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

33 Citations (Scopus)

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
StatePublished - Mar 15 2016

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Cardiac Myocytes
Wounds and Injuries
Regeneration
GATA4 Transcription Factor
Heart Injuries
Dependovirus
Ventricular Function
Gene Regulatory Networks
Cardiomegaly
Hypertrophy
Fibrosis
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Developmental Biology
  • Molecular 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

GATA4 regulates Fgf16 to promote heart repair after injury. / Yu, Wei; Huang, Xiuzhen; Tian, Xueying; Zhang, Hui; He, Lingjuan; Wang, Yue; Nie, Yu; Hu, Shengshou; Lin, Zhiqiang; Zhou, Bin; Pu, William; Lui, Kathy O.; Zhou, Bin.

In: Development (Cambridge), Vol. 143, No. 6, 15.03.2016, p. 936-949.

Research output: Contribution to journalArticle

Yu, W, Huang, X, Tian, X, Zhang, H, He, L, Wang, Y, Nie, Y, Hu, S, Lin, Z, Zhou, B, Pu, W, Lui, KO & Zhou, B 2016, 'GATA4 regulates Fgf16 to promote heart repair after injury', Development (Cambridge), vol. 143, no. 6, pp. 936-949. https://doi.org/10.1242/dev.130971
Yu W, Huang X, Tian X, Zhang H, He L, Wang Y et al. GATA4 regulates Fgf16 to promote heart repair after injury. Development (Cambridge). 2016 Mar 15;143(6):936-949. https://doi.org/10.1242/dev.130971
Yu, Wei ; Huang, Xiuzhen ; Tian, Xueying ; Zhang, Hui ; He, Lingjuan ; Wang, Yue ; Nie, Yu ; Hu, Shengshou ; Lin, Zhiqiang ; Zhou, Bin ; Pu, William ; Lui, Kathy O. ; Zhou, Bin. / GATA4 regulates Fgf16 to promote heart repair after injury. In: Development (Cambridge). 2016 ; Vol. 143, No. 6. pp. 936-949.
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