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Updated: May 21, 2025
Isolation of Mouse Interstitial Valve Cells to Study the Calcification of the Aortic Valve In Vitro
Published on: May 10, 2021
Uric acid promotes aortic valve calcification via mediating valve interstitial cell osteogenic differentiation and
Jialiang Zhang1,2,3, Wenhua Lei1,2,3, Jing Zhou1,2,3
1Laboratory of Cardiac Structure and Function, Institute of Cardiovascular Diseases, West China Hospital, Sichuan University, Chengdu, P.R. China.
Insights
High uric acid levels causally contribute to aortic valve calcification. Lowering uric acid or inhibiting hypoxia-inducible factor-1alpha (HIF-1α) may offer new therapeutic strategies for this condition.
Area of Science:
- Cardiovascular Biology
- Metabolic Disease Research
- Vascular Biology
Background:
- Aortic valve calcification is a severe condition with limited treatment options.
- The role of uric acid in aortic valve calcification pathogenesis is not well understood.
Purpose of the Study:
- To investigate the causal link between uric acid and aortic valve calcification.
- To elucidate the molecular mechanisms by which uric acid influences aortic valve calcification.
Main Methods:
- Two-sample Mendelian randomization analyses were conducted.
- Clinical data from patients with aortic valve calcification were analyzed.
- Aortic valve calcification was studied in apolipoprotein E knockout mice models.
- RNA sequencing was performed on valve interstitial cells and endothelial cells.
Main Results:
- Mendelian randomization confirmed a causal effect of uric acid on valvular heart disease.
- Elevated serum uric acid correlated positively with aortic valve calcium scores.
- Hyperuricemia accelerated aortic valve calcification in mice.
- Uric acid promoted osteogenic differentiation and endothelial dysfunction via HIF-1α activation.
Conclusions:
- Hyperuricemia plays a significant role in the development of aortic valve calcification.
- Inhibition of HIF-1α mitigates uric acid-induced osteogenic differentiation and endothelial injury.
- Uric acid-lowering therapies and HIF-1α inhibition represent potential therapeutic avenues.
Abstract:
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.
