Overexpression of circRNA SNRK targets miR-103-3p to reduce apoptosis and promote cardiac repair through GSK3β/β-catenin pathway in rats with myocardial infarction.
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ABSTRACT:
SUBMITTER: Zhu Y
PROVIDER: S-EPMC8055694 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A limited delivery of oxygen and metabolic substrate to the heart caused by myocardial infarction (MI) impairs the cardiac function, and often results in heart failure. Here, we identified a circRNA (circ-SNRK) from SNRK (sucrose nonfermenting 1-related kinase, which can increase the cardiac mitochondrial efficiency) in cardiomyocytes (CMs). Circ-SNRK can sponge the miR-33 and in turn improved the ATP synthesis via SNRK, proving the existence of circ-SNRK - miR-33 - SNRK axis. Furthermore, we found that protein NOVA1 (NOVA alternative splicing regulator 1) could accelerate the circ-SNRK formation; a cleaved peptide (~55 kDa) from SNRK enters the nucleus and blocks the cyclization of circ-SNRK via binding to NOVA1. The aforementioned negative feedback of SNRK to circ-SNRK limited the SNRK at a proper level, and inhibited the protective role of circ-SNRK in ischemic heart. In addition, our in vivo experiment indicated that the overexpression of exogenic circ-SNRK could break this loop and improves the cardiac function post-MI in rats. Together, our results demonstrated that the negative loop of circ-SNRK with SNRK regulates the energy metabolism in CMs, thus might be a potential therapeutic target for heart failure.
| S-EPMC8989981 | biostudies-literature
Project description:Background: Acute myocardial infarction (AMI) is one of the main fatal diseases of cardiovascular diseases. Circular RNA (circRNA) is a non-coding RNA (ncRNA), which plays a role in cardiovascular disease as a competitive endogenous RNA (ceRNA). However, their role in AMI has not been fully clarified. This study aims to explore the mechanism of circRNA-related ceRNA network in AMI, and to identify the corresponding immune infiltration characteristics. Materials and Methods: The circRNA (GSE160717), miRNA (GSE24548), and mRNA (GSE60993) microarray datasets of AMI were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed circRNAs (DEcircRNAs), miRNAs (DEmiRNAs), and mRNAs (DEmRNAs) were identified by the "limma" package. After integrating the circRNA, miRNA and mRNA interaction, we constructed a circRNA-miRNA-mRNA network. The "clusterProfiler" package and String database were used for functional enrichment analysis and protein-protein interaction (PPI) analysis, respectively. After that, we constructed a circRNA-miRNA-hub gene network and validated the circRNAs and mRNAs using an independent dataset (GSE61144) as well as qRT-PCR. Finally, we used CIBERSORTx database to analyze the immune infiltration characteristics of AMI and the correlation between hub genes and immune cells. Results: Using the "limma" package of the R, 83 DEcircRNAs, 54 DEmiRNAs, and 754 DEmRNAs were identified in the microarray datasets of AMI. Among 83 DEcircRNAs, there are 55 exonic DEcircRNAs. Then, a circRNA-miRNA-mRNA network consists of 21 DEcircRNAs, 11 DEmiRNAs, and 106 DEmRNAs were predicted by the database. After that, 10 hub genes from the PPI network were identified. Then, a new circRNA-miRNA-hub gene network consists of 14 DEcircRNAs, 7 DEmiRNAs, and 9 DEmRNAs was constructed. After that, three key circRNAs (hsa_circ_0009018, hsa_circ_0030569 and hsa_circ_0031017) and three hub genes (BCL6, PTGS2 and PTEN) were identified from the network by qRT-PCR. Finally, immune infiltration analysis showed that hub genes were significantly positively correlated with up-regulated immune cells (neutrophils, macrophages and plasma cells) in AMI. Conclusion: Our study constructed a circRNA-related ceRNA networks in AMI, consists of hsa_circ_0031017/hsa-miR-142-5p/PTEN axis, hsa_circ_0030569/hsa-miR-545/PTGS2 axis and hsa_circ_0009018/hsa-miR-139-3p/BCL6 axis. These three hub genes were significantly positively correlated with up-regulated immune cells (neutrophils, macrophages and plasma cells) in AMI. It helps improve understanding of AMI mechanism and provides future potential therapeutic targets.
| S-EPMC9002054 | biostudies-literature
Project description:BackgroundMyocardial infarction (MI) is one of the main causes of disability and death in the world, leading to myocarditis and cardiomyocyte apoptosis. Studies have shown that microRNA (miRNA) is involved in myocarditis and apoptosis. The main purpose of this study was to explore the regulatory mechanism of miR-223-3p on myocarditis and apoptosis after MI.MethodsWe cultured H9c2 cells and detected the expression of miR-223-3p in cells treated with different concentrations of H2O2. Sprague Dawley (SD) rats were fed with normal diet, constructed an MI model and detect the expression of miR-223-3p in heart tissue. Overexpression or inhibition of miR-223-3p was conducted in MI model cells in vitro, and the contents of the inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10) in cell supernatant were detected by enzyme-linked immunosorbent assay (ELISA). Cell apoptosis was detected by flow cytometry. Luciferase activity assay was used to detect the targeting relationship between miR-223-3p and FBXW7, and the expression of FBXW7 in cells was also detected. Overexpression of miR-223-3p was performed in MI rats to detect the expression of inflammatory factors, FBXW7, and apoptosis in rat cardiac tissue.ResultsThe expression of miR-223-3p was down regulated in MI models established in vitro and in vivo. Overexpression of miR-223-3p can inhibit inflammatory response and apoptosis in H9c2 cells and cardiac tissues. It was revealed that miR-223-3p can inhibit the expression of FBXW7, reduce myocarditis and apoptosis after MI, and improve cardiac function.ConclusionsIt is possible that miR-223-3p reduces myocarditis and apoptosis after MI and improves cardiac function by targeted inhibition of FBXW7 expression.
| S-EPMC9096303 | biostudies-literature
Project description:Reactive oxygen species (ROS) derived from oxygen-dependent mitochondrial metabolism are the essential drivers of cardiomyocyte (CM) cell-cycle arrest in adulthood. Mitochondria-localized circular RNAs (circRNAs) play important roles in regulating mitochondria-derived ROS production, but their functions in cardiac regeneration are still unknown. Herein, we investigated the functions and underlying mechanism of mitochondria-localized circSamd4 in cardiac regeneration. We found that circSamd4 was selectively expressed in fetal and neonatal CMs. The transcription factor Nrf2 controlled circSamd4 expression by binding to the promoter of circSamd4 host gene. CircSamd4 overexpression reduced while circSamd4 silenced increased mitochondrial oxidative stress and subsequent oxidative DNA damage. Moreover, circSamd4 overexpression induced CM proliferation and prevented CM apoptosis, which reduced the size of the fibrotic area and improved cardiac function after myocardial infarction (MI). Mechanistically, circSamd4 reduced oxidative stress generation and maintained mitochondrial dynamics by inducing the mitochondrial translocation of the Vcp protein, which downregulated Vdac1 expression and prevented the mitochondrial permeability transition pore (mPTP) from opening. Our findings suggest that circSamd4 is a novel therapeutic target for heart failure after MI.
| S-EPMC9637749 | biostudies-literature
Project description:Reactive oxygen species, such as hydrogen peroxide (H(2)O(2)), contribute to progression of dysfunction after myocardial infarction (MI). However, chronic overexpression studies do not agree with acute protein delivery studies. The purpose of the present study was to assess the temporal role of cardiomyocyte-derived H(2)O(2) scavenging on cardiac function after infarction using an inducible system.We developed a tamoxifen-inducible, cardiomyocyte-specific, catalase-overexpressing mouse. Catalase overexpression was induced either 5 days before or after MI. Mice exhibited a 3-fold increase in cardiac catalase activity that was associated with a significant decrease in H(2)O(2) levels at both 7 and 21 days. However, cardiac function improved only at the later time point. Proinflammatory and fibrotic genes were acutely upregulated after MI, but catalase overexpression abolished the increase despite no acute change in function. This led to reduced overall scar formation, with lower levels of Collagen 1A and increased contractile Collagen 3A expression at 21 days.In contrast to prior studies, there were no acute functional improvements with physiological catalase overexpression before MI. Scavenging of H(2)O(2), however, reduced proinflammatory cytokines and altered cardiac collagen isoforms, associated with an improvement in cardiac function after 21 days. Our results suggest that sustained H(2)O(2) levels rather than acute levels immediately after MI may be critical in directing remodeling and cardiac function at later time points.
| S-EPMC3076122 | biostudies-literature
Project description:Long noncoding RNAs (lncRNAs) play crucial roles in cardiovascular diseases. To date, only limited studies have reported the role of mitochondria-derived lncRNAs in heart failure (HF). In the current study, recombinant adeno-associated virus 9 was used to manipulate lncRNA cytb (lnccytb) expression in vivo. Fluorescence in situ hybridization (FISH) assay was used to determine the location of lnccytb, while microRNA (miRNA) sequencing and bioinformatics analyses were applied to identify the downstream targets. The competitive endogenous RNA (ceRNA) function of lnccytb was evaluated by biotin-coupled miRNA pull-down assays and luciferase reporter assays. Results showed that lnccytb expression was decreased in the heart of mice with transverse aortic constriction (TAC), as well as in the heart and plasma of patients with HF. FISH assay and absolute RNA quantification via real-time reverse transcription PCR suggested that the reduction of the lnccytb transcripts mainly occurred in the cytosol. Upregulation of cytosolic lnccytb attenuated cardiac dysfunction in TAC mice. Moreover, overexpression of cytosolic lnccytb in cardiomyocytes alleviated isoprenaline-induced reactive oxidative species (ROS) production and hypertrophy. Mechanistically, lnccytb acted as a ceRNA via sponging miR-103-3p, ultimately mitigating the suppression of PTEN by miR-103-3p. In summary, we demonstrated that the overexpression of cytosolic lnccytb could ameliorate HF.
| S-EPMC8881631 | biostudies-literature
Project description:Myocardial infarction (MI) may cause heart failure and seriously harm human health. During the genesis of cardiac fibrosis after MI, the proliferation and migration of cardiac fibroblasts contribute to secretion and maintenance of extracellular matrix (ECM) components. Many miRNAs have been highly implicated in the processes of cardiac fibrosis after MI. However, the molecular mechanisms for how miRNAs involve in cardiac fibrosis remain largely unexplored. Based on MI model in miniature pigs, the potential miRNAs involved in MI were identified by using small RNA sequencing. Using human cardiac fibroblasts (HCFs) as a cellular model, EdU, Transwell, and the expression of ECM-related proteins were applied to investigate the cell proliferation, migration and collagen synthesis. In this study, using MI model based on miniature pigs, 84 miRNAs were identified as the differentially expressed miRNAs between MI and control group, and miR-144-3p, one of differentially expressed miRNAs, was identified to be higher expressed in infarct area. The cell proliferation, migration activity, and the mRNA and protein levels of the ECM-related genes were significantly increased by miR-144-3p mimic but significantly decreased by miR-144-3p inhibitor in cardiac fibroblasts. Furthermore, miR-144-3p was observed to repress transcription and translation of PTEN, and interfering with the expression of PTEN up-regulated the mRNAs and proteins levels of ?-SMA, Col1A1, and Col3A1, and promoted the proliferation and migration of cardiac fibroblasts, which was in line with that of miR-144-3p mimics, but this observation could be reversed by miR-144-3p inhibitor. Collectively, miR-144-3p promotes cell proliferation, migration, and collagen production by targeting PTEN in cardiac fibroblasts, suggesting that miR-144-3p-mediated-PTEN regulation might be a novel therapeutic target for cardiac fibrosis after MI.
| S-EPMC6828614 | biostudies-literature
Project description:Infiltration by dendritic cells (DCs) is markedly increased in the infarcted area following myocardial infarction (MI), and DC ablation has been shown to impair angiogenesis in mice post‑MI. Exosomes (EXs) have long been known to act as messengers between cells; however, whether EXs derived from DCs can enhance myocardial angiogenesis post‑MI remains unknown. The aim of the present study was to elucidate whether EXs derived from DCs induce myocardial angiogenesis via paracrine signaling post‑MI. In vitro, suspensions of mouse bone marrow‑derived DCs (BMDCs) were incubated with the supernatant of necrotic or normal cultured HL‑1 myocardial cells (as the MI or control group, respectively) for 24 h. EXs isolated from the supernatant of BMDCs were termed DEXs, which were added to primary cultures of rat cardiac microvascular endothelial cells (CMECs), and angiogenesis was evaluated by measuring tube formation and vascular endothelial growth factor (VEGF) expression. In vivo, different groups of DEXs were injected into the infarcted myocardium of MI model mice. Then, angiogenesis was evaluated by measuring the number of vessels and the expression of VEGF and CD31 in the infarcted myocardium using immunohistochemistry. Moreover, the expression profile of microRNAs (miRNAs or miRs) in splenic DCs of MI model mice was analyzed by Affymetrix miRNA 4.0 chip assays, then certified in DEXs by reverse transcription‑quantitative PCR analysis. Finally, miRNA‑loaded DEXs were used to induce tube formation by CMECs and angiogenesis in MI model mice. It was observed that, compared with the control group, DEXs from the MI group significantly upregulated the expression of VEGF in CMECs, enhanced tube formation by CMECs, and upregulated the expression of VEGF and CD31 in the infarcted myocardium of MI model mice. miR‑494‑3p and miR‑16a‑5p, which are associated with angiogenesis, were significantly upregulated in splenic DCs of MI model mice by Affymetrix miRNA 4.0 chip assays, miR‑494‑3p was significantly upregulated and highly enriched in DEXs from the MI group compared with the control, and DEX‑miR‑494‑3p enhanced tube formation by CMECs and angiogenesis in mice post‑MI. These results suggest that miR‑494‑3p may be secreted from DCs via EXs and promotes angiogenesis post‑MI. These findings indicate a novel DEX‑based approach to the treatment of MI.
| S-EPMC7723512 | biostudies-literature
Project description:BackgroundCircular RNA (circRNA) plays an important role in the regulation of gene expression and the occurrence of human diseases. However, studies on the role of circRNA in acute myocardial infarction (AMI) are limited. This study was performed to explore novel circRNA-related regulatory networks in AMI, aiming to better understand the molecular mechanism of circRNAs involvement in AMI and provide basis for further scientific research and clinical decision-making.MethodsThe AMI-related microarray datasets GSE160717 (circRNA), GSE31568 (miRNA), GSE61741 (miRNA), and GSE24519 (mRNA) were obtained from the Gene Expression Omnibus (GEO) database. After differential expression analysis, the regulatory relationships between these DERNAs were identified by online databases circBank, circInteractome, miRDB, miRWalk, Targetscan, and then two circRNA-miRNA-mRNA regulatory networks were constructed. Differentially expressed genes (DEGs) in this network were selected followed by enrichment analysis and protein-protein interaction (PPI) analysis. Hub genes were identified using Cytohubba plug-in of Cytoscape software. Hub genes and hub gene-related miRNAs were used for receiver operating characteristic curve (ROC) analysis to identify potential biomarkers. The relative expression levels of these biomarkers were further assessed by GSE31568 (miRNA) and GSE66360 (mRNA). Finally, on the basis of the above analysis, myocardial hypoxia model was constructed to verify the expression of Hub genes and related circRNAs.ResultsA total of 83 DEcircRNAs, 109 CoDEmiRNAs and 1204 DEGs were significantly differentially expressed in these datasets. The up-regulated circRNAs and down-regulated circRNAs were used to construct a circRNA-miRNA-mRNA regulatory network respectively. These circRNA-related DEGs were mainly enriched in the terms of "FOXO signaling pathway," "T cell receptor signaling pathway," "MAPK signaling pathway," "Insulin resistance," "cAMP signaling pathway," and "mTOR signaling pathway." The top 10 hub genes ATP2B2, KCNA1, GRIN2A, SCN2B, GPM6A, CACNA1E, HDAC2, SRSF1, ANK2, and HNRNPA2B1 were identified from the PPI network. Hub genes GPM6A, SRSF1, ANK2 and hub gene-related circRNAs hsa_circ_0023461, hsa_circ_0004561, hsa_circ_0001147, hsa_circ_0004771, hsa_circ_0061276, and hsa_circ_0045519 were identified as potential biomarkers in AMI.ConclusionIn this study, the potential circRNAs associated with AMI were identified and two circRNA-miRNA-mRNA regulatory networks were constructed. This study explored the mechanism of circRNA involvement in AMI and provided new clues for the selection of new diagnostic markers and therapeutic targets for AMI.
| S-EPMC9300925 | biostudies-literature
Project description:The membrane type-1 matrix metalloproteinase (MT1-MMP) is a unique member of the MMP family, but induction patterns and consequences of MT1-MMP overexpression (MT1-MMPexp), in a left ventricular (LV) remodeling process such as myocardial infarction (MI), have not been explored. MT1-MMP promoter activity (murine luciferase reporter) increased 20-fold at 3 days and 50-fold at 14 days post-MI. MI was then induced in mice with cardiac restricted MT1-MMPexp (n = 58) and wild type (WT, n = 60). Post-MI survival was reduced (67% versus 46%, p < 0.05), and LV ejection fraction was lower in the post-MI MT1-MMPexp mice compared with WT (41 ± 2 versus 32 ± 2%,p < 0.05). In the post-MI MT1-MMPexp mice, LV myocardial MMP activity, as assessed by radiotracer uptake, and MT1-MMP-specific proteolytic activity using a specific fluorogenic assay were both increased by 2-fold. LV collagen content was increased by nearly 2-fold in the post-MI MT1-MMPexp compared with WT. Using a validated fluorogenic construct, it was discovered that MT1-MMP proteolytically processed the pro-fibrotic molecule, latency-associated transforming growth factor-1 binding protein (LTBP-1), and MT1-MMP-specific LTBP-1 proteolytic activity was increased by 4-fold in the post-MI MT1-MMPexp group. Early and persistent MT1-MMP promoter activity occurred post-MI, and increased myocardial MT1-MMP levels resulted in poor survival, worsening of LV function, and significant fibrosis. A molecular mechanism for the adverse LV matrix remodeling with MT1-MMP induction is increased processing of pro-fibrotic signaling molecules. Thus, a proteolytically diverse portfolio exists for MT1-MMP within the myocardium and likely plays a mechanistic role in adverse LV remodeling.
| S-EPMC2943310 | biostudies-literature