Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 43, Pages 13255-13260Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1511209112
Keywords
heart regeneration; cardiomyocyte; zebrafish; NF-kappa B; epicardium
Categories
Funding
- NIH [K08-HL116485, R01-HL081674]
- Howard Hughes Medical Institute
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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-kappa B signaling is induced in cardiomyocytes following injury. Myocardial inhibition of NF-kappa B activity blocks heart regeneration with pleiotropic effects, decreasing both cardiomyocyte proliferation and epicardial responses. Activation of gata4 regulatory sequences is also prevented by NF-kappa B signaling antagonism, suggesting an underlying defect in cardiomyocyte dedifferentiation. Our results implicate NF-kappa B signaling as a key node between cardiac injury and tissue regeneration.
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