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2022-11-05

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cc by-nc-nd (c ) Rodríguez Rovira, Isaac et al.,2022
Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/190800

Allopurinol blocks aortic aneurysm in a mouse model of Marfan syndrome via reducing aortic oxidative stress

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https://doi.org/10.1016/j.freeradbiomed.2022.11.001

Abstract

Background Increasing evidence indicates that redox stress participates in MFS aortopathy, though its mechanistic contribution is little known. We reported elevated reactive oxygen species (ROS) formation and NADPH oxidase NOX4 upregulation in MFS patients and mouse aortae. Here we address the contribution of xanthine oxidoreductase (XOR), which catabolizes purines into uric acid and ROS in MFS aortopathy. Methods and results In aortic samples from MFS patients, XOR protein expression, revealed by immunohistochemistry, increased in both the tunicae intima and media of the dilated zone. In MFS mice (Fbn1C1041G/+), aortic XOR mRNA transcripts and enzymatic activity of the oxidase form (XO) were augmented in the aorta of 3-month-old mice but not in older animals. The administration of the XOR inhibitor allopurinol (ALO) halted the progression of aortic root aneurysm in MFS mice. ALO administrated before the onset of the aneurysm prevented its subsequent development. ALO also inhibited MFS-associated endothelial dysfunction as well as elastic fiber fragmentation, nuclear translocation of pNRF2 and increased 3′-nitrotyrosine levels, and collagen maturation remodeling, all occurring in the tunica media. ALO reduced the MFS-associated large aortic production of H2O2, and NOX4 and MMP2 transcriptional overexpression. Conclusions Allopurinol interferes in aortic aneurysm progression acting as a potent antioxidant. This study strengthens the concept that redox stress is an important determinant of aortic aneurysm formation and progression in MFS and warrants the evaluation of ALO therapy in MFS patients.

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Aneurismes aòrtics, Malalties del teixit connectiu, Estrès oxidatiu, Àcid úric, Inhibidors enzimàtics, Metal·loproteïnases

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Aortic aneurysms, Connective tissues diseases, Oxidative stress, Uric acid, Enzyme inhibitors, Metalloproteinases

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Articles publicats en revistes (Biomedicina)

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RODRÍGUEZ ROVIRA, Isaac, et al. Allopurinol blocks aortic aneurysm in a mouse model of Marfan syndrome via reducing aortic oxidative stress. Free Radical Research. 2022. Vol. 193, num. Pt, pags. 538-550. ISSN 1071-5762. [consulted: 9 of June of 2026]. Available at: https://hdl.handle.net/2445/190800

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