2. Academic Validation
  3. Versican accumulation drives Nos2 induction and aortic disease in Marfan syndrome via Akt activation

Versican accumulation drives Nos2 induction and aortic disease in Marfan syndrome via Akt activation

  • EMBO Mol Med. 2024 Jan 2. doi: 10.1038/s44321-023-00009-7.
María Jesús Ruiz-Rodríguez 1 2,  Jorge Oller # 2 3,  Sara Martínez-Martínez # 1 2,  Iván Alarcón-Ruiz 1 2,  Marta Toral 1 2,  Yilin Sun 4,  Ángel Colmenar 1 2,  María José Méndez-Olivares 1 2,  Dolores López-Maderuelo 1 2,  Christine B Kern 5,  J Francisco Nistal 2 6,  Arturo Evangelista 7,  Gisela Teixido-Tura 2 8,  Miguel R Campanero # 9 10,  Juan Miguel Redondo # 11 12 13
Affiliations

Affiliations

  • 1 Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, 28029, Spain.
  • 2 Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
  • 3 Laboratory of Vascular Pathology, Hospital IIS-Fundación Jiménez Díaz, 28040, Madrid, Spain.
  • 4 Cell-Cell Communication & Inflammation Unit, Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, 28049, Spain.
  • 5 Medical University of South Carolina (MUSC), Charleston, SC, 29425, USA.
  • 6 Cardiovascular Surgery, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Valdecilla (IDIVAL), Facultad de Medicina, Universidad de Cantabria, Santander, 39005, Spain.
  • 7 Teknon Medical Centre-Quironsalud. Heart Institute, Barcelona, Spain.
  • 8 Department of Cardiology, Hospital Universitari Vall d'Hebron (VHIR), Barcelona, 08035, Spain.
  • 9 Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain. [email protected].
  • 10 Cell-Cell Communication & Inflammation Unit, Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, 28049, Spain. [email protected].
  • 11 Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, 28029, Spain. [email protected].
  • 12 Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain. [email protected].
  • 13 Cell-Cell Communication & Inflammation Unit, Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, 28049, Spain. [email protected].
  • # Contributed equally.
PMID: 38177536 DOI: 10.1038/s44321-023-00009-7
Abstract

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition associated with Marfan syndrome (MFS), a disease caused by fibrillin-1 gene mutations. While various conditions causing TAAD exhibit aortic accumulation of the proteoglycans versican (Vcan) and aggrecan (Acan), it is unclear whether these ECM proteins are involved in aortic disease. Here, we find that Vcan, but not Acan, accumulated in Fbn1C1041G/+ aortas, a mouse model of MFS. Vcan haploinsufficiency protected MFS mice against aortic dilation, and its silencing reverted aortic disease by reducing Nos2 protein expression. Our results suggest that Acan is not an essential contributor to MFS aortopathy. We further demonstrate that Vcan triggers Akt activation and that pharmacological Akt pathway inhibition rapidly regresses aortic dilation and Nos2 expression in MFS mice. Analysis of aortic tissue from MFS human patients revealed accumulation of VCAN and elevated pAKT-S473 staining. Together, these findings reveal that Vcan plays a causative role in MFS aortic disease in vivo by inducing Nos2 via Akt activation and identify Akt signaling pathway components as candidate therapeutic targets.

Keywords

Akt; Aortic Aneurysm; Marfan Syndrome; Nos2; Versican.

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