Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of hearts from DTG-positive mice before and after the induction of the transgene Akt1 at different time points to investigate molecular mechanisms involved in the development of cardiac hypertrophy and heart failure

ABSTRACT: To investigate molecular mechanisms involved in the development of cardiac hypertrophy and heart failure, a tetracycline-regulated transgenic system to conditionally switch a constitutively-active form of the Akt1 protein kinase on or off in the adult heart was developed. Short-term activation (2 weeks) of Akt1 resulted in completely reversible hypertrophy with maintained contractility. In contrast, chronic Akt1 activation (6 weeks) induced extensive cardiac hypertrophy, severe contractile dysfunction, and massive interstitial fibrosis. The focus of this study was to create a transcript expression profile of the heart as it undergoes reversible Akt1-mediated hypertrophy and during the transition from compensated hypertrophy to heart failure. Heart tissue was analyzed before transgene induction, 2 weeks after transgene induction, 2 weeks of transgene induction followed by 2 days of repression, 6 weeks after transgene induction and 6 weeks of transgene induction followed by 2 weeks of repression. Acute over expression of Akt1 (2 weeks) leads to changes in the expression of 826 transcripts relative to non-induced hearts, whereas chronic induction (6 weeks) led to changes in the expression of 1611, of which 65% represented transcripts that were regulated during the pathological phase of heart growth. Another set of genes identified were uniquely regulated during heart regression but not growth, indicating that non-overlapping transcription programs participate in the processes of cardiac hypertrophy and atrophy. These data define the gene regulatory programs downstream of Akt that control heart size and contribute to the transition from compensatory hypertrophy to heart failure. Experiment Overall Design: Gene expression data from DTG-positive mouse hearts were examined before the induction of the transgene Akt1 (time point 1), 2 weeks after the induction of the transgene Akt1(time point 2), 2 weeks after the induction of the transgene Akt1 and 2 days after the repression of the transgene Akt1 (time point 3), 6 weeks after the induction of the transgene Akt1(time point 4) and 6 weeks after the induction of the transgene Akt1 and 2 weeks after the repression of the transgene Akt1 (time point 5). N = 3 to 4 sets of independent hybridizations from individual mice were performed for each time point.

ORGANISM(S): Mus musculus

SUBMITTER: Stephan Schiekofer

PROVIDER: E-GEOD-3383 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Microarray analysis of Akt1 activation in transgenic mouse hearts reveals transcript expression profiles associated with compensatory hypertrophy and failure.

Schiekofer Stephan S Shiojima Ichiro I Sato Kaori K Galasso Gennaro G Oshima Yuichi Y Walsh Kenneth K

Physiological genomics 20060801 2

To investigate molecular mechanisms involved in the development of cardiac hypertrophy and heart failure, we developed a tetracycline-regulated transgenic system to conditionally switch a constitutively active form of the Akt1 protein kinase on or off in the adult heart. Short-term activation (2 wk) of Akt1 resulted in completely reversible hypertrophy with maintained contractility. In contrast, chronic Akt1 activation (6 wk) induced extensive cardiac hypertrophy, severe contractile dysfunction, ...[more]

PMID: 16882883

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Project description:Three major MAP kinase signaling cascades, ERK, p38 and JNK, play significant roles in the development of cardiac hypertrophy and heart failure in response to external stress and neural/hormonal stimuli. In order to study the specific function of each MAP kinase branch in adult heart, we have generated three transgenic mouse models with cardiac specific and temporally regulated expression of activated mutants of Ras, MKK3 and MKK7, which are selective upstream activators for ERK, p38 and JNK, respectively. Gene expression profiles in transgenic adult hearts were determined using cDNA microarrays at both early (4-7 days) and late (2-4 weeks) time points following transgene induction. From this study, we revealed common changes in gene expression among the three models, particularly involving extracellular matrix remodeling. However, distinct expression patterns characteristic for each pathway were also identified in cell signaling, growth and physiology. In addition, genes with dynamic expression differences between early vs. late stages illustrated primary vs. secondary changes upon MAP kinase activation in adult hearts. These results provide an overview to both short term and long term effects of MAP kinase activation in heart and support some common as well as unique roles for each MAP kinase cascade in the development of heart failure. Experiment Overall Design:MHC-floxed-HRas-v12/MKK3bE/MKK7D transgenic mice were bred with MHC-Mer-Cre-Mer (MCM) mice (from Dr. J. Molkentin, Cincinnati Children's Hospital) to generate double transgenic animals harboring both floxed transgenes and Mer-Cre-Mer transgene. At 12 weeks of age the double transgenic mice and non-transgenic littermate controls were treated via i.p. injection of tamoxifen at a dosage of 20mg/kgBW once a day for 3 consecutive days as reported. The hearts were harvested at an early (4-7 days post first tamoxifen injection) and a late (2-4 weeks) time point. Left ventricles were dissected and rapidly frozen in liquid nitrogen and stored at -80C prior to protein and RNA analysis. Transcription profiling of

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 hearts from DTG-positive mice before and after the induction of the transgene Akt1 at different time points to investigate molecular mechanisms involved in the development of cardiac hypertrophy and heart failure

Publications

Microarray analysis of Akt1 activation in transgenic mouse hearts reveals transcript expression profiles associated with compensatory hypertrophy and failure.

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