Versican accumulation drives Nos2 induction and aortic disease in Marfan syndrome via Akt activation
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Published on: September 28, 2015
María Jesús Ruiz-Rodríguez1,2, Jorge Oller2,3, Sara Martínez-Martínez1,2
1Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, 28029, Spain.
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.
Insights
Versican (Vcan) accumulation drives Marfan syndrome (MFS) aortic disease by activating the Akt pathway and increasing Nos2 expression. Inhibiting Akt signaling offers a potential therapeutic strategy for MFS aortopathy.
Area of Science:
- Cardiovascular Biology
- Genetics
- Proteomics
Background:
- Thoracic aortic aneurysm and dissection (TAAD) is a severe complication of Marfan syndrome (MFS), often linked to fibrillin-1 gene mutations.
- The role of extracellular matrix (ECM) proteins, specifically versican (Vcan) and aggrecan (Acan), in MFS-related aortic disease remains unclear.
Purpose of the Study:
- To investigate the involvement of Vcan and Acan in the pathogenesis of MFS-associated thoracic aortopathy.
- To identify molecular mechanisms underlying Vcan's contribution to aortic disease in MFS.
- To explore potential therapeutic targets for MFS aortic disease.
Main Methods:
- Utilized a mouse model of Marfan syndrome (Fbn1C1041G/+).
- Assessed Vcan and Acan accumulation in mouse aortas.
- Investigated the effect of Vcan haploinsufficiency and silencing on aortic dilation and Nos2 expression.
- Examined the role of the Akt signaling pathway in Vcan-mediated aortic disease.
- Analyzed human MFS patient aortic tissue for VCAN and pAKT-S473 levels.
Main Results:
- Vcan, but not Acan, accumulated in the aortas of MFS mice.
- Vcan haploinsufficiency and silencing ameliorated aortic dilation and reduced Nos2 expression in MFS mice.
- Vcan triggered Akt activation, and Akt inhibition rapidly regressed aortic dilation and Nos2 expression.
- Human MFS patient aortas showed VCAN accumulation and elevated pAKT-S473.
Conclusions:
- Versican (Vcan) plays a critical, causative role in Marfan syndrome (MFS) aortopathy.
- Vcan promotes MFS aortic disease by inducing Nos2 expression through Akt pathway activation.
- The Akt signaling pathway represents a promising therapeutic target for MFS-related thoracic aortic disease.
