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

• Published in: Nature cell biology Vol. 15; no. 11; pp. 1282 - 1293
• Main Authors: Dirkx, Ellen, Gladka, Monika M., Philippen, Leonne E., Armand, Anne-Sophie, Kinet, Virginie, Leptidis, Stefanos, el Azzouzi, Hamid, Salic, Kanita, Bourajjaj, Meriem, da Silva, Gustavo J. J., Olieslagers, Servé, van der Nagel, Roel, de Weger, Roel, Bitsch, Nicole, Kisters, Natasja, Seyen, Sandrine, Morikawa, Yuka, Chanoine, Christophe, Heymans, Stephane, Volders, Paul G. A., Thum, Thomas, Dimmeler, Stefanie, Cserjesi, Peter, Eschenhagen, Thomas, da Costa Martins, Paula A., De Windt, Leon J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2013; Nature Publishing Group
• Subjects: 631/136; 631/136/142; 631/136/1425; Animals; Base Sequence; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cancer Research; Cardiology; Cardiovascular diseases; Cell Biology; Cell cycle; Cellular signal transduction; Development and progression; Developmental Biology; Disease; Gene expression; Gene Expression Profiling; Gene Silencing; Genetic aspects; Heart failure; Heart Failure - metabolism; Humans; Life Sciences; Mammals; Mice; Mice, Knockout; MicroRNAs - genetics; MicroRNAs - metabolism; MicroRNAs - physiology; NFATC Transcription Factors - metabolism; NFATC Transcription Factors - physiology; Pathology; Properties; RNA Processing, Post-Transcriptional; Sequence Homology, Nucleic Acid; Stem Cells; Testing; Transcription factors; Transcription, Genetic; United States > US; Netherlands; Germany
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb2866

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. Reactivation of fetal gene programs has been linked to hypertrophy of postnatal cardiomyocytes and heart disease, but so far the transcription factors responsible for this effect have not been well defined. De Windt and colleagues have found that the fetal cardiac transcription factor Hand2 is re-expressed in response to stress signalling and induces cardiac hypertrophy.