Nfat and miR-25 cooperate to reactivate the transcription factor Hand2 in heart failure
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Nfat and miR-25 cooperate to reactivate the transcription factor Hand2 in heart failure. / 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.
in: NAT CELL BIOL, Jahrgang 15, Nr. 11, 01.11.2013, S. 1282-93.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Nfat and miR-25 cooperate to reactivate the transcription factor Hand2 in heart failure
AU - Dirkx, Ellen
AU - Gladka, Monika M
AU - Philippen, Leonne E
AU - Armand, Anne-Sophie
AU - Kinet, Virginie
AU - Leptidis, Stefanos
AU - El Azzouzi, Hamid
AU - Salic, Kanita
AU - Bourajjaj, Meriem
AU - da Silva, Gustavo J J
AU - Olieslagers, Servé
AU - van der Nagel, Roel
AU - de Weger, Roel
AU - Bitsch, Nicole
AU - Kisters, Natasja
AU - Seyen, Sandrine
AU - Morikawa, Yuka
AU - Chanoine, Christophe
AU - Heymans, Stephane
AU - Volders, Paul G A
AU - Thum, Thomas
AU - Dimmeler, Stefanie
AU - Cserjesi, Peter
AU - Eschenhagen, Thomas
AU - da Costa Martins, Paula A
AU - De Windt, Leon J
PY - 2013/11/1
Y1 - 2013/11/1
N2 - 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.
AB - 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.
KW - Animals
KW - Base Sequence
KW - Basic Helix-Loop-Helix Transcription Factors
KW - Gene Expression Profiling
KW - Gene Silencing
KW - Heart Failure
KW - Humans
KW - Mice
KW - Mice, Knockout
KW - MicroRNAs
KW - NFATC Transcription Factors
KW - RNA Processing, Post-Transcriptional
KW - Sequence Homology, Nucleic Acid
KW - Transcription, Genetic
U2 - 10.1038/ncb2866
DO - 10.1038/ncb2866
M3 - SCORING: Journal article
C2 - 24161931
VL - 15
SP - 1282
EP - 1293
JO - NAT CELL BIOL
JF - NAT CELL BIOL
SN - 1465-7392
IS - 11
ER -