2.1 miRNAs and atherosclerosis
MiRNAs (typically 20–25 nucleotides) are single-stranded RNA molecules that can bind to complementary sequences within the 3’ untranslated region of mRNA targets. Once the miRNA binds to the mRNA, it can degrade the mRNA via cleavage or inhibit the translation of mRNAs into protein (Thum & Mayr, 2012; Winter, Jung, Keller, Gregory, & Diederichs, 2009). MiRNAs are the most studied ncRNAs in atherosclerosis and have been shown to regulate the fate and function of atherosclerosis associated cells, including endothelial cells, inflammatory cells, and vascular smooth muscle cells (VSMCs). MiRNAs can affect endothelial cell function by exacerbating senescence of endothelial cells, which is considered as a key mechanism of atherosclerosis (Fiedler & Thum, 2016; Menghini et al., 2009). There are many miRNAs involved in the regulation of endothelial cell senescence, such as miR-146a and miR-217 (Z. Wang, Shi, Zhang, Yuan, & Tao, 2021; Xiao et al., 2021). Studies have found that mesenchymal stem cell-derived extracellular vesicles attenuate endothelial cell senescence by regulating miR-146a/Src signaling (Xiao et al., 2021). MiR-217 can also promote endothelial cell senescence through the SIRT1/p53 signaling pathway (Z. Wang et al., 2021). In addition, miRNAs can control the inflammatory state of the vasculature by affecting leukocyte activation and infiltration (Pankratz et al., 2018; Perez-Sanchez et al., 2017). In the setting of atherosclerosis, miR-126 promotes macrophage polarization to the M2 phenotype by downregulating VEGFA and KLF4 (Shou, Wang, Jiang, Chen, & Liu, 2023). MiRNAs have also been shown to affect foam cell formation and subsequent plaque formation (Eken et al., 2017; Maitrias et al., 2017). MiR-302a has been shown to promote the formation of foam cells and increase the outflow of cholesterol in macrophage by increasing ATP-binding cassette transporter A1 (ABCA1) activity (Meiler, Baumer, Toulmin, Seng, & Boisvert, 2015). In addition, the function of VSMCs can also be regulated by miRNAs. For example, miR-146b-5p reduces the expression of its target genes Bag1 and Mmp16, thereby affecting the proliferation and migration of VSMCs during atherosclerosis (D. Sun et al., 2020). A study also found that miR-374 may be a potential biomarker for the diagnosis of atherosclerosis, and overexpression of miR-374 promotes the proliferation and migration of VSMCs (W. Wang, Ma, & Zhang, 2020). MiR-663 can target HMGA2 to inhibit the proliferation of VSMCs, thereby delaying the development of atherosclerosis (Deng & Li, 2022). In conclusion, miRNAs regulate atherosclerosis through affecting the function of endothelial cells, macrophages, and VSMCs.