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MicroRNA-22 promoted osteogenic differentiation of valvular interstitial cells by inhibiting CAB39 expression during aortic valve calcification

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Abstract

Calcific aortic valve disease (CAVD) is a common valve disease characterized by the fibro-calcific remodeling of the aortic valves, which is an actively regulated process involving osteogenic differentiation of valvular interstitial cells (VICs). MicroRNA (miRNA) is an essential regulator in diverse biological processes in cells. The present study aimed to explore the role and mechanism of miR-22 in the osteogenic differentiation of VICs. The expression profile of osteogenesis-related miRNAs was first detected in aortic valve tissue from CAVD patients (n = 33) and healthy controls (n = 12). miR-22 was highly expressed in calcified valve tissues (P < 0.01), and the expression was positively correlated with the expression of OPN (rs = 0.820, P < 0.01) and Runx2 (rs = 0.563, P < 0.01) in VICs isolated from mild or moderately calcified valves. The sustained high expression of miR-22 was also validated in an in-vitro VICs osteogenic model. Adenovirus-mediated gain-of-function and loss-of-function experiments were then performed. Overexpression of miR-22 significantly accelerated the calcification process of VICs, manifested by significant increases in calcium deposition, alkaline phosphate activity, and expression of osteoblastic differentiation markers. Conversely, inhibition of miR-22 significantly negated the calcification process. Subsequently, calcium-binding protein 39 (CAB39) was identified as a target of miR-22. Overexpression of miR-22 significantly reduced the expression of CAB39 in VICs, leading to decreased catalytic activity of the CAB39–LKB1–STRAD complex, which, in turn, exacerbated changes in the AMPK–mTOR signaling pathway, and ultimately accelerated the calcification process. In addition, ROS generation and autophagic activity during VIC calcification were also regulated by miR-22/CAB39 pathway. These results indicate that miR-22 is an important accelerator of the osteogenic differentiation of VICs, and a potential therapeutic target in CAVD.

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Acknowledgements

We thank Dr. Chen Wang for discussions and comments on the manuscript.

Funding

This work was supported by National Natural Science Foundation of China (81800341, 81800342, and 82000364), National Key Research and Development Program of China (2016YFC1100900), and Shanghai Science and Technology Innovation Action Plan “Science and Technology Support Project in Biomedical Science” (21S11906000).

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  1. Fan Yang, Suxuan Liu and Ying Gu contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiovascular Surgery, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China

    Fan Yang, Yan Yan, Liangjian Zou, Zhiyun Xu & Guokun Wang

  2. Department of Cardiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China

    Suxuan Liu, Ying Gu & Xueyan Ding

  3. Department of Cardiology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, China

    Ying Gu

  4. Department of Cardiothoracic Surgery, No.903 Hospital of Chinese People’s Liberation Army, Hangzhou, Zhejiang, China

    Yan Yan

  5. Department of Cardiology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, 310006, Zhejiang, China

    Xueyan Ding

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Contributions

GW, ZX, and LZ conceived and designed the study. FY, SL, and YG performed the experiments. FY and XD analyzed the data. FY, and YY collected and analyzed the clinical information. GW and FY wrote the manuscript.

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Correspondence to Liangjian Zou, Zhiyun Xu or Guokun Wang.

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Yang, F., Liu, S., Gu, Y. et al. MicroRNA-22 promoted osteogenic differentiation of valvular interstitial cells by inhibiting CAB39 expression during aortic valve calcification. Cell. Mol. Life Sci. 79, 146 (2022). https://doi.org/10.1007/s00018-022-04177-6

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