ALLOPURINOL BLOCKS THE FORMATION AND PROGRESSION OF AORTIC ANEURYSM IN A MOUSE MODEL OF MARFAN SYNDROME ACTING AS A SCAVENGER OF REACTIVE OXYGEN SPECIES

The pathogenesis and progression of aortic aneurysm in Marfan syndrome (MFS) involves dysregulated TGF-{beta} and nitric oxide signaling, altered hemodynamics, and biomechanical forces. Increasing evidence indicates that redox stress participates in MFS aortopathy development, though its contribution is not well established. We reported elevated reactive oxygen species (ROS) formation and NADPH oxidase NOX4 upregulation in MFS mice and in patient aortic samples. Here we address the contribution of xanthine dehydrogenase (XDH) which catabolizes purines into uric acid plus ROS. XDH mRNA and protein expression levels are increased in the aorta of young but not older MFS mice (Fbn1C1041G/+). The protein and enzymatic activity of the oxidase form (XO) is increased with respect to the dehydrogenase. In patients, XO protein levels were increased in the dilated and the adjacent non-dilated zone of aortic aneurysm. The palliative administration of the XDH inhibitor allopurinol attenuated the progression of the aortic root aneurysm in MFS mice. Allopurinol was also protective when administrated before the appearance of aneurysm onset. 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. Mechanistically, allopurinol mediates these effects by inhibiting H2O2 overproduction, with no apparent relevance for uric acid, whose plasma levels remained constant with age. 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 allopurinol in the pharmacological treatment of MFS aortopathy. Sentence summaryAllopurinol prevents the formation and progression of Marfan syndrome aortopathy