Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Gene profiling of Hand2 target genes and transcriptional regulation of Hand2 expression in the postnatal myocardium

ABSTRACT: In humans, cardiac hypertrophy is the principal risk factor for the development of overt heart failure and sudden cardiac death from lethal arrhythmias. Although aberrant reactivation of fetal² gene programs is intricately linked to maladaptive hypertrophy of postnatal cardiomyocytes, loss of cardiac function and heart failure, the transcription factors driving these gene programs remain ill defined. We report that the basic helix-loop-helix (bHLH) transcription factor dHAND/Hand2 is re-expressed in the mammalian postnatal myocardium in response to stress signaling. Interestingly, mutant mice overexpressing Hand2 in otherwise healthy ventricular myocytes developed a phenotype of pathological hypertrophy. In contrast, conditional gene-targeted Hand2 mice demonstrated a marked resistance to pressure overload-induced hypertrophy, fibrosis, ventricular dysfunction and induction of a fetal gene program. These data suggest a critical role for the Hand2 transcription factor during hypertrophic remodeling and heart failure. To gain more mechanistically insight in the processes underlying heart failure, we here identified Hand2 target genes by microarray gene expression profiling. RNA samples were collected 4 weeks after sham or TAC surgery (to induce pressure overload) of both tamoxifen-treated Hand2f/f (WT) and MCM-Hand2f/f (KO) mice.

ORGANISM(S): Mus musculus

SUBMITTER: Leon de Windt

PROVIDER: E-MTAB-1821 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Nfat and miR-25 cooperate to reactivate the transcription factor Hand2 in heart failure.

Dirkx Ellen E Gladka Monika M MM Philippen Leonne E LE Armand Anne-Sophie AS Kinet Virginie V Leptidis Stefanos S El Azzouzi Hamid H Salic Kanita K Bourajjaj Meriem M da Silva Gustavo J J GJ Olieslagers Servé S van der Nagel Roel R de Weger Roel R Bitsch Nicole N Kisters Natasja N Seyen Sandrine S Morikawa Yuka Y Chanoine Christophe C Heymans Stephane S Volders Paul G A PG Thum Thomas T Dimmeler Stefanie S Cserjesi Peter P Eschenhagen Thomas T da Costa Martins Paula A PA De Windt Leon J LJ

Nature cell biology 20131027 11

Although aberrant reactivation of embryonic gene programs is intricately linked to pathological heart disease, the transcription factors driving these gene programs remain ill-defined. Here we report that increased calcineurin/Nfat signalling and decreased miR-25 expression integrate to re-express the basic helix-loop-helix (bHLH) transcription factor dHAND (also known as Hand2) in the diseased human and mouse myocardium. In line, mutant mice overexpressing Hand2 in otherwise healthy heart muscl ...[more]

PMID: 24161931

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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

Dataset Information

Gene profiling of Hand2 target genes and transcriptional regulation of Hand2 expression in the postnatal myocardium

Publications

Nfat and miR-25 cooperate to reactivate the transcription factor Hand2 in heart failure.

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