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The lncRNA GAS5 Inhibits the Osteogenic Differentiation and Calcification of Human Vascular Smooth Muscle Cells

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Abstract

Vascular calcification (VC), which is associated with high cardiovascular morbidity and mortality in patients with chronic kidney disease, is promoted by the osteoblastic differentiation of vascular smooth muscle cells (VSMCs). The present study explored the functional roles and molecular mechanisms of the long noncoding RNA growth arrest-specific transcript 5 (GAS5) in VC. Our results indicated that GAS5 was clearly downregulated in calcified human aortic vascular smooth muscle cells (HASMCs). Functionally, we found that overexpression of GAS5 significantly attenuated the osteogenic differentiation and calcification of HASMCs induced by high levels of phosphorus. Moreover, miR-26-5p was identified to potentially bind to GAS5, and phosphatase and tensin homolog (PTEN) was determined to be a direct target of miR-26b-5p in HASMCs. Mechanistically, enforced expression of miR-26-5p significantly attenuated PTEN protein expression in HASMCs. Rescue experiments demonstrated that cotransfection of HASMCs with miR-26-5p mimics reduced the inhibition of Lv-GAS5 on osteogenic differentiation and calcification. As a result, GAS5 was confirmed to be an miR-26b-5p sponge and to thereby increase the expression of PTEN in HASMCs. In ex vivo models, GAS5 was significantly downregulated and its expression inversely related to the expression of miR-26b-5 and positively associated with the expression of PTEN in calcified aortic rings induced by high levels of phosphorus. Together, these results suggest that the GAS5/miR-26-5p/PTEN axis could serve as a potential therapeutic target for VC in patients with chronic kidney disease.

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Acknowledgements

This study was supported by funding from the Young Scholar Support Program of China Medical University (No. QGZ2018053), the Doctoral Start-up Foundation of Liaoning Province (No. 2019-BS-286), and the 345 Talent Project in Shengjing Hospital of China Medical University.

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Authors and Affiliations

  1. Department of Radiology, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping Area, Shenyang, People’s Republic of China

    Zhihui Chang, Guangxin Yan, Jiahe Zheng & Zhaoyu Liu

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  1. Zhihui Chang
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  2. Guangxin Yan
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  3. Jiahe Zheng
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  4. Zhaoyu Liu
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Contributions

ZC and ZL conceived the project. ZC, GY, and JZ performed the experiments. ZC, GY, JZ, and ZL wrote the manuscript. All authors planned the experiments, analyzed and discussed the results, and commented on the manuscript.

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Correspondence to Zhaoyu Liu.

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Zhihui Chang, Guangxin Yan, Jiahe Zheng, and Zhaoyu Liu declare thay they have no conflict of interest.

Human and Animal Rights and Informed Consent

This study was approved by the Ethical Committee of Shenjing Hospital of China Medical University (Approval No. 2018PS225K) and was performed in accordance with relevant institutional and national guidelines and regulations.

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Chang, Z., Yan, G., Zheng, J. et al. The lncRNA GAS5 Inhibits the Osteogenic Differentiation and Calcification of Human Vascular Smooth Muscle Cells. Calcif Tissue Int 107, 86–95 (2020). https://doi.org/10.1007/s00223-020-00696-1

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  • DOI: https://doi.org/10.1007/s00223-020-00696-1

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