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.