RNA-seq of myocardial tissue from abdominal aortic-banded rats with and without systolic heart failure
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ABSTRACT:
INSTRUMENT(S): NextSeq 500
ORGANISM(S): Rattus norvegicus
SUBMITTER: Mihály Ruppert
PROVIDER: E-MTAB-12671 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Changes in gene expression contribute to the pathogenesis of heart failure. The sequence, expression level, and structure of the human cardiac transcriptome are incompletely described, as are their changes in heart disease. High throughput transcriptome sequencing (RNA-seq) is a quantitative and unbiased approach to measure transcript level and to identify novel transcribed elements or transcript splicing. Here we acquired 975.2 x 106 mapped RNA-seq reads in 15 control and 15 ischemic cardiomyopathy (ICM) hearts, obtained at the time of heart transplantation. We identified over 1000 differentially expressed transcripts, and thousands of novel transcribed elements, some of which were differentially expressed in between control and ICM groups. We found that transcript processing of several cardiac genes was deranged in ICM. For instance, the ratio between specific MYH6 exons was significantly changed in ICM compared to controls, while this type of inter-exon variation was not observed for the adjoining gene MYH7. This RNA-seq study of the human heart failure transcriptome revealed the diversity of transcripts expressed in the human heart and their complex patterns of expression in the diseased heart. Transcriptome profiling (RNA-seq) of 15 control and 15 ischemic cardiomyopathy (ICM) hearts using Illumina GAII and SOLiD
2013-12-19 | E-GEOD-48166 | biostudies-arrayexpress
Project description:Objectives: To test whether (1) electromechanical dyssynchrony induces region-specific alterations in the myocardial transcriptome and (2) dyssynchrony-induced gene expression changes can be corrected by cardiac resynchronization (CRT). Background: To date, CRT is the only heart failure treatment that can both acutely and chronically increase systolic function and prolong survival, something not yet achieved by a drug therapy. However, the mechanisms underlying the benefits of CRT remain elusive. Methods: Adult dogs underwent left bundle branch ablation (LBBB) and right atrial pacing at 200 bpm for either 6 weeks (dyssynchronous heart failure, DHF, n=12) or 3 weeks followed by 3 weeks of resynchronization by bi-ventricular pacing at the same pacing rate (CRT, n=10). Control animals without LBBB were not paced (NF, n=14). Echocardiography and invasive hemodynamic measurements were performed at 3 and 6 weeks. At 6 weeks, RNA was isolated from the anterior and lateral LV walls and hybridized onto canine-specific 44K microarrays. Results: In DHF, transcriptional changes consistent with re-expression of a fetal gene program were primarily observed in the anterior LV, resulting in increased regional heterogeneity of gene expression within the left ventricle. Dyssynchrony-induced region-specific expression changes in 1050 transcripts were reversed by CRT to levels of NF hearts (false discovery rate <5%). CRT remodeled transcripts with metabolic and cell signaling function and greatly reduced regional heterogeneity of gene expression compared with DHF. Conclusions: Our results demonstrate a profound effect of electromechanical dyssynchrony on the regional cardiac transcriptome, causing gene expression changes primarily in the anterior LV wall. CRT corrected the alterations in gene expression in the anterior wall by reversing the fetal gene expression pattern, supporting a global effect of biventricular pacing on the ventricular transcriptome that extends beyond the pacing site in the lateral wall. Designed as a 1-color experiments, samples from anterior and lateral left ventricular myocardium from non-failing, DHF and CRT animals were labeled with Cy3 and hybridized onto Agilent 44K long oligonucleotide arrays.
2010-05-16 | E-GEOD-14327 | biostudies-arrayexpress
Project description:Objectives: To test whether (1) electromechanical dyssynchrony induces region-specific alterations in the myocardial transcriptome and (2) dyssynchrony-induced gene expression changes can be corrected by cardiac resynchronization (CRT). Background: To date, CRT is the only heart failure treatment that can both acutely and chronically increase systolic function and prolong survival, something not yet achieved by a drug therapy. However, the mechanisms underlying the benefits of CRT remain elusive. Methods: Adult dogs underwent left bundle branch ablation (LBBB) and right atrial pacing at 200 bpm for either 6 weeks (dyssynchronous heart failure, DHF, n=12) or 3 weeks followed by 3 weeks of resynchronization by bi-ventricular pacing at the same pacing rate (CRT, n=10). Control animals without LBBB were not paced (NF, n=14). Echocardiography and invasive hemodynamic measurements were performed at 3 and 6 weeks. At 6 weeks, RNA was isolated from the anterior and lateral LV walls and hybridized onto canine-specific 44K microarrays. Results: In DHF, transcriptional changes consistent with re-expression of a fetal gene program were primarily observed in the anterior LV, resulting in increased regional heterogeneity of gene expression within the left ventricle. Dyssynchrony-induced region-specific expression changes in 1050 transcripts were reversed by CRT to levels of NF hearts (false discovery rate <5%). CRT remodeled transcripts with metabolic and cell signaling function and greatly reduced regional heterogeneity of gene expression compared with DHF. Conclusions: Our results demonstrate a profound effect of electromechanical dyssynchrony on the regional cardiac transcriptome, causing gene expression changes primarily in the anterior LV wall. CRT corrected the alterations in gene expression in the anterior wall by reversing the fetal gene expression pattern, supporting a global effect of biventricular pacing on the ventricular transcriptome that extends beyond the pacing site in the lateral wall. Complementary study to GSE14327. While GSE14327 was designed as a 1-color microarray experiment, this series was carried out following a 2-color design (anterior and lateral LV wall labeled with Cy3 and Cy5, respectively, including dye swaps).
2010-05-16 | E-GEOD-14338 | biostudies-arrayexpress
Project description:Background: Heart failure with preserved ejection fraction (HFpEF) constitutes more than half of all heart failure but has few effective therapies. Recent human myocardial transcriptomics and metabolomics have revealed major differences between HFpEF, HF with reduced EF (HFrEF), and controls. How this translates at the protein level is currently unknown. Methods: Myocardial tissue from patients with HFpEF and non-failing donor controls was analyzed by data-dependent (DDA, n=10 HFpEF, n=9 controls) and data-independent (DIA, n=44 HFpEF, n=5 controls) mass spectrometry-based proteomics. Previously reported myocardial proteomic data from end-stage HFrEF and controls were also used. Differential protein expression analysis, machine learning and pathway enrichment were integrated with clinical characteristics and myocardial transcriptomics. Results: DDA-MS proteomics identified 88 significantly upregulated and 248 down-regulated proteins in HFpEF vs controls, out of 1996 identified proteins. Principal component analysis of DDA-MS proteomics found HFpEF was separated into 2 sub-groups: one being similar to controls the other quite disparate. Top proteins contributing to the separation of HFpEF subgroups were enriched in actin/myosin binding, regulation of DNA replication/repair, transcription, and translation. Downregulated proteins in HFpEF vs controls were enriched in pathways related to ribosome structure, transmembrane transporters, metabolic enzymes, and oxidative phosphorylation (OxPhos) proteins. Enriched pathways for proteins upregulated in HFpEF related to actin and phospholipid binding, growth factor signaling, kinase regulation, and glycolysis. Ingenuity pathway analysis predicted downregulation of protein translation, mitochondrial function, and glucose and fat metabolism in HFpEF. OxPhos gene (increased) versus protein (decreased) expression was discordant in HFpEF. The second DIA proteomic analysis also yielded two HFpEF sub-groups; the one most different from controls also having reduced OxPhos and protein translation pathways. A higher proportion of these patients also had severe obesity. Conclusions: Integrative proteomics, transcriptomics, and pathway analysis supports a translational defect particularly involving mitochondrial, ribosomal and protein translation proteins in HFpEF. Patients with more distinct proteomic signatures from control were more often very obese. The results support therapeutic efforts targeting metabolism, mitochondrial function, and protein translation in this subgroup.
2024-03-05 | PXD045677 | Pride
Project description:Myocardial infarction (MI) often results in left ventricular (LV) remodeling followed by heart failure (HF). It is of great clinical importance to understand the molecular mechanisms that trigger transition from compensated LV injury to HF and to identify relevant diagnostic biomarkers. In this study, we performed transcriptional profiling of LVs in rats with a wide range of experimentally induced infarct sizes and of peripheral blood mononuclear cells (PBMCs) in animals that developed HF. We used microarrays to investigate gene expression in the left ventricle (LV) accompanying myocardial infarction and concomitant heart failure (HF) in a well validated model of post-infarcted heart failure and to evaluate their reflection in peripheral blood mononuclear cells (PBMCs) Myocardial infarction (MI) was induced in male Wistar rats by ligation of the proximal left coronary artery. The sham-operated group (control group) was subjected to the same protocol, except that the suture was not tied around the proximal left coronary artery. Sham-operated rats (n=6) and rats with small (n=6), moderate (n=6), and large (n=5) MI size were included into the experiment two months after the operation. Then, left ventricules and blood samples were obtained for RNA extraction and hybridization on Affymetrix microarrays. Microarrays were used to compare the LV and PBMCs transcriptomes of control and experimental animals. The development of heart failure was estimated by echocardiography and catheterization.
2013-11-15 | E-GEOD-47495 | biostudies-arrayexpress
Project description:We demonstrate an age-independent loss of type H bone endothelium in heart failure after myocardial infarction in both mice and in humans. Using single-cell RNA sequencing, we delineate the transcriptional heterogeneity of human bone marrow endothelium showing increased expression of inflammatory genes, including IL1B and MYC, in ischemic heart failure. Endothelial-specific overexpression of MYC was sufficient to induce type H bone endothelial cells, whereas inhibition of NLRP3-dependent IL-1 production partially prevents the post-myocardial infarction loss of type H vasculature in mice.
2021-05-13 | E-MTAB-10448 | biostudies-arrayexpress
Project description:The study aimed to investigate the mechanisms of Jianxin (JX) granules, a Traditional Chinese Medicine formulation, in the treatment of heart failure (HF) using metabolomic profiling. The HF model was established by ligation of left coronary artery. The successfully modeled rats were randomly divided into three groups: the model group, the JX granules group, and Sacubitril/Valsartan (S/V) group. Four weeks after treatment, LV tissue samples were collected. Proteomics was used to identify the differentially expressed proteins and potential pathways. The differential expressed proteins (DEPs) were obtained with Tandem Mass Tags approach. As compared to the control group, 150 DEPs were identified in model rats, comprising 112 up-regulated and 38 down-regulated proteins. Notably, in the JX granules group, 25 DEPs were identified compared to the model rats, encompassing 18 up-regulated and 7 down-regulated proteins. In comparison with the control group, 228 DEPs in the JX granules group were obtained, which comprised of 128 up-regulated and 100 down-regulated proteins. As compared with the control group, BP in the model group was mainly enriched in humoral immune response, positive regulation of apoptotic cell clearance, and the response to metal ions; Meanwhile, CC was mainly related to contractile and stress fibers, actin filaments, and extracellular space; MF was mainly enriched in the serine-type peptidase activity, actin binding, and peptidase activity. Furthermore, DEPs indicated by KEGG analysis were primarily linked to pathways such as the complement and coagulation cascades, regulation of the actin cytoskeleton, and adrenergic signaling. In contrast to the model group, BP in JX granules group was primarily associated with processes involving nucleosome organization, chromatin assembly or disassembly, DNA conformation change and small molecule catabolic processes; CC was primarily related to the protein-DNA complex, mitochondrion, intracellular, nucleosome, cytoplasm; MF displayed significant enrichment in protein dimerization and homodimerization activity, catalase activity, chromatin and nucleosomal DNA binding. Considering KEGG enrichment information, DEPs in the JX granules group were mainly enriched in metabolic pathways and ribosome pathway. The key differential genes, such as triosephosphate isomerase 1 (TPI1), lactate dehydrogenase B (LDHB), pyruvate kinase M (PKM), protein kinase B (Akt), and lactate dehydrogenase A (LDHA) were identified. The vital pathways including carbon metabolism, the PI3K-Akt signaling pathway, pyruvate metabolism, and HIF-1α signaling pathway were obtained.
2024-01-26 | PXD048915 | Pride
Project description:Analysis of changes of gene expression profiles in the left ventricle (LV) during the progression of heart failure (HF) in the canine tachypacing induced HF model. Gene expression profiling was performed on samples collected at different time points representing various stages of LV dysfunction, i.e. tachypaced for 3 days (Day-3), 1 week (Week-1), 2 weeks (Week-2), 3-4 weeks (End stage), and unpaced controls (Day-0). Results provide insights into molecular mechanisms of heart failure progression. Keywords: time course This work aims to study changes of gene expression profiles in the left ventricle (LV) during the progression of heart failure (HF) in the canine tachypacing induced HF model. LV transmural tissue sections were collected at different time points after initiating rapid pacing representing various stages of LV dysfunction, i.e. tachypaced for 3 days (Day-3), 1 week (Week-1), 2 weeks (Week-2), 3-4 weeks (End stage), and unpaced controls (Day-0). As biological replicates, tissues were collected separately from 3 individual dogs at each of the time points. In total we collected 15 tissue samples for all 5 time points. Three RNA samples were independently isolated from each of the 15 tissue samples as technical replicates. The resulting 45 RNA samples were used for microarray experiment. Affymetrix gene expression profiles of the 45 RNA samples were used for all data analysis in this study.
2010-05-19 | E-GEOD-9794 | biostudies-arrayexpress
Project description:LV hypertrophy is associated with Western diet consumption, while intake of n-3 polyunsaturated fatty acids is associated with anti-hypertrophic effects. We treated rats for 12 weeks with either a Control diet, a Western diet or a Western + DHA diet. For each of the 3 dietary treatments there were 2 pooled samples of heart tissue (with each pooled sample representing 5 rats) for a total of 6 arrays. Microarray analysis identified 66 differentially expressed transcripts. Pathways were identified using Ingenuity and DAVID software. Array results from two pooled samples (5 rats in each pool) for n=10 per treatment group were used for comparisons. Comparisons between Western vs. Control, Western + DHA vs. Control and Western + DHA vs. Western diets was subjected to analysis to generate log fold changes. A dietary treatment of 12 weeks was used in an effort to produce LVH while limiting the development of comorbidities. Microarray analysis was performed on pooled samples, followed by qRT-PCR and Western blot analysis. Groups were Control, Western and Western + DHA. Comparisons between groups are expressed as LogFC (i.e. LogFC_WESvCTRL, LogFC_DHAVCTRL, LogFC_DHAvWES), available in Series supplementary files.
2013-11-22 | E-GEOD-52603 | biostudies-arrayexpress
Project description:To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, 12/15 lipoxygenase (12/15-LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that 12/15-LOX transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in 12/15-LOX transgenic mice with advancing age, and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein-1 (Mcp-1) was up-regulated in 12/15-LOX transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenotic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells, but not in cardiomyocytes. Inhibition of Mcp-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in 12/15-LOX transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac Mcp-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition. Heart failure is still one of the leading causes of death worldwide. Therefore, it is important to elucidate the underlying mechanisms of heart failure and develop more effective treatments for this condition. To clarify the molecular mechanisms of heart failure, we performed microarray analysis using cardiac tissue samples obtained from a hypertensive heart failure model (Dahl salt-sensitive rats). ~300 genes showed significant changes of expression in the failing hearts compared with control hearts. Among the genes analyzed, 12/15-lipoxygenase (12/15-LOX) was most markedly up-regulated in failing hearts compared with control hearts .
2009-06-06 | E-GEOD-16199 | biostudies-arrayexpress