Zhang Jialiang, Lei Wenhua, Zhou Jing, Zhang Yaoyu, Huang Fangyang, Chen Mao
Laboratory of Cardiac Structure and Function, Institute of Cardiovascular Diseases, West China Hospital, Sichuan University, Chengdu, P.R. China.
Department of Cardiology, West China Hospital, Sichuan University, Chengdu, P.R. China.
FASEB J. 2025 Mar 31;39(6):e70437. doi: 10.1096/fj.202402831R.
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.
主动脉瓣钙化是一种缺乏有效药物治疗的致命性心脏瓣膜疾病。然而，尿酸是否参与主动脉瓣钙化的发展尚不清楚。两样本孟德尔随机化（MR）分析证实了尿酸与心脏瓣膜疾病之间的因果关系。在有/无主动脉瓣钙化的患者的主动脉瓣组织中评估尿酸水平。为了研究高尿酸血症对主动脉瓣钙化的影响，给喂食高脂饮食（HFD）的载脂蛋白E基因敲除（ApoE）小鼠喂食腺嘌呤饮食，其中一些小鼠在饮用水中添加别嘌呤醇。对有/无尿酸处理的瓣膜间质细胞（VICs）和内皮细胞（VECs）进行RNA测序。MR分析揭示了尿酸水平对心脏瓣膜疾病的因果效应。此外，我们的临床数据表明血清尿酸水平升高与主动脉瓣钙评分呈正相关。具体而言，钙化瓣膜中的尿酸水平上调。在ApoE小鼠中，腺嘌呤饮食诱导的高尿酸血症加速了主动脉瓣钙化。RNA测序分析表明，尿酸主要通过激活缺氧诱导因子-1α（HIF-α）促进成骨分化。此外，尿酸通过激活HIF-α损害内皮屏障功能，导致ApoE小鼠中巨噬细胞浸润增加。在体外和体内，在有尿酸存在的情况下，抑制HIF-1α可抑制成骨分化并减少内皮损伤。本研究揭示了高尿酸血症在主动脉瓣钙化中的新作用，提示降低尿酸的药物或抑制HIF-1α可能是相关主动脉瓣钙化的潜在治疗方法。
