl cysteine improved arterial dysfunction in Jak2V617F mice. In conclusion, JAK2V617F MPNs are characterized by exacerbated vasoconstrictor responses resulting from increased endothelial oxidative stress caused by circulating erythrocyte-derived microvesicles. Simvastatin appears to be a promising therapeutic strategy in this setting.
Databáze: MEDLINE