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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE70413 | GEO | 2016/05/19

SECONDARY ACCESSION(S): PRJNA288575

REPOSITORIES: GEO

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Project description:Loss of cardiomyocytes (CMs) following injury can lead to myocardial dysfunction, heart failure (HF) and ultimately death. The limited regenerative ability of the adult human heart after injury, however, poses a significant obstacle to restore cardiac function effectively. While mammalian hearts, including those of mice and humans, do have the potential to regenerate, this capacity is restricted to a narrow window during early stages of life. The molecular mechanisms governing the regenerative capacity of mammalian hearts remain incompletely understood. Exploring a comparative transcriptome analysis in regenerative neonatal vs. non-regenerative adult mouse CMs, we identified N-Cadherin, a member of Ca2+-dependent cell adhesion protein cadherin superfamily, as a potential novel regulator of CM proliferation/renewal. The primary objectives of this study were to elucidate the molecular mechanisms through which N-Cadherin regulates cardiomyocyte proliferation and regeneration, and to determine the therapeutic potential to promote CM renewal and restore cardiac function following injury by targeting N-Cadherin. Cardiac N-Cadherin expression exhibits a strong positive correlation with that of cell cycle- and proliferation-related genes. Its expression levels show an age-dependent reduction, with a 75% decrease of N-Cadherin in adult, compared to P1 neonatal, CMs. N-Cadherin expression is upregulated in the neonatal mouse heart in response to apical resection, especially in the peri-injury region, coinciding with increased CM mitotic activities in the neonatal heart. Knocking down N-Cadherin reduced, whereas overexpression of N-Cadherin increased, the proliferation activity of neonatal mouse CMs and human induced pluripotent stem cell-derived CMs. Mechanistically, increased N-Cadherin potentiates CM renewal through direct binding with and stabilization of a pro-mitotic transcription regulator β-Catenin, leading to increased CMs proliferative activity. Deletion of β-Catenin-binding domain on N-Cadherin abrogated its pro-regenerative activity. Importantly, targeted depletion of N-Cadherin in CMs resulted in incomplete cardiac repair/regeneration and excessive fibrotic scar formation in neonatal mouse hearts following injury. Cardiac-specific overexpression of N-Cadherin in adult mouse heart using adeno-associated viral vectors, by contrast, resulted in increased CM proliferation and protected against myocardial infarction-induced adverse remodeling and contractile dysfunction. Adherent junction protein N-cadherin is demonstrated to play a crucial role in maintaining CM renewal potential by post-translational stabilization of β-Catenin. Enhancing N-cadherin expression levels and downstream signaling activities in the heart, therefore, could be a powerful new approach to promote cardiac regeneration and restore myocardial function in adult human heart following injury.

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

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