Genetic dissection of the impact of lncRNA AI662270 during the development of atherosclerosis

Abstract

Background Atherosclerosis is driven by synergistic interactions between pathological biomechanical and lipid metabolic factors. Long noncoding RNAs (LncRNAs) have been implicated in atherogenesis. The purpose of this study was to investigate the potential mechanism of lncRNA AI662270 on macrophage cholesterol transport in atherosclerosis. Methods Apolipoprotein E deficiency (ApoE−/−) mice were fed a high fat diet for 16 weeks to construct atherosclerotic model, and the mice were injected with recombinant lentivirus carrying AI662270 gene to overexpress AI662270. Macrophages were cleared by liposomal clondronate in vivo. Fundamental experiments and functional assays, hematoxylin and eosin staining, oil red O staining and others, were performed to evaluate the function of AI662270 on atherogenesis. Peritoneal macrophages were treated with oxidized low density lipoprotein (ox-LDL) to simulate in vitro model. Mechanism assays, RNA-interacting protein immunoprecipitation, RNA–protein pulldown and others, were performed to study the regulatory mechanism of AI662270 in macrophages. Results The novel AI662270 was mainly enriched in macrophages, but not in endothelial cells, smooth muscle cells and fibroblasts of mouse atherosclerotic lesions and was upregulated by ox-LDL. Overexpression of AI662270 resulted in lipid accumulation, larger atherosclerotic plaques and cardiac dysfunction in vivo. After macrophages were removed, the pro-atherogenic effect of AI662270 disappeared. Downregulation of AI662270 in macrophages protected against foam cell formation by potentiating cholesterol efflux and reducing intracellular total cholesterol. The opposite effect was observed in macrophage-specific AI662270-overexpressed cells in vitro. AI662270 bound to adenosine triphosphate-binding cassette transporter A1 (Abca1) responsible for regulating cholesterol efflux in macrophages. Forced expression of AI662270 in macrophages decreased Abca1 expression. The reverse occurred when expression of AI662270 was repressed. Conclusion These findings reveal an essential role for AI662270 in atherosclerosis progression by regulating cholesterol efflux from macrophages.

Transcriptome analysis of long non-coding RNAs in Mycobacterium avium complex–infected macrophages

“…In fact, we observed a radical decline in Bcl2l11 expression when Morrbid was upregulated ( Figure 7B ). Among the downregulated lncRNAs, eight had at least one citation; AI662270 , AU020206 , and Snhg15 were of particular interest ( Figure 7C ), as it has been reported that AI662270 and AU020206 are involved in the atherosclerosis induced by macrophages ( 33 , 34 ) and Snhg15 is involved in inflammation ( 35 ).…”

Identification and coregulation pattern analysis of long noncoding RNAs in the mouse brain after Angiostrongylus cantonensis infection

“…In addition, both AI662270 and the lncRNA Mexis are highly expressed during the progression of atherosclerosis [ 67 ]. AI662270 accelerates the progression of atherosclerosis by directly binding to Abca1 to attenuate Abca1 expression and activity and inhibiting SR-BI expression to promote foam cell formation [ 68 ]. Mexis promotes the coactivator action of DDX17, which enhances LXR-mediated Abca1 expression, resulting in increased cholesterol efflux from macrophages, which in turn affects atherosclerotic plaque development [ 69 ].…”

Non-coding RNAs are key players and promising therapeutic targets in atherosclerosis

“…There is a close relationship between diet and AS, and there is evidence that the intake of specific foods can reduce AS risk (Riccardi et al, 2022). Astaxanthin is a common nutrient that has been reported to have AS-protective effects, and a recent study demonstrated that the protective effect of astaxanthin on AS arises through the CircTPP2/miR-3073b-5p/ABCA1 axis that promotes macrophage cholesterol efflux and thus reduces foam cell formation (Zhang Z. et al, 2023). In addition, the side effects of some drugs used to treat other diseases may contribute to AS, and ncRNAs may be crucial regulators of these processes.…”

“…AI662270 overexpression promotes lipid accumulation, reduces the cholesterol outflow of macrophages, and accelerates the formation of foam cells, yielding an AS-promoting effect. AI662270 knockdown exerts a therapeutic effect on AS (Hong et al, 2023). Moreover, there is evidence that MIAT can affect lesion formation and plaque destabilization in AS.…”