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JCI Insight. 2017 Sep 7;2(17). pii: 94904. doi: 10.1172/jci.insight.94904. eCollection 2017 Sep 7.

Wnt11 regulates cardiac chamber development and disease during perinatal maturation.

Author information

1
The Children's Discovery and Innovation Institute (CDI), Department of Pediatrics.
2
Cardiovascular Research Laboratory.
3
Department of Neurology.
4
Bioinformatics Interdepartmental Program.
5
Department of Cardiothoracic Surgery.
6
Department of Anesthesiology, and.
7
Department of Anesthesiology, Physiology and Medicine, University of California, Los Angeles, California, USA.

Abstract

Ventricular chamber growth and development during perinatal circulatory transition is critical for functional adaptation of the heart. However, the chamber-specific programs of neonatal heart growth are poorly understood. We used integrated systems genomic and functional biology analyses of the perinatal chamber specific transcriptome and we identified Wnt11 as a prominent regulator of chamber-specific proliferation. Importantly, downregulation of Wnt11 expression was associated with cyanotic congenital heart defect (CHD) phenotypes and correlated with O2 saturation levels in hypoxemic infants with Tetralogy of Fallot (TOF). Perinatal hypoxia treatment in mice suppressed Wnt11 expression and induced myocyte proliferation more robustly in the right ventricle, modulating Rb1 protein activity. Wnt11 inactivation was sufficient to induce myocyte proliferation in perinatal mouse hearts and reduced Rb1 protein and phosphorylation in neonatal cardiomyocytes. Finally, downregulated Wnt11 in hypoxemic TOF infantile hearts was associated with Rb1 suppression and induction of proliferation markers. This study revealed a previously uncharacterized function of Wnt11-mediated signaling as an important player in programming the chamber-specific growth of the neonatal heart. This function influences the chamber-specific development and pathogenesis in response to hypoxia and cyanotic CHDs. Defining the underlying regulatory mechanism may yield chamber-specific therapies for infants born with CHDs.

KEYWORDS:

Cardiology; Cardiovascular disease; Cell cycle; Genetics; Molecular biology

PMID:
28878122
PMCID:
PMC5621892
DOI:
10.1172/jci.insight.94904
[Indexed for MEDLINE]
Free PMC Article

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