miR-210-5p Promotes Pulmonary Hypertension by Blocking ATP2A2

Boxiang Wang; Yidin Xu; Yilun Huang; Siming Shao; Dongshan Xu; Yiying Zhang; Lingxia Pang; Zhuofan Nan; Qianxi Ye; Yang Wang; Wantie Wang; Keke Jin; Linbo Yuan

doi:10.1007/s10557-024-07568-y

miR-210-5p Promotes Pulmonary Hypertension by Blocking ATP2A2

Cardiovasc Drugs Ther. 2024 Apr 24. doi: 10.1007/s10557-024-07568-y. Online ahead of print.

Authors

Boxiang Wang^#¹, Yidin Xu^#², Yilun Huang^#³, Siming Shao^#², Dongshan Xu¹, Yiying Zhang³, Lingxia Pang⁴, Zhuofan Nan^{2

5}, Qianxi Ye^{1

6}, Yang Wang⁷, Wantie Wang⁷, Keke Jin⁷, Linbo Yuan⁸

Affiliations

¹ The First Clinical Medical College, Wenzhou Medical University, Wenzhou, People's Republic of China.
² The Second Clinical Medical College, Wenzhou Medical University, Wenzhou, People's Republic of China.
³ Alberta Institute, Wenzhou Medical University, Wenzhou, People's Republic of China.
⁴ Functionality Experimental Teaching Center, Basic Medical School, Wenzhou Medical University, Wenzhou, People's Republic of China.
⁵ Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
⁶ Department of Cardiovascular Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, People's Republic of China.
⁷ Department of Pathophysiology, Basic Medical School, Wenzhou Medical University, Wenzhou, People's Republic of China.
⁸ Department of Physiology, Basic Medical School, Wenzhou Medical University, Wenzhou, People's Republic of China. ylb@wmu.edu.cn.

^# Contributed equally.

PMID: 38656637
DOI: 10.1007/s10557-024-07568-y

Abstract

Aim: Aberrant expression of ATPase sarcoplasmic/endoplasmic retic Ca²⁺ transporting 2 (ATP2A2) has attracted attention for its pathophysiologic role in pulmonary hypertension (PH). Several miRNAs, including miR-210-5p, have also been reported to be pathogenic factors in PH, but their exact mechanisms remain unknown. This study aimed to elucidate the potential mechanisms of miR-210-5p and ATP2A2 in MCT-induced PH.

Methods: Eighteen Sprague-Dawley rats were randomly divided into two groups-monoclonal (MCT) group and control group-and then administered MCT (60 mg/kg) and saline, respectively. mPAP, PVR, RVHI, WT%, and WA% were significantly increased in PH rats after 3 weeks, confirming that the modeling of PH rats was successful. Subsequently, we determined the expression of ATP2A2 and miR-210-5p in lung tissues using WB and qRT-PCR methods. We established an in vitro model using BMP4 and TGF-β1 treatment of pulmonary artery smooth muscle cells (PASMCs) and examined the expression of ATP2A2 and miR-210-5p using the same method. To further elucidate the regulatory relationship between ATP2A2 and miR-210-5p, we altered the expression level of miR-210-5p and detected the corresponding changes in ATP2A2 levels. In addition, we demonstrated the relationship by dual luciferase experiments. Finally, the effect of silencing ATP2A2 could be confirmed by the level of cell membrane Ca²⁺ in PAMSCs.

Results: Up-regulation of miR-210-5p and down-regulation of ATP2A2 were observed in the MCT group compared with the control group, which was confirmed in the in vitro model. In addition, elevated miR-210-5p expression decreased the level of ATP2A2 while increasing the proliferation of PASMCs, and the results of the dual luciferase assay further confirmed that ATP2A2 is a downstream target of miR-210-5p. Additionally, silencing ATP2A2 resulted in increased cytoplasmic Ca²⁺ levels in PAMSCs.

Conclusion: In MCT-induced PH, miR-210-5p promotes pulmonary vascular remodeling by inhibiting ATP2A2.

Keywords: ATP2A2; Pulmonary hypertension; Pulmonary vascular remodeling; miR-210-5p.

Abstract

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