title: Myocardial NF-κB activation is essential for zebrafish heart regeneration.
abstract: Heart regeneration offers a novel therapeutic strategy for heart failure. Unlike mammals, lower vertebrates such as zebrafish mount a strong regenerative response following cardiac injury. Heart regeneration in zebrafish occurs by cardiomyocyte proliferation and reactivation of a cardiac developmental program, as evidenced by induction of gata4 regulatory sequences in regenerating cardiomyocytes. Although many of the cellular determinants of heart regeneration have been elucidated, how injury triggers a regenerative program through dedifferentiation and epicardial activation is a critical outstanding question. Here, we show that NF-κB signaling is induced in cardiomyocytes following injury. Myocardial inhibition of NF-κB activity blocks heart regeneration with pleiotropic effects, decreasing both cardiomyocyte proliferation and epicardial responses. Activation of gata4 regulatory sequences is also prevented by NF-κB signaling antagonism, suggesting an underlying defect in cardiomyocyte dedifferentiation. Our results implicate NF-κB signaling as a key node between cardiac injury and tissue regeneration.
authors.affiliation: Department of Medicine, Duke University School of Medicine, Durham, NC 27710;
authors.forename: Ravi
authors.initials: R
authors.lastname: Karra
authors.affiliation: Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Knecht
authors.affiliation: Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710.
authors.forename: Kazu
authors.initials: K
authors.lastname: Kikuchi
authors.affiliation: Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710 kenneth.poss@duke.edu.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Poss
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D005455:Fluorescent Antibody Technique; D006321:Heart / Q000502:physiology*; D006652:Histological Techniques; D007091:Image Processing, Computer-Assisted; D017403:In Situ Hybridization; D018613:Microscopy, Confocal; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012038:Regeneration / Q000502:physiology*; D015027:Zebrafish / Q000502:physiology*
chemical_list: D017931:DNA Primers; D016328:NF-kappa B
keywords: NF-κB; cardiomyocyte; epicardium; heart regeneration; zebrafish