ALLOPURINOL BLOCKS THE FORMATION AND PROGRESSION OF AORTIC ANEURYSM IN A MOUSE MODEL OF MARFAN SYNDROME ACTING AS SCAVENGER OF REACTIVE OXYGEN SPECIES
BackgroundIncreasing 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 ResultsIn 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, fibrotic collagen remodeling, nuclear translocation of pNRF2 and increased 3-nitrotyrosine levels all occurring in the tunica media. ALO reduced the MFS-associated large aortic production of H2O2, and NOX4 and MMP2 transcriptional overexpression. ConclusionsAllopurinol 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. HIGHLIGHTSO_LIXanthine oxidoreductase (XOR) is upregulated in the aortic aneurysm of Marfan syndrome (MFS) both in patients and young mice. C_LIO_LIAllopurinol halts the formation and progression of aortic aneurysm in MFS mice C_LIO_LIAllopurinol reduces a variety of oxidative stress-associated molecular reactions. C_LIO_LIAllopurinol prevents MFS endothelial-dependent vasodilator dysfunction. C_LIO_LIThe antioxidant action of allopurinol suggests its repositioning for pharmacological use in MFS aortopathy. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/464182v5_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1e6f784org.highwire.dtl.DTLVardef@84075eorg.highwire.dtl.DTLVardef@1ffcb5borg.highwire.dtl.DTLVardef@800503_HPS_FORMAT_FIGEXP M_FIG C_FIG