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

Myocardial infarction results in compromised myocardial function with heart failure due to insufficient cardiomyocyte self-renewal. Unlike lower vertebrates, mammalian hearts only have a transient neonatal renewal capacity. Reactivating the primitive reparative ability in the fully mature heart requires an intimate knowledge of the molecular mechanisms promoting early heart repair. Here we identified a novel factor that can sufficiently promote heart muscle repair. By screening an established Hippo-deficient heart regeneration model for renewal promoting factors, we found that PITX2 protein expression in ventricles was induced after cardiomyocyte injury. Moreover, Pitx2-deficient neonatal hearts failed to repair after apex resection. Pitx2-gain-of-function in ventricular cardiomyocytes conferred reparative ability to the adult mouse heart after myocardial infarction. Integrated genomic analyses indicated that Pitx2 activated genes encoding electron transport chain components and reactive oxygen species scavengers. Pitx2 mutant myocardium had elevated reactive oxygen species levels while supplement of antioxidants suppressed the Pitx2-loss-of-function phenotype. Furthermore, PITX2 directly binds NFE2L2 and translocates from cytoplasm to nucleus upon oxidative stress.