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

Abstract

The transcription factor Pitx2 is upregulated in injured neonatal and Hippo-deficient mouse hearts, where it interacts with the Hippo effector protein Yap to activate reactive oxygen species scavengers, thus preventing the heart from oxidative damage. The mammalian heart has only a transient neonatal renewal capacity, so there is therapeutic potential in the possibility of reactivating this capacity in the mature heart. Here James Martin and colleagues identify a mechanism that promotes heart repair both in neonatal mice and in the Hippo-deficient heart regeneration mouse model through upregulation of the Pitx2 transcription factor. Pitx2 interacts with the Hippo pathway effector Yap to activate reactive oxygen species scavengers, thus preventing oxidative damage of the heart. 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.