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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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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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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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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DOI: https://doi.org/10.1038/nm.4266
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