3.2 Astragaloside IV
Astragaloside IV is a saponin isolated from Astragalus membranaceus (Fisch.) Bunge, which has excellent cardioprotective effects (Y. Q. Tan, Chen, & Li, 2020). Astragaloside IV has been reported to protect endothelial cells from oxidative damage caused by ox‑LDL through regulating the LOX-1/NLRP3 signaling pathway (Qian et al., 2019). Recently, a study found that circ_0000231 is the key downstream target of astragaloside IV, which regulates miR-135a-5p to target chloride intracellular channel 4 (CLIC4) and contributes to the protective role of astragaloside IV in ox-LDL-induced endothelial cell injury (Shao, Liu, Liu, Lin, & Deng, 2021). CLIC4 is also a protein associated with endothelial cell apoptosis (X. Zhang et al., 2020), indicating astragaloside IV may also inhibit endothelial cell apoptosis by regulating CLIC4 through circ_0000231. Several miRNAs have been shown to be the targets of astragaloside IV. For example, astragaloside IV can protect cardiomyocytes from hypoxia-induced injury by downregulating miR-23a and miR-92a (Gong et al., 2018). ABCA1, a membrane transporter that mediates cholesterol efflux (L. Chen, Zhao, Zeng, Zhou, & Yin, 2022), has been proved to be a target of miR-33a (J. H. Gao et al., 2018). A study has found that astragaloside IV can promote cholesterol efflux in macrophages and inhibit atherosclerosis through regulating miR-33a/ABCA1 pathway (H. W. Qin et al., 2018). The serum miR-17-5p is elevated in patients with atherosclerosis and miR-17-5p knockdown can alleviate atherosclerotic lesions and inhibit the proliferation and migration of VSMCs by directly up-regulating very low density lipoprotein receptor (VLDLR), or indirectly regulate VLDLR by affecting proprotein convertase subtilisin kexin 9 (PCSK9) (L. Tan, Meng, Shi, & Yu, 2017). Astragaloside IV has been shown to down-regulate miR-17-5p and further affect VLDLR expression, thus inhibiting vascular inflammation (H. W. Qin, Zhang, Li, Li, & Wang, 2022). In addition, lncRNA H19 has also been reported to mediate astragaloside IV’s anti-atherosclerotic effect. H19 negatively regulates dual-specificity phosphatase 5 (DUSP5) expression and represses DUSP5/ERK1/2 axis (Tao et al., 2016). Astragaloside IV could attenuate autophagy and mineralization of VSMCs in atherosclerosis by up-regulating H19 and inhibiting DUSP5 (Z. Song et al., 2019). In summary, astragaloside IV can regulate the function of endothelial cells, VSMCs, and macrophages in atherosclerosis by targeting multiple miRNAs, lncRNAs and circRNAs. Therefore, it can be expected that astragaloside IV can exert an excellent anti-atherosclerotic effect through ncRNAs in the clinic.