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

Nature. 2016 Jun 2;534(7605):119-23. doi: 10.1038/nature17959. Epub 2016 May 25.

Abstract

Myocardial infarction results in compromised myocardial function and heart failure owing to insufficient cardiomyocyte self-renewal. Unlike many vertebrates, mammalian hearts have only a transient neonatal renewal capacity. 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 response, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Animals, Newborn
  • Antioxidants / metabolism*
  • Antioxidants / pharmacology
  • Cell Cycle Proteins
  • Disease Models, Animal
  • Electron Transport / drug effects
  • Electron Transport / genetics
  • Female
  • Free Radical Scavengers / metabolism
  • Heart Injuries / genetics
  • Heart Injuries / metabolism*
  • Heart Injuries / pathology
  • Heart Ventricles / drug effects
  • Heart Ventricles / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Male
  • Mice
  • Myocardial Infarction / genetics
  • Myocardial Infarction / metabolism*
  • Myocardial Infarction / pathology
  • Myocardium / metabolism
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • NF-E2-Related Factor 2 / metabolism
  • Phosphoproteins / metabolism
  • Protein-Serine-Threonine Kinases / deficiency
  • Reactive Oxygen Species / metabolism
  • Regeneration / drug effects
  • Regeneration / genetics
  • Regeneration / physiology*
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Wound Healing / drug effects
  • Wound Healing / genetics
  • Wound Healing / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Antioxidants
  • Cell Cycle Proteins
  • Free Radical Scavengers
  • Homeodomain Proteins
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Phosphoproteins
  • Reactive Oxygen Species
  • Transcription Factors
  • Yap protein, mouse
  • homeobox protein PITX2
  • Hippo protein, mouse
  • Protein-Serine-Threonine Kinases