Buscar

Estamos realizando la búsqueda. Por favor, espere...

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

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.

 Fuente: EMBO Molecular Medicine, 2024, 16, 132-157

 Editorial: Wiley-Blackwell

 Año de publicación: 2024

 Nº de páginas: 26

 Tipo de publicación: Artículo de Revista

 DOI: 10.1038/s44321-023-00009-7

 ISSN: 1757-4676,1757-4684

 Proyecto español: CEX2021-001154-S; CEX2020-001041-S

Autoría

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.

EVANGELISTA, ARTURO

TEIXIDO-TURA, GISELA

CAMPANERO, MIGUEL R.

REDONDO, JUAN MIGUEL