miR-214 Attenuates Aortic Valve Calcification by Regulating Osteogenic Differentiation of Valvular Interstitial Cells

Ning Li; Yifan Bai; Guangwei Zhou; Ye Ma; Mengwei Tan; Fan Qiao; Xin Li; Ming Shen; Xiaowei Song; Xianxian Zhao; Xiaohong Liu; Zhiyun Xu

doi:10.1016/j.omtn.2020.10.016

miR-214 Attenuates Aortic Valve Calcification by Regulating Osteogenic Differentiation of Valvular Interstitial Cells

Mol Ther Nucleic Acids. 2020 Oct 15:22:971-980. doi: 10.1016/j.omtn.2020.10.016. eCollection 2020 Dec 4.

Authors

Ning Li^{1

2}, Yifan Bai¹, Guangwei Zhou¹, Ye Ma¹, Mengwei Tan¹, Fan Qiao¹, Xin Li¹, Ming Shen³, Xiaowei Song³, Xianxian Zhao³, Xiaohong Liu¹, Zhiyun Xu¹

Affiliations

¹ Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
² Department of Cardiothoracic Surgery, Naval Medical Center of PLA, Second Military Medical University, Shanghai, 200052, China.
³ Department of Cardiology, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.

Abstract

Calcific aortic valve disease (CAVD) is a common heart valve disease in aging populations, and aberrant osteogenic differentiation of valvular interstitial cells (VICs) plays a critical role in the pathogenesis of ectopic ossification of the aortic valve. miR-214 has been validated to be involved in the osteogenesis process. Here, we aim to investigate the role and mechanism of miR-214 in CAVD progression. miR-214 expression was significantly downregulated in CAVD aortic valve leaflets, accompanied by upregulation of osteogenic markers. Overexpression of miR-214 suppressed osteogenic differentiation of VICs, while silencing the expression of miR-214 promoted this function. miR-214 directly targeted ATF4 and Sp7 to modulate osteoblastic differentiation of VICs, which was proved by dual luciferase reporter assay and rescue experiment. miR-214 knockout rats exhibited higher mean transvalvular velocity and gradient. The expression of osteogenic markers in aortic valve leaflets of miR-214 knockout rats was upregulated compared to that of the wild-type group. Taken together, our study showed that miR-214 inhibited aortic valve calcification via regulating osteogenic differentiation of VICs by directly targeting ATF4 and Sp7, indicating that miR-214 may act as a profound candidate of targeting therapy for CAVD.

Keywords: ATF4; Sp7; calcific aortic valve disease; microRNA-214; valvular interstitial cells.