Abstract
Regulatory RNAs like microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) control vascular and immune cells' phenotype and thus play a crucial role in atherosclerosis. Moreover, the mutual interactions between miRNAs and lncRNAs link both types of regulatory RNAs in a functional network that affects lesion formation. In this review, we deduce novel concepts of atherosclerosis from the analysis of the current data on regulatory RNAs' role in endothelial cells (ECs) and macrophages. In contrast to arterial ECs, which adopt a stable phenotype by adaptation to high shear stress, macrophages are highly plastic and quickly change their activation status. At predilection sites of atherosclerosis, such as arterial bifurcations, ECs are exposed to disturbed laminar flow, which generates a dysadaptive stress response mediated by miRNAs. Whereas the highly abundant miR-126-5p promotes regenerative proliferation of dysadapted ECs, miR-103-3p stimulates inflammatory activation and impairs endothelial regeneration by aberrant proliferation and micronuclei formation. In macrophages, miRNAs are essential in regulating energy and lipid metabolism, which affects inflammatory activation and foam cell formation.Moreover, lipopolysaccharide-induced miR-155 and miR-146 shape inflammatory macrophage activation through their oppositional effects on NF-kB. Most lncRNAs are not conserved between species, except a small group of very long lncRNAs, such as MALAT1, which blocks numerous miRNAs by providing non-functional binding sites. In summary, regulatory RNAs' roles are highly context-dependent, and therapeutic approaches that target specific functional interactions of miRNAs appear promising against cardiovascular diseases.
Highlights
RNA molecules have a great variety of functions in the cell, including the transfer of protein-coding information in the primary nucleotide sequence of the mRNA, reading the codons and matching them to amino acids by tRNA, catalysis of peptide bond formation by rRNA, and splicing of pre-mRNA by small nuclear RNAs in the spliceosome
In LdlrÀ/À mice, only deletion of Mir33 in bone marrow cells slightly reduces lesion formation, whereas the whole-body knockout of Mir33 surprisingly does not affect atherosclerosis (Price et al 2017). These results indicate that the expression of miR-33-5p in bone marrow cells promotes atherosclerosis in LdlrÀ/À mice, whereas its expression in non-bone-marrow cells is athero-protective
The small number of conserved lncRNAs plays an essential role in regulating miRNA activities in atherosclerosis
Summary
RNA molecules have a great variety of functions in the cell, including the transfer of protein-coding information in the primary nucleotide sequence of the mRNA, reading the codons and matching them to amino acids by tRNA, catalysis of peptide bond formation by rRNA, and splicing of pre-mRNA by small nuclear RNAs in the spliceosome. MiR-92a3p targets several other transcripts in ECs, like KLF2, SOCS5, and SIRT1 (Chen et al 2015), which contributes to the inflammatory phenotype of dysadapted ECs. inhibition of miR-92a-3p by antisense oligonucleotides in ApoeÀ/ À and LdlrÀ/À mice reduced atherosclerosis and endothelial inflammation (Chen et al 2015; Loyer et al 2014). Knockout of the miR-106b-25 cluster in ApoeÀ/À mice decreases atherosclerosis, reduces the cholesterol content in VLDL and LDL in the blood, and increases VLDL and LDL receptor expression in splenocytes (Semo et al 2019) These findings indicate that the miRNAs of the miR-106b-25 cluster elevate plasma lipid levels by suppressing lipoprotein clearance by the spleen (Semo et al 2019)
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