2026-06-14T03:56:07Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/271612026-01-22T01:18:59Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Rochano-Ortiz, Antonio author San Sebastián-Jaraba, Irene author Zamora, Carmen author Simó, Carolina author García-Cañas, Virginia author Martínez-Albaladejo, Sacramento author Fernández-Gómez, María José author Marcos-Ríos, Daniel author Martínez-Núñez, Patricia author Martín-Lorenzo, Marta author Velho, Tiago R author Ruíz-Rodríguez, María Jesús author Leal-Zafra, Amanda author Gabandé-Rodríguez, Enrique author Martínez-Martínez, Sara author Guala, Andrea author Lorenzo, Óscar author Blanco-Colio, Luis Miguel author Martín-Ventura, José Luís author Álvarez-Llamas, Gloria author Aldamiz-Echevarría, Gonzalo author Teixidó-Tura, Gisela author Forteza, Alberto author Nistal, Juan Francisco author Redondo, Juan Miguel author Méndez-Barbero, Nerea author Mittelbrunn, María author Oller, Jorge author 2025-12-01 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. Hexosamine biosynthetic pathway activation was analysed in aortas from an MFS mouse model, a β-aminopropionitrile-induced 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. 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. 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. Eur Heart J. 2025 Dec 1;46(45):4988-5005. European Heart Journal 40720766 https://hdl.handle.net/20.500.12105/27161 Aortic medial degeneration Hexosamine Biosynthetic pathway Integrated stress response Marfan Syndrome Thoracic aortic aneurysm Excessive glycosylation drives thoracic aortic aneurysm formation through integrated stress response.