Abstract 12781: NF-κB Activity is Required for Heart Regeneration

Abstract

Objectives: In contrast to humans, zebrafish recover from cardiac injury through a robust regenerative response. Recent work suggests that the mammalian heart is able to undergo low-grade cardiomyocyte turnover in response to injury. However, this level of turnover in not sufficient for cardiac recovery. A better understanding of the mechanisms that contribute to zebrafish heart regeneration can instruct approaches to achieve therapeutic heart regeneration in humans. Methods and Results: We performed expression profiling of regenerating zebrafish hearts by RNA-Seq to identify factors that modify heart regeneration. Expression levels for members of the NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) pathway were significantly enriched in regenerating hearts. Using a transgenic reporter strain for NF-κB activity, we found NF-κB to be induced in cardiomyocytes following injury. Moreover, NF-κB activity overlaps with the activation of gata4 regulatory sequences that are induced in regenerating cardiomyocytes. We subsequently developed a transgenic zebrafish strain to conditionally inhibit NF-κB signaling in cardiomyocytes by expression of mutant IκBα. Zebrafish hearts with loss of NF-κB activity scar following injury, indicative of impaired regeneration. Conclusions: NF-κB mediates an early transcriptional response to injury in cardiomyocytes that is required for heart regeneration.