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

Ellen Dirkx, Monika M. Gladka, Leonne E. Philippen, Anne-Sophie Armand, Virginie Kinet, Stefanos Leptidis, Hamid el Azzouzi, Kanita Salic, Meriem Bourajjaj, Gustavo J. J. da Silva, Serve Olieslagers, Roel van der Nagel, Roel de Weger, Nicole Bitsch, Natasja Kisters, Sandrine Seyen, Yuka Morikawa, Christophe Chanoine, Stephane Heymans, Paul G. A. VoldersThomas Thum, Stefanie Dimmeler, Peter Cserjesi, Thomas Eschenhagen, Paula A. da Costa Martins*, Leon J. De Windt

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.
Original languageEnglish
Pages (from-to)1282-1293
JournalNature Cell Biology
Issue number11
Publication statusPublished - Nov 2013

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