2026-06-14T03:33:42Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/69242024-09-27T08:09:30Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

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 10.1038/nm.4266 1546-170X 1078-8956 Nature medicine 28067899 http://hdl.handle.net/20.500.12105/6924 Nitric oxide mediates aortic disease in mice deficient in the metalloprotease Adamts1 and in a mouse model of Marfan syndrome