title: 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.
authors.affiliation: Gene regulation in cardiovascular remodeling and inflammation group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Oller
authors.affiliation: Gene regulation in cardiovascular remodeling and inflammation group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
authors.forename: Nerea
authors.initials: N
authors.lastname: Méndez-Barbero
authors.affiliation: Gene regulation in cardiovascular remodeling and inflammation group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
authors.forename: E Josue
authors.initials: EJ
authors.lastname: Ruiz
authors.affiliation: Gene regulation in cardiovascular remodeling and inflammation group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Villahoz
authors.affiliation: Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.
authors.forename: Marjolijn
authors.initials: M
authors.lastname: Renard
authors.affiliation: Gene regulation in cardiovascular remodeling and inflammation group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
authors.forename: Lizet I
authors.initials: LI
authors.lastname: Canelas
authors.affiliation: Department of Pharmacology, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Briones
authors.affiliation: Gene regulation in cardiovascular remodeling and inflammation group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
authors.forename: Rut
authors.initials: R
authors.lastname: Alberca
authors.affiliation: Gene regulation in cardiovascular remodeling and inflammation group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Lozano-Vidal
authors.affiliation: Cardiovascular Surgery and Department of Physiology and Pharmacology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Facultad de Medicina, Universidad de Cantabria, Santander, Spain.
authors.forename: María A
authors.initials: MA
authors.lastname: Hurlé
authors.affiliation: Division of Medical Genetics, University of Texas, Houston, USA.
authors.forename: Dianna
authors.initials: D
authors.lastname: Milewicz
authors.affiliation: Servei de Cardiologia, Hospital Vall d'Hebron, Barcelona, Spain.
authors.forename: Arturo
authors.initials: A
authors.lastname: Evangelista
authors.affiliation: Department of Pharmacology, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Salaices
authors.affiliation: Cardiovascular Surgery and Department of Physiology and Pharmacology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Facultad de Medicina, Universidad de Cantabria, Santander, Spain.
authors.forename: J Francisco
authors.initials: JF
authors.lastname: Nistal
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares and Hospital de la Princesa, Madrid, Spain.
authors.forename: Luis Jesús
authors.identifier: http://orcid.org/0000-0001-5870-237X
authors.initials: LJ
authors.lastname: Jiménez-Borreguero
authors.affiliation: Department of Pharmacology, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Julie
authors.identifier: http://orcid.org/0000-0001-8878-1507
authors.initials: J
authors.lastname: De Backer
authors.affiliation: Department of Cancer Biology, Instituto de Investigaciones Biomedicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Miguel R
authors.initials: MR
authors.lastname: Campanero
authors.affiliation: Gene regulation in cardiovascular remodeling and inflammation group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.|Centro de Investigaciones Biomédicas en RED en Enfermedades Cardiovasculares (CIBERCV), Spain.
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Redondo
mesh_terms: D000071097:ADAMTS1 Protein / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000784:Aortic Dissection / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism*; D001014:Aortic Aneurysm / Q000235:genetics* / Q000378:metabolism; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D000071838:Fibrillin-1 / Q000235:genetics; D055785:Gene Knockdown Techniques; D057895:Haploinsufficiency; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008382:Marfan Syndrome / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D054392:Adipokines
chemical_list: D000071097:ADAMTS1 Protein; D004791:Enzyme Inhibitors; D000071838:Fibrillin-1; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C000605724:Fbn1 protein, mouse; D054392:Adipokines; C496319:NOS2 protein, human; C496317:Nos2 protein, mouse; C103859:ADAMTS1 protein, human; C486323:Adamts1 protein, mouse