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

• Published in: Journal of cell communication and signaling 2023-09, Vol.17 (3), p.863-879
• Main Authors: Liu, Xing, Zheng, Qiang, Wang, Kan, Luo, Jinjing, Wang, Zhijie, Li, Huadong, Liu, Zongtao, Dong, Nianguo, Shi, Jiawei
• Format: Article
• Language: English
• Subjects: Adaptor proteins; Aortic valve; Autophagy; Biomedical and Life Sciences; Biomedicine; Calcification (ectopic); CAVD; Cell Biology; Cell differentiation; Gene expression; Heart diseases; hVICs; Inflammation; Interstitial cells; Life Sciences; Mitosis; Osteogenic differentiation; Phosphorylation; Research Article; Rheumatic heart disease; RNA-binding protein; Sam68; Signal transduction; STAT3; Stat3 protein; Therapeutic targets; Tumor necrosis factor-TNF; Tumor necrosis factor-α
• ISSN: 1873-9601; 1873-961X
• DOI: 10.1007/s12079-023-00733-2

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