2024-03-28T13:16:53Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/69242022-11-03T18:49:10Zcom_20.500.12105_2145com_20.500.12105_2051com_20.500.12105_2144col_20.500.12105_2146
00925njm 22002777a 4500
dc
Oller, Jorge
author
Mendez-Barbero, Nerea
author
Ruiz, E Josue
author
Villahoz, Silvia
author
Renard, Marjolijn
author
Canelas, Lizet I
author
Briones, Ana M
author
Alberca, Rut
author
Lozano-Vidal, Noelia
author
Hurlé, María A
author
Milewicz, Dianna
author
Evangelista, Arturo
author
Salaices, Mercedes
author
Nistal, J Francisco
author
Jimenez-Borreguero, Luis J.
author
De Backer, Julie
author
Campanero, Miguel R
author
Redondo, Juan Miguel
author
2017-02
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.
Nat Med. 2017; 23(2):200-212
1078-8956
http://hdl.handle.net/20.500.12105/6924
28067899
10.1038/nm.4266
1546-170X
Nature medicine
Nitric oxide mediates aortic disease in mice deficient in the metalloprotease Adamts1 and in a mouse model of Marfan syndrome