Allopurinol improves cardiovascular phenotypes of a mouse model for Williams-Beuren syndrome reducing redox stress
Cardiovascular disease represents the primary cause of morbidity in Williams-Beuren syndrome (WBS), a neurodevelopmental disorder resulting from a hemizygous deletion of 26-28 genes on chromosome 7q11.23. The clinical phenotype includes systemic hypertension, cardiac dysfunction, and progressive vascular remodelling, features that are further exacerbated by increased oxidative stress. Given the early onset and progression of these cardiovascular manifestations, patients often require long-term pharmacological management from childhood. This raises important concerns about cumulative drug toxicity, dosing strategies, and the long-term safety of therapeutic interventions in pediatric populations. Using the Complete deletion (CD) mouse model of WBS, this study aims to evaluate whether pediatric-equivalent doses of Allopurinol (ALO) (20mg/kg/day equivalent to 1,66mg/kg/day in humans) a highly specific xanthine oxidoreductase (XOR) inhibitor, and Losartan (LOS) (12,5 mg/kg/day equivalent to 1 mg/kg/day in humans) an angiotensin II type1 receptor antagonist, will exert beneficial effects on the cardiovascular phenotype of CD mice. To enable comparative analysis, the pharmacological effects of ALO and LOS were evaluated against both untreated CD mice and wild-type (WT) controls. In CD mice, both treatments significantly reduced systemic blood pressure; however, their effects on cardiac outcomes were different. While treatment with ALO improved cardiac pathology, treatment with LOS did not. ALO likely acts by reducing XOR protein levels, reactive oxygen species (ROS) production and NRLP3 activation. These findings support a therapeutic model in which minimal doses of ALO offers broader cardiovascular protection in WBS.