Aldo-keto reductase family 1 member B induces aortic valve calcification by activating hippo signaling in valvular interstitial cells
Aldo-keto reductase family 1 member B induces aortic valve calcification by activating hippo signaling in valvular interstitial cells
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醛酮还原酶家族 1 成员 B 通过激活瓣膜间质细胞中的 hippo 信号传导诱导主动脉瓣钙化
DOI：
10.1016/j.yjmcc.2020.10.002
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发表时间：
2021-01-01
影响因子：
5
通讯作者：
Wang, Jian'an
中科院分区：
文献类型：
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作者：
Gao, Chenyang;Hu, Wangxing;Wang, Jian'an
目的：钙化性主动脉瓣疾病（CAVD）是心血管死亡的主要原因;然而，其机制尚不清楚。目前，没有有效的药物治疗CAVD。醛酮还原酶家族1成员B（Akr 1B 1）已被确定为瓣膜间质细胞钙化的潜在治疗靶点。在此，我们假设抑制Akr 1B 1可以减弱主动脉瓣calculation.Methods和结果：正常和退行性三尖瓣钙化瓣膜从人类样本进行了分析，免疫印迹和免疫组化。结果显示，Akr 1B 1在CAVD小叶中显著上调。Akr 1B 1抑制减弱成骨培养基中主动脉瓣间质细胞的钙化。相反，Akr 1B 1的过度表达加重了成骨介质中的钙化。从机制上讲，使用RNA测序（RNAseq），我们揭示了Hippo-YAP信号传导在Akr 1B 1下游发挥作用。此外，我们确定Hippo-YAP信号传导效应器活性-YAP的蛋白水平与Akr 1B 1呈正相关。抑制雅普可逆转Akr 1B 1过表达诱导的Runx 2上调。此外，雅普以ChIP和荧光素酶报告系统介导的方式通过TEAD 1激活Runx 2启动子。动物实验表明，Akr 1B 1抑制剂依帕司他可减轻由西方饮食诱导的LDLR-/-小鼠主动脉瓣钙化。结论：本研究表明，抑制Akr 1B 1可减轻体外和体内钙化程度。Akr 1B 1抑制剂依帕司他可能是CAVD的潜在治疗选择。
Aims: Calcific aortic valve disease (CAVD) is a primary cause of cardiovascular mortality; however, its mechanisms are unknown. Currently, no effective pharmacotherapy is available for CAVD. Aldo-keto reductase family 1 member B (Akr1B1) has been identified as a potential therapeutic target for valve interstitial cell calcification. Herein, we hypothesized that inhibition of Akr1B1 can attenuate aortic valve calcification.Methods and results: Normal and degenerative tricuspid calcific valves from human samples were analyzed by immunoblotting and immunohistochemistry. The results showed significant upregulation of Akr1B1 in CAVD leaflets. Akr1B1 inhibition attenuated calcification of aortic valve interstitial cells in osteogenic medium. In contrast, overexpression of Akr1B1 aggravated calcification in osteogenic medium. Mechanistically, using RNA sequencing (RNAseq), we revealed that Hippo-YAP signaling functions downstream of Akr1B1. Furthermore, we established that the protein level of the Hippo-YAP signaling effector active-YAP had a positive correlation with Akr1B1. Suppression of YAP reversed Akr1B1 overexpression-induced Runx2 upregulation. Moreover, YAP activated the Runx2 promoter through TEAD1 in a manner mediated by ChIP and luciferase reporter systems. Animal experiments showed that the Akr1B1 inhibitor epalrestat attenuated aortic valve calcification induced by a Western diet in LDLR-/- mice.Conclusion: This study demonstrates that inhibition of Akr1B1 can attenuate the degree of calcification both in vitro and in vivo. The Akr1B1 inhibitor epalrestat may be a potential treatment option for CAVD.