@article{10902/38816,
year = {2025},
url = {https://hdl.handle.net/10902/38816},
abstract = {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.},
organization = {A.R.-O. is supported by the Conchita-Rábago Foundation 2024 grant. J.O. is supported by a Ramón y Cajal contract (RYC2021-033343-I) and grant from Spanish Ministerio de Ciencia e Innovación grant (PID2022-137730OA-I00) funded by MCIN/AEI/10.13039/ 501100011033/FEDER, EU; granted by Fundación MERCK-FEDER ‘Investigación clínica en enfermedades raras 2022’, Marfan Spanish Association (SIMA, www.Marfan.es) and by ‘V-Ayudas Muévete por los que no pueden 2021’. Research in M.M.’s lab was supported by European Research Council grant ERC-2021-CoG 101044248- LetTBe and the Y2020/BIO-6350 NutriSION-CM synergy grant from Comunidad de Madrid, Ministerio de Ciencia e Innovacion, Spain (grants PID2022-141169OB-I00 and PID2022-138295OB-I00). European Research Council. M.M.-L., G.A.-L., and G.A.-E. are funded by Instituto de Salud Carlos III through the projects PI20/01103, PI23/00100, and CP22/00100 (co-funded by European Regional Development Fund/European Social Fund ‘A way to make Europe’/ ‘Investing in your future’). J.L.M.-V. is supported by grant from Spanish Ministerio de Ciencia e Innovación (PID2022-136979OB- I00). L.M.B.-C. is supported by Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III (ISCIII/FEDER PI22/00233). G.T.-T. and A.G. are supported by Spanish Society of Cardiology (SEC/FEC-INV- CLI 20/015). O.L. is supported by grant from Spanish Health Ministry or Spanish Ministerio de Sanidad (PI20/00923 Instituto Carlos III). J.F.N. is supported by grant from Spanish Health Ministry or Spanish Ministerio de Sanidad (PI21/00084 FIS) and a grant from Health Research Institute Valdecilla (INNVAL21/24). N.M-B. is supported by Spanish Health Ministry or Spanish Ministeiro de Sanidad (PI21/ 01126). M.J.F.-G. is supported by Spanish Health Ministry or Spanish Ministerio de Sanidad contract (FIS22/00140). J.M.R. has received funding from La Caixa Foundation (HR18-00068); Spanish Ministerio de Ciencia e Innovación grant PID2021-122388OB-100 funded by MCIN/AEI/10.13039/501100011033; and Instituto de Salud Carlos III (CIBER-CV CB16/11/00264); Fundació La Marató TV3 grant 202334- 31, and Spanish Ministerio de Ciencia e Innovación contract FPI BES-2016-077649) to M.J.R.-R. The CBMSO is supported by Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid. CBMSO is a Severo Ochoa Centers of Excellence (grant CEX2021-001154-S) funded by MICIN/AEI/10.13039/501100011033.},
publisher = {Oxford University Press},
publisher = {European Heart Journal, 2025, 46(45), 4988-5005},
title = {Excessive glycosylation drives thoracic aortic aneurysm formation through integrated stress response},
author = {Rochano Ortiz, Antonio and San Sebastián Jaraba, Irene and Zamora, Carmen and Simó, Carolina and García Cañas, Virginia and Martínez Albaladejo, Sacramento and Fernández Gómez, María José and Marcos Ríos, Daniel and Martínez Núñez, Patricia and Martín Lorenzo, Marta and Velho, Tiago R. and Ruíz Rodríguez, María Jesús and Leal Zafra, Amanda and Gabandé Rodríguez, Enrique and Martínez Martínez, Sara and Guala, Andrea and Lorenzo, Óscar and Blanco Colio, Luis Miguel and Martín Ventura, José Luís and Nistal Herrera, Juan Francisco},
}