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  3. Excessive glycosylation drives thoracic aortic aneurysm formation through integrated stress response.

Excessive glycosylation drives thoracic aortic aneurysm formation through integrated stress response.

Fecha de publicación: Fecha Ahead of Print:

Autores de IDIVAL

Autores ajenos al IDIVAL

  • Rochano-Ortiz A
  • San Sebastián-Jaraba I
  • Zamora C
  • Simó C
  • García-Cañas V
  • Martínez-Albaladejo S
  • Fernández-Gómez MJ
  • Marcos-Ríos D
  • Martínez-Núñez P
  • Martín-Lorenzo M
  • Velho TR
  • Ruíz-Rodríguez MJ
  • Leal-Zafra A
  • Gabandé-Rodríguez E
  • Martínez-Martínez S
  • Guala A
  • Lorenzo Ó
  • Blanco-Colio LM
  • Martín-Ventura JL
  • Álvarez-Llamas G
  • Aldamiz-Echevarría G
  • Teixidó-Tura G
  • Forteza A
  • Redondo JM
  • Méndez-Barbero N
  • Mittelbrunn M
  • Oller J

Unidades

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 ß-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. RESULTS: Hexosamine biosynthetic pathway was up-regulated in both an MFS mouse model and ß-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.

© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.

Datos de la publicación

ISSN/ISSNe:
0195-668X, 1522-9645

EUROPEAN HEART JOURNAL  OXFORD UNIV PRESS

Tipo:
Article
Páginas:
4988-5005
PubMed:
40720766

Citas Recibidas en Web of Science: 3

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Keywords

  • Aortic medial degeneration; Hexosamine Biosynthetic pathway; Integrated stress response; Marfan Syndrome; Thoracic aortic aneurysm

Campos de Estudio

Financiación

Comunidad de Madrid (Y2020/BIO-6350 NutriSION-CM)
Conchita-Rabago Foundation
Consejo Superior de Investigaciones Cientificas
European Regional Development Fund/European Social Fund 'A way to make Europe'/'Investing in your future'
European Research Council
European Research Council (ERC-2021-CoG 101044248-LetTBe)
Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III (ISCIII/FEDER PI22/00233)
Fundacio La Marato TV3 grant (202334-31)
FUNDACION INSTITUTO DE INVESTIGACION MARQUES DE VALDECILLA (INNVAL21/24)
Fundacion MERCK-FEDER 'Investigacion clinica en enfermedades raras 2022', Marfan Spanish Association
Instituto de Salud Carlos III (CIBER-CV CB16/11/00264)
Instituto de Salud Carlos III (CP22/00100)
Instituto de Salud Carlos III (PI20/01103)
Instituto de Salud Carlos III (PI23/00100)
La Caixa Foundation (HR18-00068)
MICIN/AEI (CEX2021-001154-S)
Ministerio de Ciencia e Innovacion, Spain (PID2022-138295OB-I00)
Ministerio de Ciencia e Innovacion, Spain (PID2022-141169OB-I00)
Ramon y Cajal contract (RYC2021-033343-I)
Spanish Health Ministry or Spanish Ministerio de Sanidad (FIS22/00140)
Spanish Health Ministry or Spanish Ministerio de Sanidad (PI20/00923)
Spanish Health Ministry or Spanish Ministerio de Sanidad (PI21/00084 FIS)
Spanish Health Ministry or Spanish Ministerio de Sanidad (PI21/01126)
Spanish Ministerio de Ciencia e Innovacion - MCIN/AEI (PID2021-122388OB-100)
Spanish Ministerio de Ciencia e Innovacion (PID2022-136979OB-I00)
Spanish Ministerio de Ciencia e Innovacion contract FPI (BES-2016-077649)
Spanish Ministerio de Ciencia e Innovacion grant - MCIN/AEI/FEDER, EU (PID2022-137730OA-I00)
Spanish Society of Cardiology (SEC/FEC-INV-CLI 20/015)
Universidad Autonoma de Madrid
V-Ayudas Muevete por los que no pueden 2021

Proyectos asociados

Transcriptómica e inteligencia artificial para la predicción de remodelado cardiaco desfavorable en pacientes operados por estenosis valvular aórtica

Investigador Principal: Juan Francisco Nistal Herrera

INNVAL21/24 . FUNDACION INSTITUTO DE INVESTIGACION MARQUES DE VALDECILLA . 2021

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