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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Gene Expression Omnibus
The sequencing data set has been deposited in the NCBI Gene Expression Omnibus (GEO) under accession number GSE70413.
The project was supported in part by IDDRC grant number 1U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development. This project was supported by the Mouse Phenotyping Core at Baylor College of Medicine with funding from the National Institutes of Health (NIH) (U54 HG006348). The project was also supported by grants from the NIH (DE 023177 and HL 118761 to J.F.M.; DE 13941 to B.A.A.; HL-077439, HL-111665, HL-093039, DK-099653 and U01-HL-100401 to E.N.O.), and the Vivian L. Smith Foundation (J.F.M.). J.F.M. was supported by Transatlantic Network of Excellence Award LeDucq Foundation Transatlantic Networks of Excellence in Cardiovascular Research 14CVD01: “Defining the genomic topology of atrial fibrillation”. E.N.O. was supported by Fondation Leducq Networks of Excellence, Cancer Prevention and Research Institute of Texas and the Robert A. Welch Foundation (grant 1-0025). G.T. was supported by American Heart Association (AHA) (13POST17040027). P.C.K was supported by German Research Foundation (DFG) (KA4018/1-1).
Extended data figures
This file contains the uncropped scans with size marker indications.
About this article
Current Cardiology Reports (2018)