Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of human inflammatory cardiomyopathy vs controls (DCMi) suggests novel therapeutic targets.

ABSTRACT: Since targeting of specific pathogenic pathways may be more efficient than current unspecific heart failure treatment, we obtained genomewide expression profiles of a DCM subtype characterized by cardiac inflammation (DCMi) in association with parvovirus B19. This study was entirely based on RNA isolated from endomyocardial biopsies so far only rarely used for genomic expression profiling. Experiment Overall Design: Samples derived from 8 DCMi and 4 healthy control patients were hybridised onto Affymetrix U133 Plus arrays.

ORGANISM(S): Homo sapiens

SUBMITTER: Henning Witt

PROVIDER: E-GEOD-4172 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Genomic expression profiling of human inflammatory cardiomyopathy (DCMi) suggests novel therapeutic targets.

Wittchen F F Suckau L L Witt H H Skurk C C Lassner D D Fechner H H Sipo I I Ungethüm U U Ruiz P P Pauschinger M M Tschope C C Rauch U U Kühl U U Schultheiss H-P HP Poller W W

Journal of molecular medicine (Berlin, Germany) 20061115 3

The clinical phenotype of human dilated cardiomyopathy (DCM) encompasses a broad spectrum of etiologically distinct disorders. As targeting of etiology-related pathogenic pathways may be more efficient than current standard heart failure treatment, we obtained the genomic expression profile of a DCM subtype characterized by cardiac inflammation to identify possible new therapeutic targets in humans. In this inflammatory cardiomyopathy (DCMi), a distinctive cardiac expression pattern not describe ...[more]

PMID: 17106732

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Project description:Global expression profiling of airway epithelial cells infected with Pseudomonas aeruginosa and the rsmA mutant. Recent work in our laboratory investigated the impact of RsmA on a number of airway epithelial cell phenotypes including actin depolymerization, cytotoxicity and invasion. These cellular phenotypes were influenced by the positive effect of RsmA on the expression of the TTSS in P. aeruginosa (Mulcahy et al. 2006. Infect. Immun.). Pseudomonas aeruginosa is an important opportunistic pathogen which is capable of causing both acute and chronic infections in immunocompromised patients. Successful adaptation of the bacterium to its host environment relies on the ability of the organism to tightly regulate gene expression. RsmA, a small RNA-binding ; protein, controls the expression of a large number of virulence-related genes in P. aeruginosa, including those encoding the type III secretion system and associated effector proteins, with important consequences for epithelial cell morphology and cytotoxicity. In order to examine the influence of RsmA-regulated functions in ; the pathogen on gene expression in the host, we compared global expression profiles of airway epithelial cells in response to infection with P. aeruginosa PAO1 and an rsmA mutant. The RsmA-dependent response of host cells was characterized by significant changes in the global transcriptional pattern, including the increased expression of two Kruppel-like factors, KLF2 and KLF6. This increased expression was mediated by specific type III effector proteins. ExoS was required for the enhanced expression of KLF2, whereas both ExoS and ExoY were required for the enhanced expression of KLF6. Neither ExoT nor ExoU influenced the expression of the transcription factors. Additionally, the increased gene expression of KLF2 and KLF6 was associated with ExoS-mediated cytotoxicity. Therefore, this study identifies for the first time the human transcription factors ; KLF2 and KLF6 as targets of the P. aeruginosa type III exoenzymes S and Y, with potential importance in host cell death. Experiment Overall Design: RNA isolation and microarray sample preparation Experiment Overall Design: Biological samples from two independent infection experiments were used in two independent microarray experiments as outlined below. Total RNA was isolated from epithelial cells using a RNeasy Kit (Qiagen) according to manufacturer's instructions. Genomic DNA was removed using DNA-free (Ambion) and confirmed by PCR to be free of DNA, prior to cDNA synthesis. Isolated RNA was used in the preparation of fragmented cRNA for microarray hybridization according to the manufacturer's protocol (Affymetrix). Briefly, 8.5ug of RNA was converted to double stranded cDNA by reverse transcription, using a Superscript cDNA synthesis kit (Invitrogen), with an oligo dT primer containing a T7 RNA polymerase site added 3' of the poly (T) (Affymetrix). After second strand synthesis, cDNA was converted to biotin-labelled cRNA by in vitro transcription (Enzo). The labelled cRNA was purified using Genechip clean up module (Qiagen). Total cRNA quality and yield was measured using a GeneQuant spectrophotometer and 20ug of cRNA was fragmented at 94ÂºC for 35 mins in fragmentation buffer (40 mM tris acetate, pH 8.1, 100 mM potassium acetate, 30 mM magnesium acetate). Full length and fragmented cRNA sample integrity was assessed by electrophoresis on a 1% agarose-TBE gel visualized by staining with SyBr green. Fragmented cRNA was sent to MRC geneservice (Cambridge, UK) for assessment of RNA quality using a Bioanalyzer (Agilent) before hybridization and scanning. The arrays were washed and stained in a fluidics station and scanned according to the manufacturer's protocols (Affymetrix). Experiment Overall Design: Microarray data analysis Experiment Overall Design: Raw image analysis was performed using Microarray Suite v5.0 software (Affymetrix). Downstream data analysis was performed using GeneSight software version 2.7 (Biodiscovery). For all analyses, the signal intensities from two independent infection and microarray experiments were used. Statistically significant changes in gene expression were identified by firstly performing analysis of variance (ANOVA), for comparison between multiple groups, with a P value of < 0.05. The list of transcripts generated using ANOVA was then subjected to a Student's t-test, for comparison between two groups, with a P value of < 0.05. To identify different levels of gene expression compared to baseline, a fold change cut-off of greater than or equal to 1.5 was applied to this data.

Project description:Aims: We investigate sex differences and the role of oestrogen receptor beta (ERbeta) in a mouse model of pressure overload-induced myocardial hypertrophy. Methods and results: We performed transverse aortic constriction (TAC) or sham surgery in male and female wild-type (WT) and ER knockout (ERbeta-/-) C57Bl6 mice. All mice were characterised by echocardiography and haemodynamic measurements and were sacrificed nine weeks after surgery. Left ventricular (LV) samples were analysed by microarray profiling, real-time RT-PCR and histology. After nine weeks, WT males showed more hypertrophy and heart failure signs than WT females. Notably, WT females developed a concentric form of hypertrophy, while males developed eccentric hypertrophy. These sex differences were abolished in ERbeta-/- mice. ERbeta deletion augmented the TAC-induced increase in cardiomyocyte diameter in both sexes. Gene expression profiling revealed that male WT hearts had a stronger induction of matrix-related genes and a stronger repression of mitochondrial genes than female hearts. ERbeta-/- mice exhibited a different transcriptome. Induction of pro-apoptotic genes after TAC occurred in ERbeta-/- mice of both sexes with a stronger expression in ERbeta-/- males. Histological analysis revealed, that cardiac fibrosis was more pronounced in male WT TAC than in female mice. This was abolished in ERbeta-/- mice. Apoptosis was significantly induced in both sexes of ERbeta-/- TAC mice, but it was most prominent in males. Conclusion: Female sex offers protection against ventricular chamber dilation in the TAC model. Both the female sex and ER attenuate the development of fibrosis and apoptosis; thus slowing the progression to heart failure. The influence of sex (male/female) and estrogen receptor beta expression (ERbeta knockout/wildtype) on cardiac hypertrophy (transverse aortic constriction/sham operated) was investigated. The left ventricular transcriptome of four individual mice for each combination of the three factors (sex, genotype, surgery) was detected with Affymetrix RAE 430 2.0 GeneChip arrays.

Dataset Information

Transcription profiling of human inflammatory cardiomyopathy vs controls (DCMi) suggests novel therapeutic targets.

Publications

Genomic expression profiling of human inflammatory cardiomyopathy (DCMi) suggests novel therapeutic targets.

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