Editors' ChoicePhysiology

Repairing the Heart

Sci. Signal.  20 Aug 2013:
Vol. 6, Issue 289, pp. ec192
DOI: 10.1126/scisignal.2004642

Whereas zebrafish can regenerate cardiac muscle after injury, in humans and mice heart damage causes fibrotic remodeling. By detecting ribosome-associated mRNAs using translating ribosome affinity purification (TRAP), Fang et al. identified proteins that promote heart muscle regeneration in adult zebrafish. In isolated ventricles, the active translation of 138 mRNAs was increased 1 day after resection injury. Of these, the translation of mRNAs for proteins in the Jak1 (Janus kinase 1)–Stat3 (signal transducer and activator of transcription) pathway were substantially increased in cardiomyocytes, including jak1, stat3, il6st (interleukin 6 signal transducer), and socs3b (suppressor of cytokine signaling 3b). At the protein level, the abundance of both Stat3 and phosphorylated Stat3 was also increased after injury. Translation of il6st and socs3b was increased throughout the heart tissue 1 day after resection, then became localized only at the injury site during regeneration. Among cytokine-encoding transcripts, only il11a and lif (leukemia inhibitory factor) mRNAs were more actively translated in injured hearts, but this activity was restricted to endocardial cells, initially in the endocardium throughout the heart but later restricted to the injury site. Transgenic fish expressing an inducible dominant-negative Stat3 (dnStat3) before ventricular resection had substantially decreased cardiomyocyte proliferation and cardiac muscularization and increased scarring. However, cardiomyocyte proliferation and growth in uninjured developing transgenic fish were normal, suggesting that Stat3 signaling may be critical for ventricle muscle regeneration but dispensable for normal development. Compared with wild-type fish, fish expressing dnStat3 had markedly reduced translation of rln3a, which encodes the hormone Relaxin 3a. Stat3 bound to multiple sites in the promoter of the rln3a gene, and injection with recombinant human RLN3A rescued initial cardiomyocyte proliferation after injury in dnStat3 fish, indicating that Rln3a contributes to the regenerative process in fish. The findings suggest that Jak1-Stat3 signaling mediates cardiac regeneration in fish and that human JAK1-STAT3 pathway proteins may also have this potential.

Y. Fang, V. Gupta, R. Karra, J. E. Holdway, K. Kikuchi, K. D. Poss, Translational profiling of cardiomyocytes identifies an early Jak1/Stat3 injury response required for zebrafish heart regeneration. Proc. Natl. Acad. Sci. U.S.A. 110, 13416–13421 (2013). [Abstract] [Full Text]

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