Excessive glycosylation drives thoracic aortic aneurysm formation through integrated stress response

Background and Aims Thoracic aortic aneurysms and dissections (TAADs) are depicted by aortic medial degeneration characterized by glycan-rich matrix accumulation. Marfan syndrome (MFS) is the most common inherited connective tissue disorder associated with TAAD. Although vascular smooth muscle cell...

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Detalles Bibliográficos
Autores: Rochano Ortiz, Antonio, San Sebastián Jaraba, Irene, Zamora, Carmen, Simó, Carolina, García Cañas, Virginia, Martínez Albaladejo, Sacramento, Fernández Gómez, María José, Marcos Ríos, Daniel, Martínez Núñez, Patricia, Martín Lorenzo, Marta, Velho, Tiago R., Ruíz Rodríguez, María Jesús, Leal Zafra, Amanda, Gabandé Rodríguez, Enrique, Martínez Martínez, Sara, Guala, Andrea, Lorenzo, Óscar, Blanco Colio, Luis Miguel, Martín Ventura, José Luís, Nistal Herrera, Juan Francisco|||0000-0002-4152-7621
Tipo de recurso: artículo
Fecha de publicación:2025
País:España
Institución:Universidad de Cantabria (UC)
Repositorio:UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:inglés
OAI Identifier:oai:repositorio.unican.es:10902/38816
Acceso en línea:https://hdl.handle.net/10902/38816
Access Level:acceso abierto
Palabra clave:Thoracic aortic aneurysm
Marfan Syndrome
Aortic medial degeneration
Hexosamine Biosynthetic pathway
Integrated stress response
Descripción
Sumario:Background and Aims Thoracic aortic aneurysms and dissections (TAADs) are depicted by aortic medial degeneration characterized by glycan-rich matrix accumulation. Marfan syndrome (MFS) is the most common inherited connective tissue disorder associated with TAAD. Although vascular smooth muscle cell metabolic dysfunction has emerged as a pathogenic driver of TAAD, surgical repair remains the mainstay of treatment. This study aimed to investigate the role of the hexosamine biosynthetic pathway (HBP) in sporadic and genetic TAAD pathophysiology. Methods Hexosamine biosynthetic pathway activation was analysed in aortas from an MFS mouse model, a β-aminopropionitrileinduced non-genetic TAAD model, and patients with sporadic TAAD using transcriptomic and metabolomic approaches. Aortic dilatation was monitored by ultrasound imaging. Pharmacological inhibition of HBP and integrated stress response (ISR) was performed to assess their therapeutic potential. Results Hexosamine biosynthetic pathway was up-regulated in both an MFS mouse model and β-aminopropionitrile-induced TAAD, as well as in aortic samples from MFS and sporadic TAAD patients. Enhanced HBP activity contributed to aortic dilatation and medial degeneration via vascular smooth muscle cell dysfunction and ISR activation. Inhibition of HBP or ISR reversed these effects in the MFS model. Conclusions The HBP–ISR axis drives medial degeneration in TAAD. These findings identify HBP and ISR as a potential target in TAAD of both genetic and non-genetic origin.

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