Nfat and miR-25 cooperate to reactivate the transcription factor Hand2 in heart failure
| Autor: | Peter Cserjesi, Christophe Chanoine, Leonne E Philippen, Monika M Gladka, Natasja Kisters, Roel van der Nagel, Nicole Bitsch, Kanita Salic, Paula A. da Costa Martins, Servé Olieslagers, Stefanos Leptidis, Roel A. de Weger, Hamid el Azzouzi, Leon J. De Windt, Virginie Kinet, Ellen Dirkx, Paul G.A. Volders, Sandrine R.M. Seyen, Anne-Sophie Armand, Stephane Heymans, Meriem Bourajjaj, Yuka Morikawa, Thomas Thum, Stefanie Dimmeler, Gustavo J. J. Silva, Thomas Eschenhagen |
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| Přispěvatelé: | Genetica & Celbiologie, RS: CARIM School for Cardiovascular Diseases, Promovendi CD, Cardiologie, RS: CARIM - R2.07 - Gene regulation, Ondersteunend personeel CD |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Transcription
Genetic 030204 cardiovascular system & hematology Muscle hypertrophy Mice 03 medical and health sciences 0302 clinical medicine Sequence Homology Nucleic Acid Basic Helix-Loop-Helix Transcription Factors medicine Animals Humans Gene silencing Gene Silencing RNA Processing Post-Transcriptional Transcription factor 030304 developmental biology Heart Failure Mice Knockout 0303 health sciences Base Sequence NFATC Transcription Factors biology Gene Expression Profiling NFAT Cell Biology medicine.disease 3. Good health Cell biology Calcineurin Gene expression profiling MicroRNAs Heart failure embryonic structures Cancer research biology.protein HAND2 |
| Zdroj: | Nature Cell Biology, 15(11), 1282-1293. Nature Publishing Group Nature Cell Biology |
| ISSN: | 1465-7392 |
| Popis: | 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 muscle cells developed a phenotype of pathological hypertrophy. Conversely, conditional gene-targeted Hand2 mice demonstrated a marked resistance to pressure-overload-induced hypertrophy, fibrosis, ventricular dysfunction and induction of a fetal gene program. Furthermore, in vivo inhibition of miR-25 by a specific antagomir evoked spontaneous cardiac dysfunction and sensitized the murine myocardium to heart failure in a Hand2-dependent manner. Our results reveal that signalling cascades integrate with microRNAs to induce the expression of the bHLH transcription factor Hand2 in the postnatal mammalian myocardium with impact on embryonic gene programs in heart failure. |
| Databáze: | OpenAIRE |
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