Widespread downregulation of cardiac mitochondrial and sarcomeric genes in patients with sepsis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE79962 | GEO | 2016/09/22
SECONDARY ACCESSION(S): PRJNA317505
REPOSITORIES: GEO
Similar Datasets
Project description:Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy primarily of the right ventricle characterized through fibrofatty replacement of cardiomyocytes. The genetic etiology in ARVC patients is most commonly caused by dominant inheritance and high genetic heterogeneity. Though histological examinations of ARVC affected human myocardium reveals fibrolipomatous replacement, the molecular mechanisms leading to loss of cardiomyocytes are largely unknown. We therefore analyzed the transcriptomes of 6 ARVC specimen derived from heart transplantation candidates and compared our findings to 6 non-failing donor hearts (NF) which could not be transplanted for technical reasons. In addition, we compared our findings to 7 hearts from patients with idiopathic dilated cardiomyopathy. From each heart left (LV) and right ventricular (RV) myocardial samples were analyzed by Affymetrix HG-U133 Plus 2.0 arrays, adding up to six sample groups. Unsupervised cluster analyses of the six sample groups revealed a clear separation of NF and cardiomyopathy samples. However, in contrast to the other samples, unsupervised cluster analyses revealed no distinct expression pattern in LV and RV samples from ARVC-hearts. We further identified differentially expressed transcripts using t-tests and found transcripts separating diseased and NF ventricular myocardium. Of note, in failing myocardium only about 15-16% of the genes are commonly regulated compared to NF samples. In addition both cardiomyopathies are clearly distinct on the transcriptome level. Comparison of the expression patterns between the failing RV and LV using a paired t-test revealed a lack of major differences between LV and RV gene expression in ARVC hearts. Microarrays were used to elucidate the differences between non-failing control hearts and those, suffering from arrhythmogenic right ventricular cardiomyopathy (ARVC).
2011-11-30 | E-GEOD-29819 | biostudies-arrayexpress
Project description:Our study helps to understand the molecular pathogenesis of septic cardiomyopathy in C57BL/6 mice and identifiy genes and pathways that may be potential therapeutic targets for septic cardiomyopathy treatment.
2021-04-07 | GSE171546 | GEO
Project description:Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy primarily of the right ventricle characterized through fibrofatty replacement of cardiomyocytes. The genetic etiology in ARVC patients is most commonly caused by dominant inheritance and high genetic heterogeneity. Though histological examinations of ARVC affected human myocardium reveals fibrolipomatous replacement, the molecular mechanisms leading to loss of cardiomyocytes are largely unknown. We therefore analyzed the transcriptomes of 6 ARVC specimen derived from heart transplantation candidates and compared our findings to 6 non-failing donor hearts (NF) which could not be transplanted for technical reasons. In addition, we compared our findings to 7 hearts from patients with idiopathic dilated cardiomyopathy. From each heart left (LV) and right ventricular (RV) myocardial samples were analyzed by Affymetrix HG-U133 Plus 2.0 arrays, adding up to six sample groups. Unsupervised cluster analyses of the six sample groups revealed a clear separation of NF and cardiomyopathy samples. However, in contrast to the other samples, unsupervised cluster analyses revealed no distinct expression pattern in LV and RV samples from ARVC-hearts. We further identified differentially expressed transcripts using t-tests and found transcripts separating diseased and NF ventricular myocardium. Of note, in failing myocardium only about 15-16% of the genes are commonly regulated compared to NF samples. In addition both cardiomyopathies are clearly distinct on the transcriptome level. Comparison of the expression patterns between the failing RV and LV using a paired t-test revealed a lack of major differences between LV and RV gene expression in ARVC hearts.
2011-11-30 | GSE29819 | GEO
Project description:The microtubule (MT) cytoskeleton can provide a mechanical resistance that can impede the motion of contracting cardiomyocytes. Yet a role of the MT network in human heart failure is unexplored. Here we utilize mass spectrometry to characterize changes to the cytoskeleton in human heart failure. Proteomic analysis of left ventricle tissue reveals a consistent upregulation and stabilization of intermediate filaments and MTs in human heart failure. This dataset includes left ventricular (LV) myocardium from 34 human hearts – either non-failing (NF) or failing hearts. NF hearts are subdivided into normal or compensated hypertrophy (cHyp), while failing hearts are subdivided into ischemic cardiomyopathy (ICM), dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy with preserved or reduced ejection fraction (HCMpEF and HCMrEF, respectively). Further details on patient classification and in vivo parameters on each heart are listed in sample details.txt.
2018-06-06 | PXD008934 | Pride
Project description:In ischemic cardiomyopathy (ICM), left ventricular systolic dysfunction leads to reduced blood flow and oxygen supply to the heart. Alterations in sarcomeric protein function and expression play prominent roles in the onset and progression of cardiomyopathies; however, the molecular mechanisms underlying ICM remain poorly defined. Herein, we have implemented a top-down liquid chromatography (LC)-mass spectrometry (MS)-based proteomics method for the simultaneous quantification of sarcomeric protein expression and modifications in non-failing donor (n = 16) compared to end-stage failing ICM (n = 16) human cardiac tissues. Our top-down proteomics platform provided a “bird’s eye view” of proteoform families with high mass accuracy and reproducibility. In addition, quantification of post-translational modifications (PTMs) and expression reveal significant changes in various sarcomeric proteins extracted from ICM tissues. Changes include altered phosphorylation and expression of cardiac troponin I (cTnI) and enigma homolog 2 (ENH2) as well as a marked increase in muscle LIM protein (MLP) and calsarcin-1 phosphorylation in ICM hearts. Our results imply that the contractile apparatus of the sarcomere is severely dysregulated during ICM. Thus, this study is the first to uncover significant molecular changes to multiple sarcomeric proteins in end-stage ischemic heart failure patients using LC-MS-based top-down proteomics.
2023-02-20 | PXD038066 | Pride
Project description:Objectives: This study aimed to determine the transcriptional basis of functional silencing of one of the two dominant pacemakers in failing rat hearts. Background: Recently, our laboratory presented functional and molecular evidence for the presence of two competing sinoatrial node (SAN) pacemakers in the healthy human and rat hearts. Anatomically localized near the superior vena cava and inferior vena cava, the superior and inferior SANs (sSAN and iSAN), respectively, preferentially control fast and slow normal heart rates. However, only one dominant pacemaker, primarily sSAN, was functional in the failing rat heart with hypertrophic cardiomyopathy. Methods: Ascending aortic constriction was performed on 1-week-old male Sprague-Dawley rat pups to induce left ventricular hypertrophy and heart failure. The dominant pacemaker was anatomically mapped in adult (8-12 weeks old) healthy and failing rat hearts using optical mapping in isolated right atrial tissue preparations. RNA sequencing was used to identify regional sSAN/iSAN gene expression differences between healthy and failing rat hearts. Results: In all failing rat hearts optically mapped in this study (n=4), only the sSAN pacemaker was functional, while the iSAN was silent. Compared to healthy rat hearts, a total of 3,640 genes were downregulated and 4,518 genes were upregulated in failing rat hearts. The functional quiescence of the iSAN in these failing rat hearts may be explained by their downregulation of sodium, potassium, and calcium ion channels as well as their downregulation of certain structural genes, including ankyrin, titin, and myosin heavy chain. Moreover, the iSAN showed predominant downregulation of several key transcription factors such as TBX5, TBX3, SHOX2, and SMAD9. Conclusions: Pressure-overload-induced heart failure resulted in significant downregulation of critical transcription factors, ion channels, and structural transcripts of the iSAN, which could explain the functional silencing of the iSAN in failing rat hearts.
2022-05-17 | GSE201717 | GEO
Project description:OBJECTIVES:The mechanism(s) for septic cardiomyopathy in humans is not known. To address this, we measured messenger RNA alterations in hearts from patients who died from systemic sepsis, in comparison to changed messenger RNA expression in nonfailing and failing human hearts. DESIGN:Identification of genes with altered abundance in septic cardiomyopathy, ischemic heart disease, or dilated cardiomyopathy, in comparison to nonfailing hearts. SETTING:ICUs at Barnes-Jewish Hospital, St. Louis, MO. PATIENTS:Twenty sepsis patients, 11 ischemic heart disease, nine dilated cardiomyopathy, and 11 nonfailing donors. INTERVENTIONS:None other than those performed as part of patient care. MEASUREMENTS AND MAIN RESULTS:Messenger RNA expression levels for 198 mitochondrially localized energy production components, including Krebs cycle and electron transport genes, decreased by 43% ± 5% (mean ± SD). Messenger RNAs for nine genes responsible for sarcomere contraction and excitation-contraction coupling decreased by 43% ± 4% in septic hearts. Surprisingly, the alterations in messenger RNA levels in septic cardiomyopathy were both distinct from and more profound than changes in messenger RNA levels in the hearts of patients with end-stage heart failure. CONCLUSIONS:The expression profile of messenger RNAs in the heart of septic patients reveals striking decreases in expression levels of messenger RNAs that encode proteins involved in cardiac energy production and cardiac contractility and is distinct from that observed in patients with heart failure. Although speculative, the global nature of the decreases in messenger RNA expression for genes involved in cardiac energy production and contractility suggests that these changes may represent a short-term adaptive response of the heart in response to acute change in cardiovascular homeostasis.
| S-EPMC5315660 | biostudies-literature
Project description:Oxidative stress plays a key role in development and progression of cardiovascular diseases and it is correlated with left ventricular dysfunction and heart failure (HF). Oxidative environments lead to the formation of intra- and intermolecular disulfide bonds, as well as to plethora of other reversible and irreversible oxidative amino acid modifications, affecting the functionality of the proteins. Here we report that heart failure due to ischemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM) is correlated with increase in oxidative stress compared to non-failing control hearts, manifested through decreased GSH/GSSG ratio in failing heart tissue samples and adaptations of cardiac redox proteome which occur in correlation with two different heart pathologies.
2021-09-09 | PXD021261 | Pride
Project description:The goal of this experiment was to identify gene expression changes that are common in different heart failure (HF) types or specific to an etiology of HF. HF groups studied include doxorubicin induced cardiomyopathy, familial dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic dilated cardiomyopathy, ischemic heart disease, peripartum cardiomyopathy, and viral induced cardiomyopathy. Non-diseased left ventricles (LV) were obtained from donor hearts not used for transplantation (these were considered to be unsuitable for transplantation for a variety of reasons including the lack of a tissue-compatible recipient). Failing LV were obtained from patients undergoing heart transplantation. Transmural sections of LV anterior free wall were trimmed of fat, dissected into 1-1.5 gm pieces, and immediately frozen in the operating theater. 100-200 mg of frozen transmural LV was ground to a fine powder in liquid nitrogen using a mortar and pestle. Then total RNA was isolated by a method described by Wei and Khan (A Molecular Cloning Manual). The purity of the RNA extract was assessed by measuring the absorbance at 260 nm and 280 nm. Its quantity and integrity was then examined using RNA Nano Chips on a 2100 Bioanalyzer (Agilent Technologies, Palo Alto, CA, USA). 10 ?g of RNA extracts and a universal human reference RNA (Stratagene, La Jolla, CA, USA) were reverse transcribed with Cy3-dUTP and Cy5-dUTP, respectively, to produce labeled cDNA probes using Thermoscript reverse transcriptase according Hwang JJ et. al. (Physiological Genomics 10: 31-44, 2002). Raw scanned images were processed using ScanAlyze version 2.50 (Michael Eisen, Stanford University, CA, USA). Cy3 and Cy5 scans were superimposed, local backgrounds were subtracted, and the fluorescence intensities of each spot were quantified. All further analyses of CardioChips were done using GeneSpring version 6.1 (Silicon Genetics, Redwood City, CA, USA). The data from each array was normalized first to the reference RNA and then a LOWESS curve was fit to the log-intensity versus log-ratio plot for each array and for each gene across all experiments. 40.0% of the data was used to calculate the LOWESS fit at each point. Differentially expressed genes in each HF group compared to donor hearts were identified by a one-way ANOVA test (P <0.05) with the benjamini and hochberg multiple testing corrections and we selected those genes with an average difference greater than 1.5 fold. A hierarchical clustering analysis was performed using pearson correlation with the separation ratio of 1.0 and minimum distance of 0.001 as similarity measure. Using a cardiovascular-specific gene array (CardioChip) of 42 heart failure (HF) patients from a wide range of etiology groups and 8 non-failing donors, we have identified down-regulation of LIM domain protein which may be an important pathway for the clinical progression of HF. We identified six genes, encoding LIM domain and Homer proteins, that are down-regulated in terminally failing hearts. The LIM and cysteine rich domain 1 (LMCD1) gene, in particular, was significantly down-regulated in all HF samples. This novel finding suggests that the LMCD 1 is a universal biomarker for end-stage HF. Other LIM domain genes were also down-regulated but only in non-familial dilated forms of cardiomyopathy. This is probably due to the fact that down-regulation of LIM protein expression may disrupt the cytoskeletal architecture, leading to dilated cardiomyopathy. In addition to identifying the LIM domain genes as possible regulatory genes involved in HF, we also demonstrated that the gene expression profile was able to classify multiple HF patients groups. This paper is the first to examine viral-induced cardiomyopathy, doxorubicin toxicity cardiomyopathy and perimartum cardiomyopathy and to perform the clustering analysis of those HF types providing new insights into human HF.
2010-06-10 | E-GEOD-2656 | biostudies-arrayexpress
Project description:Tumor Necrosis Factor-α is greatly implicated in heart pathophysiology, while it is upregulated in the failing myocardium. A major target in TNF-α-induced heart failure is the muscle specific intermediate filament cytoskeleton, comprised by desmin. We analysed the effect of cardiac-specific overexpression of TNF-α in the Des-/- myocardium, which is a known model of dilated cardiomyopathy. Hearts of 3 months old mice (n=3) of Des-/- and TNFαDes-/- genotypes were used for whole genome microarray hybridization analysis.
2015-05-02 | E-GEOD-56286 | biostudies-arrayexpress