Uric Acid Disrupts Heart Development in Zebrafish by Inhibiting the Wnt Signaling Pathway

Congenital heart disease (CHD) is the most common birth defect and involves intricate developmental mechanisms. Uric acid (UA), the final metabolite of purine degradation in humans, has a largely unexplored role in heart development. This study investigated the effects of elevated UA levels-both exogenous and endogenous-on cardiac development in a zebrafish model and explored the involvement of Wnt signaling in this process. UA elevation was achieved through exogenous UA exposure, in vivo overexpression of xdh, and knockdown of uox. Expression levels of Wnt pathway components (wnt1, wnt3a, wnt6b, and β-catenin), cardiac progenitor markers (mesp1 and isl1), neural crest cell markers (sox10 and crestin), and cardiac development genes (nkx2.5, tbx5a, and fgf10a) were assessed at key developmental stages. All UA-elevating strategies significantly increased UA concentrations and led to phenotypes including pericardial edema and reduced heart rate at 72 h post-fertilization (hpf). These phenotypes were accompanied by downregulation of Wnt signaling and cardiac development genes. Treatment with the Wnt activator CHIR99021 partially rescued the cardiac defects induced by UA overload. These findings demonstrate that elevated UA-whether exogenous or endogenous-can disrupt cardiac development in zebrafish, at least in part by suppressing Wnt signaling, thereby impairing downstream gene networks essential for heart morphogenesis.