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

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 uncl...

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Detalles Bibliográficos
Autores: Ruiz-Rodríguez, María Jesús, Oller, Jorge, Martínez-Martínez, Sara, Alarcón-Ruiz, Iván, Toral, Marta, Sun, Yilin, Colmenar, Ángel, Méndez-Olivares, María José, López-Maderuelo, Dolores, Kern, Christine B., Nistal Herrera, Juan Francisco|||0000-0002-4152-7621, Evangelista, Arturo, Teixido-Tura, Gisela, Campanero, Miguel R., Redondo, Juan Miguel
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Universidad de Cantabria (UC)
Repositorio:UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:inglés
OAI Identifier:oai:repositorio.unican.es:10902/32005
Acceso en línea:https://hdl.handle.net/10902/32005
Access Level:acceso abierto
Palabra clave:Akt
Aortic aneurysm
Marfan syndrome
Nos2
Versican
Descripción
Sumario: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.

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