Silence of long intergenic noncoding RNA HOTAIR ameliorates oxidative stress and inflammation response in ox‐LDL‐treated human macrophages by upregulating miR‐330‐5p

Abstract

Evidence of the involvement of long noncoding RNAs (lncRNAs) in atherosclerosis is growing but still not well characterized. Here, we concentrated on the biological roles of lncRNA HOX transcription antisense RNA (HOTAIR) in atherosclerosis. In our study, we found that oxidized low-density lipoprotein (ox-LDL) induced human macrophages THP-1 cells apoptosis dose dependently and time dependently. Meanwhile, HOTAIR was significantly increased in THP-1 cells treated with ox-LDL. Then, HOTAIR was modulated by infection of LV-short hairpin RNA (shRNA) and LV-HOTAIR into THP-1 cells. As displayed, CD36, Oil Red O staining levels, total cholesterol, triglyceride levels and dil-ox-LDL uptake rate were greatly repressed by the silence of HOTAIR while triggered by overexpression of HOTAIR. Moreover, knockdown of HOTAIR suppressed reactive oxygen species, malondialdehyde levels, increased superoxide dismutase activity and cell apoptosis were also restrained. Reversely, overexpression of HOTAIR exhibited an opposite phenomenon. In addition, interleukin 6 (IL-6), IL-1β, cyclo-oxygenase 2, and tumor necrosis factor α protein levels were significantly depressed by LV-shRNA) of HOTAIR while increased by upregulation of HOTAIR in THP-1 cells. By carrying out bioinformatics analysis, miR-330-5p was predicted as a target of HOTAIR and the correlation between them was validated in our current study. MiR-330-5p was greatly decreased in THP-1 cells incubated with ox-LDL and overexpression of miR-330-5p was able to inhibit oxidative stress and inflammation process. Taken together, it was implied that HOTAIR contributed to atherosclerosis development by downregulating miR-330-5p in human macrophages.

Long Non-Coding RNAs Link Oxidized Low-Density Lipoprotein With the Inflammatory Response of Macrophages in Atherogenesis

“…In addition, HOTAIR was also significantly increased in ox-LDL-treated RAW264.7 cells and could reduce lipid accumulation and inhibit the inflammatory response by suppressing FXR1 via the NF-κB pathway (117). In contrast, HOTAIR also found to increase the inflammatory cytokines such as IL-6, IL-1β, in ox-LDL treated THP-1 cells by sponging miR-330-5p (118). Consistently, miR-330-5p inhibited inflammation and promoted macrophage M2 polarization in diabetic mice (119).…”

Silencing of MEG3 inhibited ox‐LDL‐induced inflammation and apoptosis in macrophages via modulation of the MEG3/miR‐204/CDKN2A regulatory axis

“…Several lncRNAs have been reported to be involved in the development of AS (Aryal and Suarez, 2018;Bao et al, 2018;Luque et al, 2018;Meng et al, 2018). Liu et al (2018) demonstrated that knockdown of lncRNA HOTAIR alleviated the oxidative stress and inflammation response in ox-LDL-treated human macrophages via upregulation of miR-330-5p. In recent years, driven by the motivation to find new targets for AS therapeutics, the number of studies focused on developing a better understanding of the roles of lncRNAs and their underlying molecular mechanisms in ox-LDL-treated human macrophages is rapidly increasing.…”

Targeting Foam Cell Formation in Atherosclerosis: Therapeutic Potential of Natural Products

“…Despite reduced uptake of oxLDL by MALAT1 deficiency, heterozygous deletion of MALAT1 aggravated atherosclerosis in ApoE-deficient (ApoE 2/2 ) mice by inducing massive immune system dysregulation (Gast et al, 2019). Gain-and loss-of-function assays of homeobox protein transcription antisense RNA (HOTAIR) in oxLDL-stimulated macrophages suggest that HOTAIR controlled CD36 expression, oxLDL uptake, inflammation [interleukin-6 (IL-6), IL-1b, cyclooxygenase 2 (COX2), and tumor necrosis factor-a (TNF-a)], and macrophagederived foam cell formation via miRNA-330-5p (Liu et al, 2019). Therefore, ncRNAs present potential targets to fine-tune macrophage function within atherosclerotic lesions.…”