Uric acid promotes aortic valve calcification via mediating valve interstitial cell osteogenic differentiation and endothelial dysfunction

Aortic valve calcification is a lethal valvular heart disease lacking effective drug therapy. However, whether uric acid is involved in the development of aortic valve calcification is unclear. Two-sample Mendelian randomization (MR) analyses confirmed the causal relationship between uric acid and valvular heart disease. Uric acid levels were assessed in aortic valve tissue from patients with/without aortic valve calcification. To investigate the impact of hyperuricemia on aortic valve calcification, apolipoprotein E knockout (ApoE^-/-) mice fed a high-fat diet (HFD) were also given an adenine diet, with some receiving allopurinol in their drinking water. RNA sequencing was performed on valve interstitial cells (VICs) and endothelial cells (VECs) with/without uric acid. MR analysis has revealed a causal effect of uric acid levels on valvular heart disease. Furthermore, our clinical data indicate a positive correlation between elevated serum uric acid levels and aortic valve calcium score. Specifically, uric acid levels were upregulated in calcified valves. In ApoE^-/- mice, an adenine-diet-induced hyperuricemia accelerated aortic valve calcification. RNA sequencing analysis demonstrated that uric acid-promoted osteogenic differentiation, primarily through the activation of hypoxia-inducible factor-1alpha (HIF-α). Additionally, uric acid impaired endothelial barrier function by activating HIF-α, resulting in increased macrophage infiltration in ApoE^-/- mice. Inhibiting HIF-1α suppressed osteogenic differentiation and reduced endothelial injury both in vitro and in vivo in the presence of uric acid. This study reveals a new role of hyperuricemia in aortic valve calcification, suggesting uric acid-lowering drugs or HIF-1α inhibition as potential treatments for associated aortic valve calcification.