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

Nature Medicine volume 23, pages 200–212 (2017)Cite this article

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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.

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Figure 1: Induction of syndromic TAA by Adamts1 deficiency.
Figure 2: Knockdown of Adamts1 expression in the aorta of adult mice causes an aortic disease similar to that induced by genetic deficiency of Adamts1.
Figure 3: Knockdown of Adamts1 rapidly induces aortic dilation, hypotension and medial degeneration independently of TGF-β activation.
Figure 4: The aortopathy induced by Adamts1 deficiency is mediated by NO.
Figure 5: Nos2 is a critical mediator of the aortopathy induced by Adamts1 deficiency.
Figure 6: Adamts1 and NO have critical roles in Marfan syndrome.

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Acknowledgements

We thank B. Ibañez and G. Egea for reagents, S. Bartlett for English language editing, A.G. Arroyo, S. Lamas, J. Alegre-Cebollada and J. Ruiz-Cabello for critical reading of the manuscript and advice, and S. Pocock and J. Vazquez for advice on statistics. We also thank the CNIC histology facility, C. Velasco, A.V. Alonso and L. Flores for technical support. CNIC is supported by the Spanish Ministerio de Economía, Industria y Competitividad (MINECO) and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). Support was also provided by grants from MINECO (grants SAF2013-45258P (M.R.C.), SAF2012-34296 (J.M.R.) and SAF2015-636333R (J.M.R.)), Fundacion La Marato (TV3 grants 20151331 (J.M.R.) and 20151330 (A.E.)), CSIC (M.R.C.), the CIBERCV of Ministerio de Sanidad (grant CB16/11/00264; J.M.R.) and the Red de Investigación Cardiovascular (RIC) of Ministerio de Sanidad (grants RD12/0042/0022 (J.M.R.), RD12/0042/0021 (A.E.), RD12/0042/0024 (M.S.), RD12/0042/0056 (J.L.J.-B.) and RD12/0042/0018 (J.F.N.)), and by a Marie Skłodowska-Curie fellowship (E.J.R.) and FPI fellowships BES 2010-034552 (J.O.) and SVP-2013-067777 (S.V.). The cost of this publication has been paid in part with FEDER funds.

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Author notes

  1. Jorge Oller and Nerea Méndez-Barbero: These authors contributed equally to this work.

  2. Miguel R Campanero and Juan Miguel Redondo: These authors jointly directed this work.

Authors and Affiliations

  1. Gene regulation in cardiovascular remodeling and inflammation group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

    Jorge Oller, Nerea Méndez-Barbero, E Josue Ruiz, Silvia Villahoz, Lizet I Canelas, Rut Alberca, Noelia Lozano-Vidal & Juan Miguel Redondo

  2. Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium

    Marjolijn Renard

  3. Department of Pharmacology, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain

    Ana M Briones, Mercedes Salaices & Julie De Backer

  4. Cardiovascular Surgery and Department of Physiology and Pharmacology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Facultad de Medicina, Universidad de Cantabria, Santander, Spain

    María A Hurlé & J Francisco Nistal

  5. Division of Medical Genetics, University of Texas, Houston, USA

    Dianna Milewicz

  6. Servei de Cardiologia, Hospital Vall d'Hebron, Barcelona, Spain

    Arturo Evangelista

  7. Centro Nacional de Investigaciones Cardiovasculares and Hospital de la Princesa, Madrid, Spain

    Luis Jesús Jiménez-Borreguero

  8. Department of Cancer Biology, Instituto de Investigaciones Biomedicas Alberto Sols, Consejo Superior de Investigaciones Científicas–Universidad Autónoma de Madrid, Madrid, Spain

    Miguel R Campanero

  9. Centro de Investigaciones Biomédicas en RED en Enfermedades Cardiovasculares (CIBERCV), Spain

    Juan Miguel Redondo

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  1. Jorge Oller
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Contributions

M.R.C. and J.M.R conceived the study; J.O., N.M.-B., M.R.C. and J.M.R. designed the study and analyzed the data; J.O. and N.M.-B. performed most of the experiments, with contributions from E.J.R., S.V., L.I.C., R.A. and N.L.-V.; L.J.J.-B. supervised and analyzed the echography analysis; M.R., J.D.B., M.A.H. and J.F.N. provided human tissue samples; L.J.J.-B., M.R., A.M.B., M.A.H., D.M., A.E., M.S., J.F.N. and J.D.B. provided experimental support and ideas for the project; M.R.C. and J.M.R. wrote the manuscript with contributions from J.O. and N.M.-B. All authors read and approved the manuscript.

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Correspondence to Miguel R Campanero or Juan Miguel Redondo.

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Oller, J., Méndez-Barbero, N., Ruiz, E. et al. Nitric oxide mediates aortic disease in mice deficient in the metalloprotease Adamts1 and in a mouse model of Marfan syndrome. Nat Med 23, 200–212 (2017). https://doi.org/10.1038/nm.4266

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