Letter | Published:

Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury

Nature volume 534, pages 119123 (02 June 2016) | Download Citation

Abstract

Myocardial infarction results in compromised myocardial function and heart failure owing to insufficient cardiomyocyte self-renewal1. Unlike many vertebrates, mammalian hearts have only a transient neonatal renewal capacity2. Reactivating primitive reparative ability in the mature mammalian heart requires knowledge of the mechanisms that promote early heart repair. By testing an established Hippo-deficient heart regeneration mouse model for factors that promote renewal, here we show that the expression of Pitx2 is induced in injured, Hippo-deficient ventricles. Pitx2-deficient neonatal mouse hearts failed to repair after apex resection, whereas adult mouse cardiomyocytes with Pitx2 gain-of-function efficiently regenerated after myocardial infarction. Genomic analyses indicated that Pitx2 activated genes encoding electron transport chain components and reactive oxygen species scavengers. A subset of Pitx2 target genes was cooperatively regulated with the Hippo pathway effector Yap. Furthermore, Nrf2, a regulator of the antioxidant response3, directly regulated the expression and subcellular localization of Pitx2. Pitx2 mutant myocardium had increased levels of reactive oxygen species, while antioxidant supplementation suppressed the Pitx2 loss-of-function phenotype. These findings reveal a genetic pathway activated by tissue damage that is essential for cardiac repair.

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Gene Expression Omnibus

Data deposits

The sequencing data set has been deposited in the NCBI Gene Expression Omnibus (GEO) under accession number GSE70413.

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Acknowledgements

The project was supported in part by IDDRC grant number 1U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development. This project was supported by the Mouse Phenotyping Core at Baylor College of Medicine with funding from the National Institutes of Health (NIH) (U54 HG006348). The project was also supported by grants from the NIH (DE 023177 and HL 118761 to J.F.M.; DE 13941 to B.A.A.; HL-077439, HL-111665, HL-093039, DK-099653 and U01-HL-100401 to E.N.O.), and the Vivian L. Smith Foundation (J.F.M.). J.F.M. was supported by Transatlantic Network of Excellence Award LeDucq Foundation Transatlantic Networks of Excellence in Cardiovascular Research 14CVD01: “Defining the genomic topology of atrial fibrillation”. E.N.O. was supported by Fondation Leducq Networks of Excellence, Cancer Prevention and Research Institute of Texas and the Robert A. Welch Foundation (grant 1-0025). G.T. was supported by American Heart Association (AHA) (13POST17040027). P.C.K was supported by German Research Foundation (DFG) (KA4018/1-1).

Author information

Affiliations

  1. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA

    • Ge Tao
    • , Peter C. Kahr
    • , Min Zhang
    • , Lele Li
    •  & James F. Martin
  2. Texas Heart Institute, Houston, Texas 77030, USA

    • Yuka Morikawa
    • , Mahdis Rahmani
    • , Todd R. Heallen
    •  & James F. Martin
  3. Department of Anatomy and Cell Biology and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, Iowa 52242, USA

    • Zhao Sun
    •  & Brad A. Amendt
  4. Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA

    • Eric N. Olson
  5. Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA

    • James F. Martin
  6. Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas 77030, USA

    • James F. Martin

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Contributions

J.F.M. and G.T. conceived the project and designed the experiments. G.T., P.C.K., Y.M., M.R., T.R.H. and L.L. performed experiments and analysed data. Z.S. and B.A.A. provided reagents and performed experiments. E.N.O. provided the transgenic animal model. M.Z. and G.T. performed bioinformatics and statistical analyses. J.F.M. supervised the project and analysed data. G.T. and J.F.M. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to James F. Martin.

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DOI

https://doi.org/10.1038/nature17959

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