GATA4 regulates Fgf16 to promote heart repair after injury

Wei Yu, Xiuzhen Huang, Xueying Tian, Hui Zhang, Lingjuan He, Yue Wang, Yu Nie, Shengshou Hu, Zhiqiang Lin, Bin Zhou, William Pu, Kathy O. Lui, Bin Zhou

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Although the mammalian heart can regenerate during the neonatal stage, this endogenous regenerative capacity is lost with age. Importantly, replication of cardiomyocytes has been found to be the key mechanism responsible for neonatal cardiac regeneration. Unraveling the transcriptional regulatory network for inducing cardiomyocyte replication will, therefore, be crucial for the development of novel therapies to drive cardiac repair after injury. Here, we investigated whether the key cardiac transcription factor GATA4 is required for neonatal mouse heart regeneration. Using the neonatal mouse heart cryoinjury and apical resection models with an inducible loss of GATA4 specifically in cardiomyocytes, we found severely depressed ventricular function in the Gata4-ablated mice (mutant) after injury. This was accompanied by reduced cardiomyocyte replication. In addition, the mutant hearts displayed impaired coronary angiogenesis and increased hypertrophy and fibrosis after injury. Mechanistically, we found that the paracrine factor FGF16 was significantly reduced in the mutant hearts after injury compared with littermate controls andwas directly regulated byGATA4. Cardiac-specific overexpression of FGF16 via adeno-associated virus subtype 9 (AAV9) in the mutant hearts partially rescued the cryoinjuryinduced cardiac hypertrophy, promoted cardiomyocyte replication and improved heart function after injury. Altogether, our data demonstrate that GATA4 is required for neonatal heart regeneration through regulation of Fgf16, suggesting that paracrine factors could be of potential use in promoting myocardial repair.

Original languageEnglish (US)
Pages (from-to)936-949
Number of pages14
JournalDevelopment (Cambridge)
Volume143
Issue number6
DOIs
Publication statusPublished - Mar 15 2016

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Keywords

  • Cardiomyocyte proliferation
  • FGF16
  • GATA4
  • Heart regeneration
  • Heart repair

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

Cite this

Yu, W., Huang, X., Tian, X., Zhang, H., He, L., Wang, Y., ... Zhou, B. (2016). GATA4 regulates Fgf16 to promote heart repair after injury. Development (Cambridge), 143(6), 936-949. https://doi.org/10.1242/dev.130971