2. Academic Validation
  3. Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO

Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO

  • Nat Commun. 2021 May 11;12(1):2628. doi: 10.1038/s41467-021-22933-3.
Andrea de la Fuente-Alonso  # 1 2,  Marta Toral  # 1 2,  Alvaro Alfayate 1 2 3,  María Jesús Ruiz-Rodríguez 1 2,  Elena Bonzón-Kulichenko 2 3,  Gisela Teixido-Tura 2 4,  Sara Martínez-Martínez 1 2,  María José Méndez-Olivares 1 2,  Dolores López-Maderuelo 1 2,  Ileana González-Valdés 3,  Eusebio Garcia-Izquierdo 5,  Susana Mingo 5,  Carlos E Martín 6,  Laura Muiño-Mosquera 7,  Julie De Backer 7,  J Francisco Nistal 2 8,  Alberto Forteza 6,  Arturo Evangelista 2 4,  Jesús Vázquez 2 3,  Miguel R Campanero 9 10 11,  Juan Miguel Redondo 12 13
Affiliations

Affiliations

  • 1 Gene regulation in cardiovascular remodeling and inflammation group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
  • 2 Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
  • 3 Cardiovascular Proteomics Laboratoy, CNIC, Madrid, Spain.
  • 4 Servei de Cardiologia, Hospital Vall d'Hebron, Barcelona, Spain.
  • 5 Cardiology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
  • 6 Cardiac Surgery Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
  • 7 Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.
  • 8 Cardiovascular Surgery and Department of Physiology and Pharmacology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Facultad de Medicina, Universidad de Cantabria, Santander, Spain.
  • 9 Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain. mcampanero@cbm.csic.es.
  • 10 Department of Cancer Biology, Instituto de Investigaciones Biomedicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain. mcampanero@cbm.csic.es.
  • 11 Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain. mcampanero@cbm.csic.es.
  • 12 Gene regulation in cardiovascular remodeling and inflammation group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. jmredondo@cnic.es.
  • 13 Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain. jmredondo@cnic.es.
  • # Contributed equally.
PMID: 33976159 DOI: 10.1038/s41467-021-22933-3
Abstract

Thoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that nitric oxide (NO) signaling dysregulates actin Cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble Guanylate Cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble Guanylate Cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble Guanylate Cyclase as therapeutic targets.

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