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LincRNA-p21 alleviates atherosclerosis progression through regulating the miR-221/SIRT1/Pcsk9 axis.

ABSTRACT: Atherosclerosis (AS) is the main aetiology of coronary heart disease, cerebral infarction and peripheral vascular disease in humans. Long-noncoding RNA (LincRNA)-p21 has been reported to participate in the development of AS. Therefore, this study was designed to investigate the mechanism of LincRNA-p21 on suppressing the development of AS. We fed ApoE^-/- mice with a high-fat diet to induce an AS mouse model where the lesion area of AS and the extent of lipid deposition were measured. The binding of LincRNA-p21 and miR-221 or miR-221 and SIRT1 was measured using a dual luciferase reporter gene assay and RIP. Following loss- and gain- function assays, CCK8, EdU, Transwell assay and scratch test were performed to determine the biological processes of human aortic endothelial cells (HAECs). miR-221 was highly expressed while SIRT1 was poorly expressed in AS. LincRNA-p21 acted as a sponge for miR-221. miR-221 targeted and negatively regulated the expression of SIRT1. LincRNA-p21 promoted the deacetylation of Pcsk9 by SIRT1 by competitively binding to miR-221, whereby promoting HAEC proliferation, migration and tube formation. In conclusion, LincRNA-p21 acted as a molecular sponge for miR-221 to promote deacetylation of the promoter region of Pcsk9 by SIRT1, therefore preventing the development of AS.

SUBMITTER: Wang H

PROVIDER: S-EPMC8500963 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Ginsenoside Rg3 alleviates septic liver injury by regulating the lncRNA TUG1/miR-200c-3p/SIRT1 axis.

Project description:BackgroundStudies have shown that ginsenoside R3 (Rg3) plays a protective role in sepsis-induced organ injuries and mitochondrial dysfunction. Long noncoding RNA (lncRNA) taurine-upregulated gene 1 (TUG1) is regarded as a regulator in sepsis. However, the association between TUG1 and Rg3 remains elusive.MethodsA sepsis mouse model was established by caecal ligation and puncture (CLP), and liver injury was induced by haematoxylin-eosin (H&E) staining. Lipopolysaccharide (LPS) was used to induce hepatocyte damage. The expression levels of TUG1, microRNA (miR)-200a-3p, and silencing information regulator 1 (SIRT1) were examined by quantitative real-time polymerase chain reaction (qRT-PCR) assays. Cell viability was monitored using the Cell Counting Kit-8 (CCK-8) assay. MitoSOX Red staining and CBIC2 (JC-1) dye were employed to detect mitochondrial reactive oxygen species (ROS) and mitochondrial transmembrane potential (MTP) levels, respectively. The interaction between miR-200a-3p and TUG1 or SIRT1 was confirmed via dual-luciferase reporter or RNA immunoprecipitation (RIP) assay.ResultsRg3 upregulated TUG1 expression in liver tissues of CLP mice and LPS-induced hepatocytes. Rg3 could activate autophagy to improve mitochondrial dysfunction in LPS-treated hepatocytes, which was partially reversed by TUG1 depletion or miR-200a-3p overexpression. Importantly, TUG1 targeted miR-200a-3p to activate the SIRT1/AMP-activated protein kinase (AMPK) pathway in LPS-treated hepatocytes. Moreover, gain of TUG1 ameliorated mitochondrial dysfunction in LPS-treated hepatocytes by sequestering miR-200a-3p.ConclusionOur study revealed that Rg3 increased TUG1 expression and reduced miR-200a-3p expression to stimulate the SIRT1/AMPK pathway, thereby enhancing autophagy to improve sepsis-induced liver injury and mitochondrial dysfunction.

| S-EPMC8686388 | biostudies-literature

LincRNA 1700020I14Rik alleviates cell proliferation and fibrosis in diabetic nephropathy via miR-34a-5p/Sirt1/HIF-1α signaling.

Project description:Long intergenic noncoding RNAs (lincRNAs) have been gradually identified to be functional in a variety of different mechanisms associating with development and epigenetic regulation of cellular homeostasis. However, the study of lincRNAs in diabetic nephropathy (DN) is still in its infancy. Here, we have found dysexpressed long noncoding RNAs (lncRNAs) in renal tissues of db/db DN mice compared with db/m mice by RNA sequencing. In this study, 5 lincRNAs were confirmed to express in a consistent trend among these DN-related lncRNAs both in vivo and in vitro. Particularly, 1700020I14Rik was the downregulated one. Moreover, our data showed overexpression or knockdown of 1700020I14Rik could regulate cell proliferation and fibrosis in mouse mesangial cells (MCs). Furthermore, 1700020I14Rik was found to interact with miR-34a-5p via both the directly targeting way by bioinformatic investigation and luciferase assay and the Ago2-dependent manner by RIP assay. Results also displayed that overexpression of 1700020I14Rik inhibited cell proliferation and expressions of renal fibrosis markers through miR-34a-5p/Sirt1/HIF-1α pathway in MCs under high glucose condition, while knockdown of 1700020I14Rik could increase cell proliferation and expressions of renal fibrosis markers. In conclusion, these results provide new insights into the regulation between 1700020I14Rik and miR-34a-5p/Sirt1/HIF-1α signaling pathway during the progression of DN.

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Inhibiting miR-22 Alleviates Cardiac Dysfunction by Regulating Sirt1 in Septic Cardiomyopathy.

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Circular RNA circPSD3 alleviates hepatic fibrogenesis by regulating the miR-92b-3p/Smad7 axis.

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Identification of a Novel lincRNA-p21-miR-181b-PTEN Signaling Cascade in Liver Fibrosis.

Project description:Previously, we found that long intergenic noncoding RNA-p21 (lincRNA-p21) inhibits hepatic stellate cell (HSC) activation and liver fibrosis via p21. However, the underlying mechanism of the antifibrotic role of lincRNA-p21 in liver fibrosis remains largely unknown. Here, we found that lincRNA-p21 expression was significantly downregulated during liver fibrosis. In LX-2 cells, the reduction of lincRNA-p21 induced by TGF-?1 was in a dose- and time-dependent manner. lincRNA-p21 expression was reduced in liver tissues from patients with liver cirrhosis when compared with that of healthy controls. Notably, lincRNA-p21 overexpression contributed to the suppression of HSC activation. lincRNA-p21 suppressed HSC proliferation and induced a significant reduction in ?-SMA and type I collagen. All these effects induced by lincRNA-p21 were blocked down by the loss of PTEN, suggesting that lincRNA-p21 suppressed HSC activation via PTEN. Further study demonstrated that microRNA-181b (miR-181b) was involved in the effects of lincRNA-p21 on HSC activation. The effects of lincRNA-p21 on PTEN expression and HSC activation were inhibited by miR-181b mimics. We demonstrated that lincRNA-p21 enhanced PTEN expression by competitively binding miR-181b. In conclusion, our results disclose a novel lincRNA-p21-miR-181b-PTEN signaling cascade in liver fibrosis and suggest lincRNA-p21 as a promising molecular target for antifibrosis therapy.

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LincRNA-p21 suppresses target mRNA translation.

Project description:Mammalian long intergenic noncoding RNAs (lincRNAs) are best known for modulating transcription. Here we report a posttranscriptional function for lincRNA-p21 as a modulator of translation. Association of the RNA-binding protein HuR with lincRNA-p21 favored the recruitment of let-7/Ago2 to lincRNA-p21, leading to lower lincRNA-p21 stability. Under reduced HuR levels, lincRNA-p21 accumulated in human cervical carcinoma HeLa cells, increasing its association with JUNB and CTNNB1 mRNAs and selectively lowering their translation. With elevated HuR, lincRNA-p21 levels declined, which in turn derepressed JunB and β-catenin translation and increased the levels of these proteins. We propose that HuR controls translation of a subset of target mRNAs by influencing lincRNA-p21 levels. Our findings uncover a role for lincRNA as a posttranscriptional inhibitor of translation.

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Laminar shear stress alleviates monocyte adhesion and atherosclerosis development via miR-29b-3p/CX3CL1 axis regulation.

Project description:Laminar shear stress (Lss) is an important anti-atherosclerosis (anti-AS) factor, but its mechanism network is not clear. Therefore, this study aimed to identify how Lss acts against AS formation from a new perspective. In this study, we analyzed high-throughput sequencing data from static and Lss-treated human aortic and human umbilical vein endothelial cells (HAECs and HUVECs, respectively) and found that the expression of CX3CL1, which is a target gene closely related to AS development, was lower in the Lss group. Lss alleviated the inflammatory response in TNF-α (also known as TNF)-activated HAECs by regulating the miR-29b-3p/CX3CL1 axis, and this was achieved by blocking nuclear factor (NF)-κB signaling. In complementary in vivo experiments, a high-fat diet (HFD) induced inflammatory infiltration and plaque formation in the aorta, both of which were significantly reduced after injection of agomir-miRNA-29b-3p via the tail vein into HFD-fed ApoE-/- mice. In conclusion, this study reveals that the Lss-sensitive miR-29b-3p/CX3CL1 axis is an important regulatory target that affects vascular endothelial inflammation and AS development. Our study provides new insights into the prevention and treatment of AS.

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CircERCC2 ameliorated intervertebral disc degeneration by regulating mitophagy and apoptosis through miR-182-5p/SIRT1 axis.

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| S-EPMC6776655 | biostudies-literature

Orchestration of lincRNA-p21 and miR-155 in Modulating the Adaptive Dynamics of HIF-1α.

Project description:Hypoxia-inducible factor-1 (HIF-1) is the key regulator of cellular adaptive response to hypoxia. Accumulating evidence shows that HIF-1 induces some non-coding RNAs (ncRNAs) including lncRNAs and miRNAs to modulate its own activity, enclosing several feedback loops. How the two classes of ncRNAs are orchestrated in the HIF-1-dependent adaptive response to hypoxia is poorly understood. By selecting lincRNA-p21 and miR-155 as the representatives, we develop an integrated model of the HIF-1 network comprising interlinked positive and negative feedback loops to clarify the interplay between the two ncRNAs in the hypoxic response. By numerical simulations, we find that coordination of lincRNA-p21 and miR-155 shapes the adaptive dynamics of HIF-1α: lincRNA-p21 induction in the early phase stimulates the upregulation of HIF-1α via stabilizing it, while miR-155 induction in the late phase promotes the recovery of HIF-1α via enhancing the degradation of its mRNA. Moreover, HIF-1α-induced PHD2 plays an auxiliary role in the decline of HIF-1α. In addition, lincRNA-p21 and miR-155 modulate each other via regulating HIF-1α activity. Together, lincRNA-p21 and miR-155 coordinate in modulating HIF-1α dynamics, and our work may shed light on the role for ncRNAs in the cellular adaptation to hypoxia.

| S-EPMC7461903 | biostudies-literature

LincRNA-p21 regulates neointima formation, vascular smooth muscle cell proliferation, apoptosis, and atherosclerosis by enhancing p53 activity.

Project description:BackgroundLong noncoding RNAs (lncRNAs) have recently been implicated in many biological processes and diseases. Atherosclerosis is a major risk factor for cardiovascular disease. However, the functional role of lncRNAs in atherosclerosis is largely unknown.Methods and resultsWe identified lincRNA-p21 as a key regulator of cell proliferation and apoptosis during atherosclerosis. The expression of lincRNA-p21 was dramatically downregulated in atherosclerotic plaques of ApoE(-/-) mice, an animal model for atherosclerosis. Through loss- and gain-of-function approaches, we showed that lincRNA-p21 represses cell proliferation and induces apoptosis in vascular smooth muscle cells and mouse mononuclear macrophage cells in vitro. Moreover, we found that inhibition of lincRNA-p21 results in neointimal hyperplasia in vivo in a carotid artery injury model. Genome-wide analysis revealed that lincRNA-p21 inhibition dysregulated many p53 targets. Furthermore, lincRNA-p21, a transcriptional target of p53, feeds back to enhance p53 transcriptional activity, at least in part, via binding to mouse double minute 2 (MDM2), an E3 ubiquitin-protein ligase. The association of lincRNA-p21 and MDM2 releases MDM2 repression of p53, enabling p53 to interact with p300 and to bind to the promoters/enhancers of its target genes. Finally, we show that lincRNA-p21 expression is decreased in patients with coronary artery disease.ConclusionsOur studies identify lincRNA-p21 as a novel regulator of cell proliferation and apoptosis and suggest that this lncRNA could serve as a therapeutic target to treat atherosclerosis and related cardiovascular disorders.

| S-EPMC4244705 | biostudies-literature

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