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CircRNA mmu_circ_0000021 regulates microvascular function via the miR-143-3p/NPY axis and intracellular calcium following ischemia/reperfusion injury.

ABSTRACT: Cardiac ischemia-reperfusion (I/R) is associated with a high rate of complications. Restoring microvascular function is crucial for cardiac repair. However, the molecular mechanisms by which the circRNAs repairs microvascular dysfunction are unknown. High-throughput RNA sequencing and quantitative real-time PCR (qRT-PCR) were used to measures circRNA levels in cardiac tissue samples. We found a total of 80 up-regulated and 54 down-regulated differentially expressed circRNAs, of which mmu_circ_0000021 were consistent with bioinformatics predictions. Next, mmu_circ_0000021 knockdown and overexpression were performed to indicate the functional role of mmu_circ_0000021. The interaction of mmu_circ_0000021, miR-143-3p and NPY were evaluated using dual-luciferase assays, RNA pull-down assays and RNA immunoprecipitation (RIP). Immunohistochemistry, transmission electron microscopy, and immunofluorescence were used to determine the presence of leukocytes and changes in microvascular morphology and function. Mechanistically, mmu_circ_0000021 involved in regulating microvascular dysfunction via miR-143-3p by targeting NPY. However, the contraction of microvascular spasm caused by NPY is related to calmodulin. By regulating NPY, Circular RNA (circRNA) further affects microvascular spasm, regulates microcirculation disorders, and restores cardiac function. Our findings highlight a novel role for mmu_circ_0000021 by regulating microvascular function following I/R injury.

SUBMITTER: Xiong J

PROVIDER: S-EPMC9276824 | biostudies-literature |

REPOSITORIES: biostudies-literature

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CircZNF609 Aggravated Myocardial Ischemia Reperfusion Injury via Mediation of miR-214-3p/PTGS2 Axis.

Project description:Background and objectivesCircular RNAs were known to play vital role in myocardial ischemia reperfusion injury (MIRI), while the role of CircZNF609 in MIRI remains unclear. This study was aimed to investigate the function of CircZNF609 in MIRI.MethodsHypoxia/reoxygenation (H/R) model was established to mimic MIRI in vitro. Quantitative polymerase chain reaction was performed to evaluate gene transcripts. Cellular localization of CircZNF609 and miR-214-3p were visualized by fluorescence in situ hybridization. Cell proliferation was determined by CCK-8. TUNEL assay and flow cytometry were applied to detect apoptosis. Lactate dehydrogenase was determined by commercial kit. ROS was detected by DCFH-DA probe. Direct interaction of indicated molecules was determined by RIP and dual luciferase assays. Western blot was used to quantify protein levels. In vivo model was established to further test the function of CircZNF609 in MIRI.ResultsCircZNF609 was upregulated in H/R model. Inhibition of CircZNF609 alleviated H/R induced apoptosis, ROS generation, restored cell proliferation in cardiomyocytes and human umbilical vein endothelial cells. Mechanically, CircZNF609 directly sponged miR-214-3p to release PTGS2 expression. Functional rescue experiments showed that miR-214-3p/PTGS2 axis was involved in the function of circZNG609 in H/R model. Furthermore, data in mouse model revealed that knockdown of CircZNF609 significantly reduced the area of myocardial infarction and decreased myocardial cell apoptosis.ConclusionsCircZNF609 aggravated the progression of MIRI via targeting miR-214-3p/PTGS2 axis, which suggested CircZNF609 might act as a vital modulator in MIRI.

| S-EPMC9470495 | biostudies-literature

Targeting the miR-665-3p-ATG4B-autophagy axis relieves inflammation and apoptosis in intestinal ischemia/reperfusion.

Project description:Autophagy is an essential cytoprotective response against pathologic stresses that selectively degrades damaged cellular components. Impaired autophagy contributes to organ injury in multiple diseases, including ischemia/reperfusion (I/R), but the exact mechanism by which impaired autophagy is regulated remains unclear. Several researchers have demonstrated that microRNAs (miRNAs) negatively regulate autophagy by targeting autophagy-related genes (ATGs). Therefore, the effect of ATG-related miRNAs on I/R remains a promising research avenue. In our study, we found that autophagy flux is impaired during intestinal I/R. A miRNA microarray analysis showed that miR-665-3p was highly expressed in the I/R group, which was confirmed by qRT-PCR. Then, we predicted and proved that miR-665-3p negatively regulates ATG4B expression in Caco-2 and IEC-6 cells. In ileum biopsy samples from patients with intestinal infarction, there was an inverse correlation between miR-665-3p and ATG4B expression, which supports the in vitro findings. Moreover, based on miR-665-3p regulation of autophagy in response to hypoxia/reoxygenation in vitro, gain-of-function and loss-of-function approaches were used to investigate the therapeutic potential of miR-665-3p. Additionally, we provide evidence that ATG4B is indispensable for protection upon inhibition of miR-665-3p. Finally, we observed that locked nucleic acid-modified inhibition of miR-665-3p in vivo alleviates I/R-induced systemic inflammation and apoptosis via recovery of autophagic flux. Our study highlights miR-665-3p as a novel small molecule that regulates autophagy by targeting ATG4B, suggesting that miR-665-3p inhibition may be a potential therapeutic approach against inflammation and apoptosis for the clinical treatment of intestinal I/R.

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Knockout of circRNA single stranded interacting protein 1 (circRBMS1) played a protective role in myocardial ischemia-reperfusion injury though inhibition of miR-2355-3p/Mammalian Sterile20-like kinase 1 (MST1) axis.

Project description:Evidence suggests circRBMS1 regulates mRNA to mediate cell apoptosis, inflammation, and oxidative stress in different diseases. MST1 is reported to be the target and activator of apoptosis-related molecules and signaling pathways. Hence, the present study aims to investigate the role of circ-RBMS1/miR-2355-3p/MST1 in the development of I/R injury. In vitro experiments showed increased circ-RBMS1 and decreased miR-2355-3p in H/R-induced HCMs. CircRBMS1 served as a sponge for miR-2355-3p and miR-2355-3p targeted MST1. Furthermore, knockout of circRBMS1 attenuated cell apoptosis, oxidized stress, and inflammation in H/R-induced HCMs. In vivo experiments indicated circRBMS1 knockdown attenuated cardiac function damage, cell apoptosis, oxidative stress injury and inflammatory response through miR-2355-3p/MST1 axis in mice. In summary, these results demonstrated circRBMS1 played a protective role in myocardial I/R injury though inhibition of miR-2355-3p/MST1 axis. It might provide a new therapeutic target for cardiac I/R injury.

| S-EPMC9275998 | biostudies-literature

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| S-EPMC10216082 | biostudies-literature

Hepatoprotective effects of sevoflurane against hepatic ischemia-reperfusion injury by regulating microRNA-124-3p-mediated TRAF3/CREB axis.

Project description:The purpose of the present study is to define the role of sevoflurane (SEV) in hepatic ischemia-reperfusion (I/R) injury as well as its underlying mechanism. Initially, hepatic I/R animal models and I/R hepatocyte models were established in C57BL/6 mice and normal mouse hepatocytes (BNL CL.2) after SEV preconditioning, respectively, followed by detection of microRNA-124-3p (miR-124-3p), TRAF3, and CREB expression by RT-qPCR and Western blot analysis. In addition, miR-124-3p, TRAF3 and CREB expression in hepatocytes was altered to identify their roles in modulating the levels of glutathione transferase (GST), aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and inflammation-related factors and hepatocyte apoptosis by ELISA and flow cytometry respectively. The effects of SEV on the miR-124-3p/TRAF3/CREB axis were also verified in vitro and in vivo. IP assay was performed to verify the effect of TRAF3 on CREB ubiquitination in BNL CL.2 cells, and the cycloheximide (CHX) intervention experiment to detect the stability of CREB protein. SEV augmented the miR-124-3p expression in I/R animal and cell models. Moreover, SEV was observed to suppress I/R-induced liver damage, GST, ALT, and AST levels, hepatocyte apoptosis and inflammation. Overexpression of miR-124-3p resulted in alleviation of hepatic I/R injury, which was countered by TRAF3 overexpression. miR-124-3p targeted TRAF3, while TRAF3 promoted CREB ubiquitination and reduced protein stability of CREB. SEV could impede I/R-induced liver damage, GST, ALT, and AST levels, hepatocyte apoptosis and inflammation via mediation of the miR-124-3p/TRAF3/CREB axis in vitro and in vivo. Collectively, SEV may upregulate miR-124-3p to inhibit TRAF3 expression, thereby reducing the ubiquitination and degradation of CREB, alleviating hepatic I/R injury.

| S-EPMC8904859 | biostudies-literature

Comprehensive circRNA expression profile during ischemic postconditioning attenuating hepatic ischemia/reperfusion injury.

Project description:Ischemic postconditioning (IPO) attenuates hepatic ischemia/reperfusion (I/R) injury. The aim of this study was to explore the role of circular RNAs (circRNAs) in the protective mechanism of IPO. In this study, microarray hybridization analysis was performed to determine the circRNA expression profile. Briefly, a total of 1599 dysregulated circRNAs were detected. The competitive endogenous RNA (ceRNA) network, including 6 circRNAs, 47 miRNAs and 90 mRNAs, indicated that the potential "housekeeping" function of circRNAs is dysregulated in hepatic I/R injury. Based on the validation results of selected circRNAs, miRNAs and mRNAs following qRT-PCR amplification, the mmu_circRNA_005186-miR-124-3p-Epha2 pathway was constructed. Dual-luciferase reporter analysis showed that miR-124-3p interacted directly with mmu_circRNA_005186 and Epha2 through the predicted binding sites, which suggested that mmu_circRNA_005186, serving as a miRNA sponge for miR-124-3p, regulated the expression of Epha2. Functionally, we explored the mechanism of mmu_circRNA_005186 in LPS-treated RAW264.7 cells which simulated the inflammation in hepatic I/R injury. We found that mmu_circRNA_005186 silencing attenuated the LPS-induced inflammation and was associated with miR-124-3p upregulation and Epha2 downregulation. Our study is the first to show that circRNAs are closely related to hepatic I/R injury and IPO and suggests that targeting mmu_circRNA_005186-miR-124-3p-Epha2 pathway might attenuate hepatic I/R injury.

| S-EPMC6342922 | biostudies-literature

HIF-1? induction during reperfusion avoids maladaptive repair after renal ischemia/reperfusion involving miR127-3p.

Project description:Ischemia/reperfusion (I/R) leads to Acute Kidney Injury. HIF-1? is a key factor during organ response to I/R. We previously demonstrated that HIF-1? is induced during renal reperfusion, after ischemia. Here we investigate the role of HIF-1? and the HIF-1? dependent mechanisms in renal repair after ischemia. By interference of HIF-1? in a rat model of renal I/R, we observed loss of expression and mis-localization of e-cadherin and induction of ?-SMA, MMP-13, TGF?, and collagen I. Moreover, we demonstrate that HIF-1? inhibition promotes renal cell infiltrates by inducing IL-1?, TNF-?, MCP-1 and VCAM-1, through NFkB activity. In addition, HIF-1? inhibition induced proximal tubule cells proliferation but it did not induce compensatory apoptosis, both in vivo. In vitro, HIF-1? knockdown in HK2 cells subjected to hypoxia/reoxygenation (H/R) promote cell entry into S phase, correlating with in vivo data. HIF-1? interference leads to downregulation of miR-127-3p and induction of its target gene Bcl6 in vivo. Moreover, modulation of miR-127-3p in HK2 cells subjected to H/R results in EMT regulation: miR127-3p inhibition promote loss of e-cadherin and induction of ?-SMA and collagen I. In conclusion, HIF-1? induction during reperfusion is a protector mechanism implicated in a normal renal tissue repair after I/R.

| S-EPMC5247697 | biostudies-other

NPY cerebral ischemia data

Project description: Not available

| S-BSST1451 | biostudies-other

Mbd2 Mediates Retinal Cell Apoptosis by Targeting the lncRNA Mbd2-AL1/miR-188-3p/Traf3 Axis in Ischemia/Reperfusion Injury.

Project description:Recent studies reported that DNA methylation was involved in retinal cell death. Methyl-CpG binding domain protein 2 (Mbd2) is one of the DNA methylation readers. Its role and mechanism of regulation remain unclear. The ischemia/reperfusion (I/R) model in mice primary culture retinal ganglion cells (RGCs) and Mbd2 knockout (Mbd2-KO) mice was used in the current study. We demonstrated that Mbd2 mediates RGC apoptosis caused by I/R injury. Mechanistically, the data suggested that Mbd2 upregulated Mbd2-associated long noncoding RNA 1 (Mbd2-AL1) via demethylation of its promoter. Furthermore, Mbd2-AL1 sponged microRNA (miR)-188-3p, thus preventing tumor necrosis factor (TNF) receptor-associated factor 3 (Traf3) downregulation and inducing RGC apoptosis. This was further demonstrated by the fact that inhibition of miR-188-3p diminished the anti-apoptosis role of Mbd2-AL1 small interfering RNA (siRNA). Finally, it showed that the apoptosis of retinal cells was attenuated, and the visual function was preserved in Mbd2-KO mice, which were associated with the Mbd2-AL1/miR-188-3p/Traf3 axis. Our present study revealed the role of Mbd2 in RGC apoptosis, which may provide a novel therapeutic strategy for retinal ischemic diseases.

| S-EPMC7025978 | biostudies-literature

Long-Noncoding RNA PCAT6 Aggravates Osteosarcoma Tumourigenesis via the MiR-143-3p/ZEB1 Axis.

Project description:Introduction:The long-noncoding RNA PCAT6 plays an important regulatory role in the development of several cancers. However, the expression pattern and underlying mechanisms of PCAT6 in osteosarcoma (OS) are yet unknown. Methods:We used real-time PCR to measure PCAT6 expression in 106 tumor pairs and corresponding non-tumor tissues from OS patients. Statistical analyses were applied to evaluate the prognostic value and associations of PCAT6 expression with clinical parameters. Furthermore, the PCAT6 was silenced with siRNA in OS cells. Moreover, phenotype of PCAT6 silenced OS cells was measured using colony formation, CCK-8, cell migration and invasion assay. Finally, the molecular mechanism of PCAT6/miR-143-3p/ZEB1 axis in OS progression was explored. Results:The expression level of PCAT6 in OS tissues was significantly elevated as compared with that in the adjacent normal bone tissues and that high PCAT6 expression closely correlated with the malignant phenotype and poor survival among patients with OS. Multivariate analyses revealed PCAT6 overexpression as an independent prognostic factor for the poor outcome of patients with OS. Functional assay results demonstrated that the knockdown of PCAT6 expression notably suppressed the proliferation, migration, and invasion of OS cells. An elevated PCAT6 level aggravated the malignant phenotype of OS cells via ZEB1 expression upregulation. Mechanistic studies revealed that PCAT6 could sponge endogenous miR-143-3p and inhibit its activity, resulting in an increase in ZEB1 level. Finally, we demonstrated that the tumour-promoting role of PCAT6 in OS was dependent on the regulation of the miR-143-3p/ZEB1 axis. Conclusion:These findings highlight the potential role of PCAT6, which could serve as a valuable prognostic indicator for patients with OS.

| S-EPMC7457841 | biostudies-literature

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