title: Nfat and miR-25 cooperate to reactivate the transcription factor Hand2 in heart failure.
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.
authors.affiliation: 1] Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, 6229 ER Maastricht, The Netherlands [2].
authors.forename: Ellen
authors.initials: E
authors.lastname: Dirkx
authors.forename: Monika M
authors.initials: MM
authors.lastname: Gladka
authors.forename: Leonne E
authors.initials: LE
authors.lastname: Philippen
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Armand
authors.forename: Virginie
authors.initials: V
authors.lastname: Kinet
authors.forename: Stefanos
authors.initials: S
authors.lastname: Leptidis
authors.forename: Hamid
authors.initials: H
authors.lastname: El Azzouzi
authors.forename: Kanita
authors.initials: K
authors.lastname: Salic
authors.forename: Meriem
authors.initials: M
authors.lastname: Bourajjaj
authors.forename: Gustavo J J
authors.initials: GJ
authors.lastname: da Silva
authors.forename: Servé
authors.initials: S
authors.lastname: Olieslagers
authors.forename: Roel
authors.initials: R
authors.lastname: van der Nagel
authors.forename: Roel
authors.initials: R
authors.lastname: de Weger
authors.forename: Nicole
authors.initials: N
authors.lastname: Bitsch
authors.forename: Natasja
authors.initials: N
authors.lastname: Kisters
authors.forename: Sandrine
authors.initials: S
authors.lastname: Seyen
authors.forename: Yuka
authors.initials: Y
authors.lastname: Morikawa
authors.forename: Christophe
authors.initials: C
authors.lastname: Chanoine
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
authors.forename: Paul G A
authors.initials: PG
authors.lastname: Volders
authors.forename: Thomas
authors.initials: T
authors.lastname: Thum
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
authors.forename: Peter
authors.initials: P
authors.lastname: Cserjesi
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.forename: Paula A
authors.initials: PA
authors.lastname: da Costa Martins
authors.forename: Leon J
authors.initials: LJ
authors.lastname: De Windt
mesh_terms: D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050778:NFATC Transcription Factors / Q000378:metabolism / Q000502:physiology*; D012323:RNA Processing, Post-Transcriptional; D012689:Sequence Homology, Nucleic Acid; D014158:Transcription, Genetic
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D035683:MicroRNAs; D050778:NFATC Transcription Factors; C498766:Hand2 protein, mouse; C558895:MIRN25 microRNA, mouse