Circ-USP9X Inhibition Reduces Oxidized Low-density Lipoprotein–induced Endothelial Cell Injury via the microRNA 599/Chloride Intracellular Channel 4 Axis

Peng, Huaiyu; Sun, Jihu; Li, Yang; Zhang, Ye; Zhong, Yang

doi:10.1097/fjc.0000000000001104

Cited by 14 publications

(3 citation statements)

References 35 publications

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“…Circ_0090231 has been reported to function as a ceRNA that can regulate various biological processes by sponging miRNAs [ 26 ]. We employed Starbase 3.0 ( http://starbase.sysu.edu.cn/ ) to predict potential target miRNAs of circ_0090231.…”

Section: Resultsmentioning

confidence: 99%

Circular RNA circ_0090231 promotes atherosclerosis in vitro by enhancing NLR family pyrin domain containing 3-mediated pyroptosis of endothelial cells

Liu

Yin

et al. 2021

Bioengineered

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Atherosclerosis (AS) is an inflammatory disease caused by multiple factors. Multiple circRNAs are involved in the development of AS. The present study focusses on delineating the role of circ_0090231 in AS. Human aortic endothelial cells (HAECs) were treated with oxidized low-density lipoprotein (ox-LDL) to construct an in vitro AS model. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the levels of circ_0090231, IL-1β, and IL-18 transcripts. CircRNA/ target gene interactions were predicted using StarBase and TargetScan and confirmed using an RNA pull-down assay and dual luciferase reporter assay. Further, 3-(4,5)dimethylthiahiazo(-2)-3,5-diphenytetrazoliumromide (MTT) and lactate dehydrogenase (LDH) release assays were performed to evaluate cell viability and damage in the AS model, respectively. Cell pyroptosis and protein expression were

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Section: Resultsmentioning

confidence: 99%

Circular RNA circ_0090231 promotes atherosclerosis in vitro by enhancing NLR family pyrin domain containing 3-mediated pyroptosis of endothelial cells

Liu

Yin

et al. 2021

Bioengineered

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“…In addition, USP9X has been implicated in several neurodevelopmental and neurodegenerative disorders and malignancies. CircRNA hsa_circ_0090231 (circ- USP9X ) is derived from the USP9X gene, which was elevated in ox-LDL–treated endothelial cells and promoted endothelial cell injury via the miR-599/CLIC4 axis ( 20 ). However, the role of USP9X protein in foam cell formation and atherogenesis has rarely been reported.…”

Section: Introductionmentioning

confidence: 99%

Disruption of USP9X in macrophages promotes foam cell formation and atherosclerosis

Wang¹,

Tang²,

Liu³

et al. 2022

Journal of Clinical Investigation

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Subendothelial macrophage internalization of modified lipids and foam cell formation are hallmarks of atherosclerosis. Deubiquitinating enzymes (DUBs) are involved in various cellular activities; however, their role in foam cell formation is not fully understood. Here, using a loss-of-function lipid accumulation screening, we identified ubiquitin-specific peptidase 9 X-linked (USP9X) as a factor that suppressed lipid uptake in macrophages. We found that USP9X expression in lesional macrophages was reduced during atherosclerosis development in both humans and rodents. Atherosclerotic lesions from macrophage USP9X-deficient mice showed increased macrophage infiltration, lipid deposition, and necrotic core content than control apolipoprotein E–KO ( Apoe –/– ) mice. Additionally, loss-of-function USP9X exacerbated lipid uptake, foam cell formation, and inflammatory responses in macrophages. Mechanistically, the class A1 scavenger receptor (SR-A1) was identified as a USP9X substrate that removed the K63 polyubiquitin chain at the K27 site. Genetic or pharmacological inhibition of USP9X increased SR-A1 cell surface internalization after binding of oxidized LDL (ox-LDL). The K27R mutation of SR-A1 dramatically attenuated basal and USP9X knockdown–induced ox-LDL uptake. Moreover, blocking binding of USP9X to SR-A1 with a cell-penetrating peptide exacerbated foam cell formation and atherosclerosis. In this study, we identified macrophage USP9X as a beneficial regulator of atherosclerosis and revealed the specific mechanisms for the development of potential therapeutic strategies for atherosclerosis.

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“…Circular RNAs (circRNAs) are a new class of endogenous non-coding RNAs (ncRNAs) that do not have 5' caps and 3′ poly(A) tails and exist in their characteristic covalent closed-loop form. A growing number of studies have shown that circRNAs are widely present In Vivo, stably expressed in plasma, serum, and tissues, and involved in the regulation of eukaryotic gene expression [10,11]. circRNA-0024103 is a newly identified circRNA that has been studied to regulate MMP-10 expression in human cartilage degradation by acting as a miR-363 "sponge," but its function in cardiovascular disease is not yet clear.…”

Section: Introductionmentioning

confidence: 99%

Study on the Mechanism of circRNA‐0024103 Reducing Endothelial Cell Injury by Regulating miR‐363/MMP‐10

Tian

Zheng

Xie

et al. 2022

Contrast Media & Molecular Imaging

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Cardiovascular diseases could damage the heart and blood vessels, which cause mortality and morbidity. It is of great significance to explore targeted therapeutic approaches for atherosclerosis that is one of the most common vascular lesions and the main pathological basis of cardiovascular disease. However, the function of circRNA-0024103 in cardiovascular diseases is still not clear. Therefore, we aim to observe the effect of circRNA-0024103 modulation of miR-363/MMP-10 axis on biological behaviors such as proliferation and migration of endothelial cells after ox-LDL induction. The effects on the proliferation ability of endothelial cells were observed by CCK-8 assay and EdU assay based on overexpression of circRNA-0024103 in combination with miR-363 mimic or MMP-10 siRNA, and then, the effects on apoptosis were detected by flow cytometry analysis. The effects on cell migration, invasion, and angiogenesis were further examined by scratch assay, transwell assay, and tube formation assay. The results in CCK-8 and EdU assays showed that miR-363 mimic or MMP-10siRNA significantly attenuated the proliferation-promoting effect of overexpressed circRNA-0024103 on cell proliferation. In flow cytometry assays to detect apoptosis, overexpression of circRNA-0024103 inhibited apoptosis of endothelial cells, and the intervention of combined miR-363 mimic or MMP-10 siRNA counteracted the inhibitory effect of overexpression of circRNA-0024103 on apoptosis, resulting in a significant increase in the number of endothelial cells undergoing apoptosis. The migration, invasion, and tube-forming ability of endothelial cells were significantly enhanced when circRNA-0024103 was overexpressed, while the promotion of migration, invasion, and the tube-forming ability by overexpression of circRNA-0024103 alone was counteracted when combined with miR-363 mimic or MMP-10 siRNA. circRNA-0024103 regulates the biological behaviors of endothelial cells such as proliferation, apoptosis, migration, and invasion through the miR-363/MMP-10 axis. Our finding provides a new therapeutic target for the treatment of atherosclerosis.

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Circ-USP9X Inhibition Reduces Oxidized Low-density Lipoprotein–induced Endothelial Cell Injury via the microRNA 599/Chloride Intracellular Channel 4 Axis

Cited by 14 publications

References 35 publications

Circular RNA circ_0090231 promotes atherosclerosis in vitro by enhancing NLR family pyrin domain containing 3-mediated pyroptosis of endothelial cells

Circular RNA circ_0090231 promotes atherosclerosis in vitro by enhancing NLR family pyrin domain containing 3-mediated pyroptosis of endothelial cells

Disruption of USP9X in macrophages promotes foam cell formation and atherosclerosis

Study on the Mechanism of circRNA‐0024103 Reducing Endothelial Cell Injury by Regulating miR‐363/MMP‐10

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