Aldo-keto reductase family 1 member B induces aortic valve calcification by activating hippo signaling in valvular interstitial cells

• Published in: Journal of molecular and cellular cardiology 2021-01, Vol.150, p.54-64
• Main Authors: Gao, Chenyang, Hu, Wangxing, Liu, Feng, Zeng, Zhiru, Zhu, Qifeng, Fan, Jiaqi, Chen, Jinyong, Cheng, Si, Yu, Kaixiang, Qian, Yi, Ren, Tanchen, Zhao, Jing, Liu, Xianbao, Wang, Jian'an
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Akr1B1; Aldehyde Reductase - antagonists & inhibitors; Aldehyde Reductase - metabolism; Aldo-Keto Reductases - metabolism; Animals; Aortic Valve - drug effects; Aortic Valve - enzymology; Aortic Valve - pathology; Aortic Valve Stenosis - enzymology; Aortic Valve Stenosis - pathology; Calcific aortic valve disease; Calcinosis - enzymology; Calcinosis - pathology; Core Binding Factor Alpha 1 Subunit - metabolism; Enzyme Inhibitors - pharmacology; Gene Knockdown Techniques; Humans; Lentivirus - metabolism; Mice; Osteogenesis - drug effects; Protein Serine-Threonine Kinases - metabolism; Signal Transduction - drug effects; TEAD1; Transcription Factors - metabolism; Valve interstitial cell; YAP; YAP-Signaling Proteins
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2020.10.002

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. 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. 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. [Display omitted] •Akr1B1 was significantly upregulated in CAVD valves.•Inhibition of Akr1B1 attenuates VICs calcification in vitro and in vivo.•Akr1B1 exacerbate VICs calcification via Hippo-YAP pathway.