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. 2021 Oct 27;12:751667. doi: 10.3389/fphar.2021.751667

FIGURE 4.

FIGURE 4

ATO inhibited angiogenesis via modulating the circHIPK3/miR-149-5p/FOXO1/VEGF functional module in RA-FLS in vitro. (A) After RA-FLS were exposed to 50 ng/ml TNF-α and 2.0 µM ATO for 48h, the expression of circHIPK3 was upregulated by TNF-α induction, and this upregulation could be significantly suppressed by ATO treatment (n = 3; *p < 0.05). (B–C) The expression of FOXO1/VEGF mRNA (B) and protein (C) were significantly upregulated by FOXO1 overexpression and downregulated by ATO. Furthermore, the FOXO1/VEGF downregulation induced by ATO could be rescued partially by FOXO1 overexpression (n = 3; *p < 0.05, **p < 0.01). (D–E) The expression of FOXO1/VEGF mRNA (D) and protein (E) were significantly upregulated by miR-149-5p inhibitor, and downregulated by ATO. Additionally, the FOXO1/VEGF expression downregulated by ATO could be partially rescued by miR-149-5p inhibitor (n = 3; *p < 0.05, **p < 0.01, ***p < 0.001). (F–G) The expression of FOXO1/VEGF mRNA (F) and protein (G) were significantly upregulated by circHIPK3 overexpression, and downregulated by ATO. Moreover, the expression of FOXO1/VEGF downregulated by ATO could be partially rescued by circHIPK3 overexpression but significantly reduced again further upon miR-149-5p mimics addition (n = 3; *p < 0.05, **p < 0.01, ***p < 0.001). Results are expressed as the mean ± S.E.M. CTL = PBS control group.