PT  - JOURNAL ARTICLE
AU  - Isaac Rodríguez-Rovira
AU  - Cristina Arce
AU  - Karo De Rycke
AU  - Belén Pérez
AU  - Aitor Carretero
AU  - Marc Arbonés
AU  - Gisela Teixidò-Turà
AU  - Mari Carmen Gómez-Cabrera
AU  - Victoria Campuzano
AU  - Francesc Jiménez-Altayó
AU  - Gustavo Egea
TI  - ALLOPURINOL BLOCKS AORTIC ANEURYSM IN A MOUSE MODEL OF MARFAN SYNDROME VIA REDUCING AORTIC OXIDATIVE STRESS
AID  - 10.1101/2021.10.13.464182
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2021.10.13.464182
4099  - http://biorxiv.org/content/early/2022/03/30/2021.10.13.464182.short
4100  - http://biorxiv.org/content/early/2022/03/30/2021.10.13.464182.full
AB  - Background The pathogenesis and progression of aortic aneurysm in Marfan syndrome (MFS) involves dysregulated TGF-β and nitric oxide signaling, altered hemodynamics, and biomechanical forces. Increasing evidence indicates that redox stress participates in MFS aortopathy, though its contribution is not well established. We reported elevated reactive oxygen species (ROS) formation and NADPH oxidase NOX4 upregulation in MFS patients and mice aortic samples. Here we address the contribution of xanthine oxidoreductase (XOR), which is transcribed as dehydrogenase (XDH) and then post-translationally modified to oxidase (XO), catabolizing mainly purines into uric acid and ROS.Methods and Results We report that in MFS patients, XOR protein levels increased in aortic samples. In MFS mice (Fbn1C1041G/+), XOR mRNA transcripts augmented in the aorta of young but not older MFS mice. Moreover, the enzymatic activity of XO form increased with respect to XDH. The administration of the XOR inhibitor allopurinol (ALO) blocked the progression of aortic root aneurysm in MFS mice. ALO was also protective when administrated before the appearance of aneurysm. MFS-induced elastic fiber fragmentation, fibrotic remodeling, nuclear translocation of pNRF2, and increased 3’-nitrotyrosine levels in the aortic tunica media as well as endothelial dysfunction were all prevented by allopurinol. The large overproduction of H2O2 in MFS aorta did not occur in allopurinol-treated mice whose uric acid plasma levels remained unaltered.Conclusions This study strengthens the concept that redox stress is an important determinant of aortic aneurysm formation and progression in MFS and supports a clinical trial for ALO in the pharmacological treatment of MFS aortopathy.Competing Interest StatementThe authors have declared no competing interest.