Allopurinol Blocks The Formation And Progression Of Aortic Aneurysm In A Mouse Model Of Marfan Syndrome

Abstract

ABSTRACTWe reported elevated reactive oxygen species (ROS) formation and NADPH oxidase NOX4 upregulation in MFS mice and patient aortic samples. Here we address the contribution of xanthine dehydrogenase (XDH) which catabolizes purines into uric acid plus ROS. In MFS patients, protein levels of the oxidase form (XO) of XDH increased in the dissected aneurysm. XDH mRNA and protein expression levels increased in the aorta of young but not older MFS mice. The protein and enzymatic activity of XO increased with respect to the dehydrogenase. The XDH inhibitor allopurinol blocked the progression of the aortic root aneurysm in MFS mice, and it was also protective when administrated before the appearance of aneurysm. Elastic fiber fragmentation, fibrotic remodeling, nuclear translocation of pNRF2, increased 3’-nitrotyrosine levels in the aortic tunica media, and endothelial dysfunction were all prevented by allopurinol. MFS ascending aorta showed a large overproduction of H2O2 which did not occur in allopurinol-treated MFS mice. Allopurinol mediated the inhibition of the MFS aortopathy inhibiting ROS overproduction without altering uric acid plasma levels. This study strengthens that redox stress is an important determinant of aortic aneurysm development in MFS and supports a clinical trial for allopurinol in the pharmacological treatment of MFS aortopathy.