Zinc ameliorates human aortic valve calcification through GPR39 mediated ERK1/2 signalling pathway

Chen, Ziying; Gordillo-Martinez, Flora; Jiang, Lei; He, Pengcheng; Hong, Wanzi; Wei, Xuebiao; Staines, Katherine A.; Macrae, Vicky E.e; Zhang, Chunxiang; Yu, Danqing; Fu, Xiaodong; Zhu, Dongxing

Abstract

Aims
Calcific aortic valve disease (CAVD) is the most common heart valve disease in the Western world. It has been reported that zinc is accumulated in calcified human aortic valves. However, whether zinc directly regulates CAVD is yet to be elucidated. The present study sought to determine the potential role of zinc in the pathogenesis of CAVD.

Methods and results
Using a combination of a human valve interstitial cell (hVIC) calcification model, human aortic valve tissues, and blood samples, we report that 20 μM zinc supplementation attenuates hVIC in vitro calcification, and that this is mediated through inhibition of apoptosis and osteogenic differentiation via the zinc-sensing receptor GPR39-dependent ERK1/2 signalling pathway. Furthermore, we report that GPR39 protein expression is dramatically reduced in calcified human aortic valves, and there is a significant reduction in zinc serum levels in patients with CAVD. Moreover, we reveal that 20 μM zinc treatment prevents the reduction of GPR39 observed in calcified hVICs. We also show that the zinc transporter ZIP13 and ZIP14 are significantly increased in hVICs in response to zinc treatment. Knockdown of ZIP13 or ZIP14 significantly inhibited hVIC in vitro calcification and osteogenic differentiation.

Conclusions
Together, these findings suggest that zinc is a novel inhibitor of CAVD, and report that zinc transporter ZIP13 and ZIP14 are important regulators of hVIC in vitro calcification and osteogenic differentiation. Zinc supplementation may offer a potential therapeutic strategy for CAVD.

• Journal Article Type: Article
• Acceptance Date: Mar 31, 2020
• Online Publication Date: Apr 7, 2020
• Publication Date: 2021-03
• Deposit Date: Jun 29, 2020
• Publicly Available Date: Apr 8, 2021
• Journal: Cardiovascular Research
• Print ISSN: 0008-6363
• Electronic ISSN: 1755-3245
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 117
• Issue: 3
• Pages: 820-835
• DOI: https://doi.org/10.1093/cvr/cvaa090
• Keywords: Zinc, Valve interstitial cell calcification, Apoptosis, ERK1/2, GPR39
• Public URL: http://researchrepository.napier.ac.uk/Output/2663675