Journal article
Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury
Nature (London), Vol.534(7605), pp.119-123
06/02/2016
DOI: 10.1038/nature17959
PMCID: PMC4999251
PMID: 27251288
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.
Details
- Title: Subtitle
- Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury
- Creators
- Ge Tao - Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USAPeter C Kahr - Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USAYuka Morikawa - Texas Heart Institute, Houston, Texas 77030, USAMin Zhang - Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USAMahdis Rahmani - Texas Heart Institute, Houston, Texas 77030, USATodd R Heallen - Texas Heart Institute, Houston, Texas 77030, USALele Li - Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USAZhao Sun - Department of Anatomy and Cell Biology and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, Iowa 52242, USAEric N Olson - Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USABrad A Amendt - Department of Anatomy and Cell Biology and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, Iowa 52242, USAJames F Martin - Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas 77030, USA
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.534(7605), pp.119-123
- DOI
- 10.1038/nature17959
- PMID
- 27251288
- PMCID
- PMC4999251
- NLM abbreviation
- Nature
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Publisher
- England
- Grant note
- R01 DE013941 / NIDCR NIH HHS DK-099653 / NIDDK NIH HHS R01 DE023177 / NIDCR NIH HHS DE 023177 / NIDCR NIH HHS 13POST17040027 / American Heart Association-American Stroke Association HL 118761 / NHLBI NIH HHS HL-093039 / NHLBI NIH HHS R01 HL127717 / NHLBI NIH HHS 1U54 HD083092 / NICHD NIH HHS U54 HD083092 / NICHD NIH HHS R01 HL118761 / NHLBI NIH HHS DE 13941 / NIDCR NIH HHS HL-077439 / NHLBI NIH HHS U01-HL-100401 / NHLBI NIH HHS U54 HG006348 / NHGRI NIH HHS R01 HL130804 / NHLBI NIH HHS HL-111665 / NHLBI NIH HHS
- Language
- English
- Date published
- 06/02/2016
- Academic Unit
- Orthodontics; Anatomy and Cell Biology; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9984025451302771
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