ATP2A2 and miRNA in human myocardial infarction
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE17304 | GEO | 2012/04/30
SECONDARY ACCESSION(S): PRJNA118967
REPOSITORIES: GEO
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Project description:Cardiac sarco(endo)plasmic reticulum calcium ATPase-2 (SERCA2) plays one of the central roles in myocardial contractility. Both, SERCA2 mRNA and protein are reduced in myocardial infarction (MI), but the correlation has not been always observed. MicroRNAs (miRNAs) act by targeting 3'-UTR mRNA, causing translational repression in physiological and pathological conditions, including cardiovascular diseases. The aim of our study was to identify miRNAs that could influence SERCA2 expression in human MI. The protein SERCA2 was decreased and 43 miRNAs were deregulated in infarcted myocardium compared to remote myocardium. miRNAs binding prediction to SERCA2 identified 213 putative miRNAs. TAM and miRNApath identified 18 functional and 21 diseased states related to heart diseases. Combing all results, we identified certain miRNAs as potential regulators of SERCA2. All the samples were stored as FFPE tissue and in RNAlater. Expression of SERCA2 was analyzed by western blot and miRNA expression was analyzed by microarrays and qPCR in samples of remote and infarcted myocardium from 6 patients who died of MI. Bioinformatic analysis including six prediction programmes (TargetScan, PicTar, miRBase, miRDB, Human MicroRNA Targets, and microrna.org), TAM and miRNApath annotation, and free-energy of binding (RNA22, RNAfold), was performed. Nine up-regulated miRNAs were analyzed for free-energy of binding and flanking regions, and nine miRNAs were used for validation with qPCR. Based on qPCR the comparison between FFPE and RNAlater as well as different reference genes was also performed.
2012-04-29 | E-GEOD-17304 | biostudies-arrayexpress
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Project description:screening of signature deterimes the individual variations in the therapeutic efficacy of human umbilical cord blood-derived mesenchymal stem cells There is paucity of information whether human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) from separate donors might have different effects on improving myocardial repair after myocardial infarction (MI). We screened cell surface genes by the comparing the cells that showed the best and worst efficacy, respectively, in repairing the infarcted myocardium of rats.
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Project description:Myocardial infarction (MI) is a sterile inflammatory condition that results in the activation of T- cells targeting cardiac antigens. T-cells have been shown to contribute to reparative and maladaptive remodeling post-MI. However, the differentiation trajectories and in situ activity of heart-specific CD4+T cells and the effect of distinct T-cell phenotypes on MI repair remains poorly understood. Herein, we combined T-cell receptor transgenic models and tetramer staining targeting myocardial protein with single-cell transcriptomics (scRNAseq) and functional phenotyping to elucidate how the myosin-specific CD4+ T cells (TCR-M) differentiate in the murine infarcted myocardium and influence tissue repair. Furthermore, we transferred pro-inflammatory versus regulatory pre-differentiated heart-specific T-cells to dissect how they differentially regulate post-myocardial infarction (MI) inflammation. Flow cytometry and scRNAseq findings reveled that transferred TCR-M cells acquired an induced regulatory phenotype (iTreg) in the infarcted myocardium and blunt local inflammation. Myocardial TCR-M cells differentiated into two main lineages enriched with cell activation and pro-fibrotic transcripts (e.g. Tgfb1) or with suppressor immune checkpoints (e.g. Pdcd1), which we also found in human myocardial tissue. These cells produced high levels of latency-associated peptide (LAP) and inhibited interleukine-17 (IL-17) responses. Tetramer staining further identified endogenous myosin-specific T-cells that acquired a regulatory phenotype in the heart post-MI. Notably, TCR-M cells that were pre-differentiated in vitro towards a regulatory phenotype maintained a stable in vivo FOXP3 expression and anti-inflammatory activity whereas TH17 partially converted towards a regulatory phenotype in the injured myocardium, which was associated to blunted myocardial inflammation. Moreover, myocardial scar of Treg TCR-M transferred mice showed blunted inflammatory transcripts and enrichment for growth factors supporting fibroblasts and endothelial cells.
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Project description:Myocardial infarction (MI) causes sterile inflammation, which is characterized by recruitment and activation of innate and adaptive immune system cells. We have delineated the temporal dynamics of immune cell accumulation following MI by flow cytometry. Macrophages were numerically the predominant cells infiltrating the infarcted myocardium, increasing in number over the first week post-MI. Macrophages are functionally heterogeneous, and can be classified into M1 and M2 macrophages, respectively, based on surface-marker expression. M1 macrophages dominated at 1-3 days post-MI, whereas M2 macrophages represented the predominant macrophage subset after 5 days. We used microarrays to examine the gene expression profiles of the macrophages sorted from the hearts at different timepoints after MI. We identified the kinetics of gene expression of cardiac macrophage after MI.
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Project description:Thyroid hormone improves left ventricular remodeling and cardiac performance after myocardial infarction (MI), but the molecular basis is unknown. This study was designed to detect gene expression changes in left ventricular non-infarcted areas at 4 weeks following myocardial infarction with and without thyroid hormone treatment. The results suggest that altered expression of genes for molecular function and biological process may be involved in the beneficial effects of thyroid hormone treatment following myocardial infarction in rats. MI was produced by ligation of the left anterior descending coronary artery in female SD rats. Rats were divided into the following groups: (1) Sham MI, (2) MI, and (3) MI+T4 treatment (T4 pellet 3.3mg, 60 days release, implanted subcutaneously immediately following MI). Four weeks after surgery, total RNA was isolated from left ventricular non-infarcted areas for microarray analysis using the Illumina RatRef-12 Expression BeadChip Platform.
2012-04-30 | E-GEOD-35088 | biostudies-arrayexpress
Project description:The use of cDNA microarrays has made it possible to analyze expression of thousands of genes simultaneously. We employed microarray gene expression profiling of porcine cDNA to compare myocardial gene expression in infarct core and remote myocardium at 1 week (n=3), 4 weeks (n=3), and 6 weeks (n=3) after surgically induced myocardial infarction (MI) and in sham-operated controls (n=3). More than 8,000 cDNA sequences were identified in myocardium that showed differential expression in response to MI. Different temporal and spatial patterns of gene expression were recognized in the infarct core tissue within this large set of data. Microarray gene profiling revealed candidate genes, some of them described for the first time, which elucidate changes in biological processes at different stages after MI. We evaluated temporal gene expression in a porcine model of myocardial infarction by microarray technology. Nine female pigs (Sus scrofa crossbreed Landrace x Large White) weighing 30-40 kg were subjected to experimental MI by a double-ligation of the first marginal branch of the circumflex artery. Animals were randomly sacrificed at 1 week (n=3), 4 weeks (n=3), or 6 weeks (n=3) after MI. Three paired myocardial samples from the infarct core and remote myocardium were analyzed at each time point. Myocardial samples from sham-operated animals (open-chest cardiac exposure without coronary artery ligation; n=3) were included as physiological controls.
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Project description:Pathological expansion of self-reactive T cells is a hallmark of autoimmune diseases. Notwith-standing, T cell autoreactivity can also benefit self-maintenance and foster tissue repair. Herein, we investigated whether heart-specific T cells exert salutary or detrimental effects in the context of the post myocardial infarction (MI) healing process in mice, and whether the findings can be translated to humans. Transferred cardiac-myosin-specific CD4+ T cells (TCR-M) selectively accumulate in the myocardium and mediastinal lymph nodes (med-LNs) of infarcted mice. TCR-M cells activated in the MI-context acquire a Foxp3+ regulatory phenotype, exhibit a distinct gene expression profile enriched with growth factors, and promote cardioprotection. Massive parallel sequencing of T cell receptors revealed that CD4+ T cells infiltrating the infarcted myo-cardium display a unique repertoire signature with skewed diversity and dominated by a limited set of expanded clones - hallmarks of antigen-specific responses. CD4+ Foxp3+ cells were also detected in myocardial biopsies obtained from patients who suffered MI, especially in associa-tion with the granulation tissue (i.e., healing phase). Noninvasive positron emission tomogra-phy/computed tomography (PET/CT) imaging using a CXCR4 radioligand revealed that MI pa-tients display enlarged med-LNs with increased T cellularity. Alterations in the med-LN corre-lated with infarct size and cardiac function. Taken together, these results provide strong evidence that the MI-context induces protective T cell autoimmunity in mice, and confirm the existence of an analogous physiological heart/med-LN/T cell axis in MI patients, which offers translational potential.
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