title: Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury.
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.
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Ge
authors.initials: G
authors.lastname: Tao
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Kahr
authors.affiliation: Texas Heart Institute, Houston, Texas 77030, USA.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Morikawa
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Texas Heart Institute, Houston, Texas 77030, USA.
authors.forename: Mahdis
authors.initials: M
authors.lastname: Rahmani
authors.affiliation: Texas Heart Institute, Houston, Texas 77030, USA.
authors.forename: Todd R
authors.initials: TR
authors.lastname: Heallen
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Lele
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Anatomy and Cell Biology and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA.
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.affiliation: Department of Anatomy and Cell Biology and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Brad A
authors.initials: BA
authors.lastname: Amendt
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Texas Heart Institute, Houston, Texas 77030, USA.|Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Martin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology; D018797:Cell Cycle Proteins; D004195:Disease Models, Animal; D004579:Electron Transport / Q000187:drug effects / Q000235:genetics; D005260:Female; D016166:Free Radical Scavengers / Q000378:metabolism; D006335:Heart Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D000090683:Hippo Signaling Pathway; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency; D017382:Reactive Oxygen Species / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000091102:YAP-Signaling Proteins; D000097577:Homeobox Protein PITX2
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D018797:Cell Cycle Proteins; D016166:Free Radical Scavengers; D018398:Homeodomain Proteins; D051267:NF-E2-Related Factor 2; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D000097577:Homeobox Protein PITX2; C495636:Nfe2l2 protein, mouse; C486223:Yap1 protein, mouse