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Nitric oxide mediates aortic disease in mice deficient in the metalloprotease Adamts1 and in a mouse model of Marfan syndrome

Abstract: Heritable thoracic aortic aneurysms and dissections (TAAD), including Marfan syndrome (MFS), currently lack a cure, and causative mutations have been identified for only a fraction of affected families. Here we identify the metalloproteinase ADAMTS1 and inducible nitric oxide synthase (NOS2) as therapeutic targets in individuals with TAAD. We show that Adamts1 is a major mediator of vascular homeostasis, given that genetic haploinsufficiency of Adamts1 in mice causes TAAD similar to MFS. Aortic nitric oxide and Nos2 levels were higher in Adamts1-deficient mice and in a mouse model of MFS (hereafter referred to as MFS mice), and Nos2 inactivation protected both types of mice from aortic pathology. Pharmacological inhibition of Nos2 rapidly reversed aortic dilation and medial degeneration in young Adamts1-deficient mice and in young or old MFS mice. Patients with MFS showed elevated NOS2 and decreased ADAMTS1 protein levels in the aorta. These findings uncover a possible causative role for the ADAMTS1-NOS2 axis in human TAAD and warrant evaluation of NOS2 inhibitors for therapy.

Otras publicaciones de la misma revista o congreso con autores/as de la Universidad de Cantabria

 Fuente: Nat Med. 2017 Feb;23(2):200-212

Editorial: Nature Publishing Company

 Año de publicación: 2017

Nº de páginas: 15

Tipo de publicación: Artículo de Revista

 DOI: 10.1038/nm.4266

ISSN: 1078-8956,1546-170X

Proyecto español: SAF2013-45258P ; SAF2012-34296 ; SAF2015-636333R

Url de la publicación: https://www.doi.org/10.1038/nm.4266

Autores/as

OLLER, JORGE

MÉNDEZ-BARBERO, NEREA

RUIZ, E JOSUE

VILLAHOZ, SILVIA

RENARD, MARJOLIJN

CANELAS, LIZET I

BRIONES, ANA M

ALBERCA, RUT

LOZANO-VIDAL, NOELIA

MILEWICZ, DIANNA

EVANGELISTA, ARTURO

SALAICES, MERCEDES

JIMÉNEZ-BORREGUERO, LUIS JESÚS

BACKER, JULIE DE

CAMPANERO, MIGUEL R

REDONDO, JUAN MIGUEL