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JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm

JAK2V617F mutation is associated with an increased risk for athero-thrombotic cardiovascular disease, but its role in aortic disease development and complications remains unknown. In a cohort of patients with myeloproliferative neoplasm, JAK2V617F mutation was identified as an independent risk facto...

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Detalles Bibliográficos
Autores principales: Al-Rifai, Rida, Vandestienne, Marie, Lavillegrand, Jean-Rémi, Mirault, Tristan, Cornebise, Julie, Poisson, Johanne, Laurans, Ludivine, Esposito, Bruno, James, Chloé, Mansier, Olivier, Hirsch, Pierre, Favale, Fabrizia, Braik, Rayan, Knosp, Camille, Vilar, Jose, Rizzo, Giuseppe, Zernecke, Alma, Saliba, Antoine-Emmanuel, Tedgui, Alain, Lacroix, Maxime, Arrive, Lionel, Mallat, Ziad, Taleb, Soraya, Diedisheim, Marc, Cochain, Clément, Rautou, Pierre-Emmanuel, Ait-Oufella, Hafid
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9633755/
https://www.ncbi.nlm.nih.gov/pubmed/36329047
http://dx.doi.org/10.1038/s41467-022-34469-1
Descripción
Sumario:JAK2V617F mutation is associated with an increased risk for athero-thrombotic cardiovascular disease, but its role in aortic disease development and complications remains unknown. In a cohort of patients with myeloproliferative neoplasm, JAK2V617F mutation was identified as an independent risk factor for dilation of both the ascending and descending thoracic aorta. Using single-cell RNA-seq, complementary genetically-modified mouse models, as well as pharmacological approaches, we found that JAK2V617F mutation was associated with a pathogenic pro-inflammatory phenotype of perivascular tissue-resident macrophages, which promoted deleterious aortic wall remodeling at early stages, and dissecting aneurysm through the recruitment of circulating monocytes at later stages. Finally, genetic manipulation of tissue-resident macrophages, or treatment with a Jak2 inhibitor, ruxolitinib, mitigated aortic wall inflammation and reduced aortic dilation and rupture. Overall, JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm.