Microarray Profiling of Long Non-coding RNA (lncRNA) Associated with Hypertrophic Cardiomyopathy
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE68316 | GEO | 2015/05/08
SECONDARY ACCESSION(S): PRJNA282419
REPOSITORIES: GEO
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Project description:Approximately 1426 lncRNAs (965 up-regulated and 461 down-regulated) and 1715 mRNAs (896 up-regulated and 819 down-regulated) were aberrantly expressed in HCM patients with fold change > 2.0 Myocardial tissues were obtained from 7 HCM patients and 5 disease-free individuals, and lncRNA and mRNA expression profiles were analyzed using the CapitalBio Human LncRNA Microarray v2.0.
2015-05-08 | E-GEOD-68316 | biostudies-arrayexpress
Project description:Hypertrophic cardiomyopathy (HCM) is an important cause leading to heart failure. Preserving cardiac function particularly in cardiomyocytes (CMs) is essential for improving prognosis in HCM patients. Therefore, understanding single-cell transcriptome characteristics of CMs in HCM would be indispensable to investigate potential therapeutic targets. We applied single-cell tagged reverse transcription (STRT-seq) approach and obtained 338 CM transcriptomes. The human heart samples were collected from HCM patients who had extended septal myectomy and healthy donors. Our results revealed that in nonfailing HCM heart CMs could be categorized into three subsets: high energy synthesis cluster, high cellular metabolism cluster and intermediate cluster. The expression of mitochondrial and electron transport chain (ETC) was up-regulated in larger-sized CMs from high energy synthesis cluster. Of note, we found the expression of Cytochrome c oxidase subunit 7B (Cox7B), a subunit of Complex IV in ETC was positively correlated with CMs size. Further, after assessing Cox7B expression in HCM patients, we speculated that Cox7B was compensatory up-regulated at early-stage but down-regulated at end-stage of HCM. To test the hypothesis that Cox7B might play a cardioprotective role in the early-stage of HCM, we used adeno associated virus 9 (AAV9) to mediate the expression of Cox7B in pressure overload-induced mice. Mice in vivo data supported that knockdown of Cox7B would accelerate heart failure progression and Cox7B overexpression could restore partial cardiac function in hypertrophy.
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Project description:Heart disease remains the number one killer of women in the US. Nonetheless, studies in women and female animal models continue to be underrepresented in cardiac research. Hypertrophic cardiomyopathy (HCM), the most commonly inherited cardiac disorder, has been tied to sarcomeric protein variants. Among the susceptible genes, TNNC1—encoding cardiac troponin C (cTnC)—has contributed to a substantial HCM phenotype in mice. In this study we sought to characterize the sexual dimorphism observed within cardiac physiology and transcriptomics of adult male and female mice bearing the HCM-associated cTnC-A8V point mutation. The HCM mice showed a significant decrease in stroke volume, left ventricular diameter, volume, and relative wall thickness. Importantly, isovolumetric contraction time was significantly higher for female HCM mice. RNA sequencing revealed several altered canonical pathways within the HCM mice vs WT groups including an increase in EIF2 signaling, ILK signaling, actin nucleation by ARP-WASP complex, regulation of actin-based motility by Rho, VDR/RXR activation, and glutathione redox reactions pathways. In contrast, Valine Degradation, TCA Cycle II, Methionine Degradation, and Inositol Phosphate Compound pathways were notably down regulated in HCM mice. HCM male vs. female mice followed similar trends of the canonical pathways altered between the HCM and WT. Interestingly, seven of the genes that were differentially expressed in both the WT and HCM male vs female comparisons changed directions in fold change between the sexes. These data suggest a sexually-dimorphic HCM phenotype and identify several key pathways and genes that could be critical to sex differences seen in disease manifestation.
2020-01-23 | GSE144098 | GEO
Project description:Cardiac biopsies were obtained from hypertrophic cardiomyopathy (HCM) patients and controls and subjected to mRNA profiling.
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Project description:Hypertrophic cardiomyopathy (HCM) is a complex disease partly explained by the effects of individual gene variants on sarcomeric protein biomechanics. At the cellular level, HCM mutations most commonly enhance force production, leading to higher energy demands. Despite significant advances in elucidating sarcomeric structure-function relationships, there is still much to be learned about the mechanisms that link altered cardiac energetics to HCM phenotypes. In this work, we test the hypothesis that changes in cardiac energetics represent a common pathophysiologic pathway in HCM. We performed a comprehensive multi-omics profile of the molecular (transcripts, metabolites, and complex lipids), ultrastructural, and functional components of HCM energetics using myocardial samples from 27 HCM patients and 13 normal controls (donor hearts). Integrated omics analysis revealed alterations in a wide array of biochemical pathways with major dysregulation in fatty acid metabolism, reduction of acylcarnitines, and accumulation of free fatty acids. HCM hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites (ATP, ADP, and phosphocreatine) and a reduction in mitochondrial genes involved in the creatine kinase and ATP synthesis. Accompanying these metabolic derangements, quantitative electron microscopy showed an increased fraction of severely damaged mitochondria with reduced cristae density, coinciding with reduced citrate synthase (CS) activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species (ROS) and reduced antioxidant defenses. However, despite significant mitochondrial injury, HCM hearts failed to upregulate mitophagic clearance. Overall, our findings suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with HCM. These results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing mitochondrial injury.
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Project description:Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease and a leading cause of sudden cardiac death in young adults. HCM has been linked to mutations in genes encoding sarcomeric proteins, but how different mutations can result in a similar clinical phenotype is unknown. Analysis of surgical heart tissue samples from HCM patients with severe outflow track obstruction using high-resolution mass spectrometry-based top-down proteomics revealed a common pattern of altered sarcomeric proteoforms across HCM tissues compared to non-failing donor heart tissues. Our data suggest that common pathways are associated with clinical phenotypes in patients diagnosed with obstructive HCM, opening the door for the development of interventions that target the HCM phenotype rather than the individual sarcomeric gene mutation.
2020-07-24 | MSV000085823 | MassIVE
Project description:To understand the interplay between cardiomyocyte and nonmyocyte cell types in human obstructive and non-obstructive hypertrophic cardiomyopathy, single nuclei RNA-sequencing was performed on 2 unused donor hearts, 1 obstructive HCM specimen, and 6 non-obstructive HCM specimens.
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Project description:MicroRNAs negatively regulate gene expression and may serve as biomarkers for human cardiomyopathy. In the domestic cat, hypertrophic cardiomyopathy (HCM) represents the most common primary cardiomyopathy. In humans, the etiology of HCM is linked to mutations in genes of contractile muscle proteins, while in cats a clear proof for causal mutations is missing. The etiology of feline HCM is uncertain. Diagnosis is made by heart ultrasound examination and measuring the serum level of N-terminal pro B-type natriuretic peptide. The purpose of this study was to investigate whether microRNA profiles in the serum of cats with HCM are different from the profiles of healthy cats and whether specific miRNAs can be detected to serve as potential biomarkers for feline HCM or may help in understanding the etiology of this disease Blood was drawn from two groups of cats: 12 healthy cats and 11 cats suffering from hypertrophic cardiomyopathy. After clotting, samples were centrifuged and total mRNA was extracted from serum. These 23 serum samples were analyzed and the groups were compared
2015-07-22 | E-GEOD-49427 | biostudies-arrayexpress
Project description:Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, and its pathogenesis is still being intensively studied to explain the reasons of significant genetic and phenotypic heterogeneity of the disease. To search for possible HCM modifier genes involved in the HCM development we first attempted to analyze gene expression profile coupled with DNA methylation profile in the hypertrophied myocardium of HCM patients; the control group consisted of patients with aortic stenosis. The transcriptome analysis identified significant differences in levels of 193 genes, most of which were underexpressed in HCM. The methylome analysis revealed 1755 nominally significant differentially methylated positions (DMPs), mostly hypomethylated in HCM. The clear differences in DNA methylation profiles between the studied groups indicate the involvement of this process in the formation of primary left ventricle hypertrophy in HCM. Based on gene ontology enrichment analysis, the majority of biological processes, overrepresented by both differentially expressed genes (DEGs) and DMP-containing genes, are involved in the regulation of locomotion and muscle structure development. The intersection of 193 DEGs and 978 DMP-containing genes pinpointed eight genes, expression of which differed between studied groups and correlated with methylation levels of the neighboring DMPs. Half of these genes (AUTS2, GIGYF1, PRRT1, and SLC17A7) were found underexpressed in HCM and involved in neurogenesis and synapse functioning. Our data suggesting the possible involvement of innervation-associated genes in HCM provide additional insights in the disease pathogenesis and expand the field of further research.
2022-06-30 | GSE206978 | GEO
Project description:Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, and its pathogenesis is still being intensively studied to explain the reasons of significant genetic and phenotypic heterogeneity of the disease. To search for possible HCM modifier genes involved in the HCM development we first attempted to analyze gene expression profile coupled with DNA methylation profile in the hypertrophied myocardium of HCM patients; the control group consisted of patients with aortic stenosis. The transcriptome analysis identified significant differences in levels of 193 genes, most of which were underexpressed in HCM. The methylome analysis revealed 1755 nominally significant differentially methylated positions (DMPs), mostly hypomethylated in HCM. The clear differences in DNA methylation profiles between the studied groups indicate the involvement of this process in the formation of primary left ventricle hypertrophy in HCM. Based on gene ontology enrichment analysis, the majority of biological processes, overrepresented by both differentially expressed genes (DEGs) and DMP-containing genes, are involved in the regulation of locomotion and muscle structure development. The intersection of 193 DEGs and 978 DMP-containing genes pinpointed eight genes, expression of which differed between studied groups and correlated with methylation levels of the neighboring DMPs. Half of these genes (AUTS2, GIGYF1, PRRT1, and SLC17A7) were found underexpressed in HCM and involved in neurogenesis and synapse functioning. Our data suggesting the possible involvement of innervation-associated genes in HCM provide additional insights in the disease pathogenesis and expand the field of further research.
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