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Sam68 promotes osteogenic differentiation of aortic valvular interstitial cells by TNF-α/STAT3/autophagy axis

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Journal of Cell Communication and Signaling Aims and scope

Abstract

Calcified aortic valve disease (CAVD) is a major non-rheumatic heart valve disease in the world, with a high mortality rate and without suitable pharmaceutical therapy due to its complex mechanisms. Src-associated in mitosis 68-KD (Sam68), an RNA binding protein, has been reported as a signaling adaptor in numerous signaling pathways (Huot in Mol Cell Biol, 29(7), 1933-1943, 2009), particularly in inflammatory signaling pathways. The effects of Sam68 on the osteogenic differentiation process of hVICs and its regulation on signal transducer and activator of transcription 3 (STAT3) signaling pathway have been investigated in this study. Human aortic valve samples detection found that Sam68 expression was up-regulated in human calcific aortic valves. We used tumor necrosis factor α (TNF-α) as an activator for osteogenic differentiation in vitro and the result indicated that Sam68 was highly expressed after TNF-α stimulation. Overexpression of Sam68 promoted osteogenic differentiation of hVICs while Sam68 knockdown reversed this effect. Sam68 interaction with STAT3 was predicted by using String database and was verified in this study. Sam68 knockdown reduced phosphorylation of STAT3 activated by TNF-α and the downstream gene expression, which further influenced autophagy flux in hVICs. STAT3 knockdown alleviated the osteogenic differentiation and calcium deposition promoted by Sam68 overexpression. In conclusion, Sam68 interacts with STAT3 and participates in its phosphorylation to promote osteogenic differentiation of hVICs to induce valve calcification. Thus, Sam68 may be a new therapeutic target for CAVD.

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Regulatory of Sam68 in TNF-α/STAT3/Autophagy Axis in promoting osteogenesis of hVICs

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Acknowledgements

We acknowledge the technical support given by Dr. Kang Xu and Dr. Jiangyang Chi.

Funding

This research was funded by the National Natural Science Foundation of China, the grant number 81770387.

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  1. Xing Liu and Qiang Zheng contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei, 430022, People’s Republic of China

    Xing Liu, Qiang Zheng, Kan Wang, Jinjing Luo, Zhijie Wang, Huadong Li, Zongtao Liu, Nianguo Dong & Jiawei Shi

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  1. Xing Liu
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Contributions

XL; QZ and JS performed study concept and design; KW; ZW. JL and HL Performed development of methodology; XL; QZ; HL and JS performed writing, review and revision of the paper; KW; XL; QZ; ZL provided acquisition, analysis and interpretation of data, and statistical analysis; ND provided technical and material support. All authors read and approved the final paper.

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Correspondence to Jiawei Shi.

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The study was conducted in accordance with the Declaration of Helsinki, and approved by Ethics Committee of Huazhong University of Science and technology (S036).

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Liu, X., Zheng, Q., Wang, K. et al. Sam68 promotes osteogenic differentiation of aortic valvular interstitial cells by TNF-α/STAT3/autophagy axis. J. Cell Commun. Signal. 17, 863–879 (2023). https://doi.org/10.1007/s12079-023-00733-2

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