학술논문
Nfat and miR-25 cooperate to reactivate the transcription factor Hand2 in heart failure.
Document Type
Article
Author
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.
Source
Subject
*TRANSCRIPTION factors
*MYOCARDIUM
*HEART failure
*PROTEINS
*CARDIAC arrest
*MUSCLE cells
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Language
ISSN
1465-7392
Abstract
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. [ABSTRACT FROM AUTHOR]