Wnt11 regulates cardiac chamber development and disease during perinatal maturation
Marlin Touma, Xuedong Kang, Fuying Gao, Yan Zhao, Ashley A. Cass, Reshma Biniwale, Xinshu Xiao, Mansuoreh Eghbali, Giovanni Coppola, Brian Reemtsen, Yibin Wang
Marlin Touma, Xuedong Kang, Fuying Gao, Yan Zhao, Ashley A. Cass, Reshma Biniwale, Xinshu Xiao, Mansuoreh Eghbali, Giovanni Coppola, Brian Reemtsen, Yibin Wang
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Research Article Cardiology Genetics

Wnt11 regulates cardiac chamber development and disease during perinatal maturation

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.

Authors

Marlin Touma, Xuedong Kang, Fuying Gao, Yan Zhao, Ashley A. Cass, Reshma Biniwale, Xinshu Xiao, Mansuoreh Eghbali, Giovanni Coppola, Brian Reemtsen, Yibin Wang

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Figure 4

Wnt11 may play important roles in human congenital heart defects (CHDs).

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Wnt11 may play important roles in human congenital heart defects (CHDs)....
(A) Expression array of Wnt molecules and cell cycle genes in cyanotic (hypoxemic) versus noncyanotic (nonhypoxemic) human CHD phenotypes. Graphs: Representative illustrations of CHD cases. VSD, ventricular septal defect (n = 3); TOF, Tetralogy of Fallot (n = 3); DORV, double-outlet right ventricle (n = 2). Red, upregulated; blue, downregulated. (B) Correlation plot demonstrating Wnt11 association with preoperative O2 saturation levels in heart tissue specimens from TOF patients with different baseline O2 saturation levels (n = 6). r, Pearson’s correlation coefficient; P, correlation P value. Wnt11 expression data were obtained from M. Touma’s unpublished observations (RNA-Seq data set) of human heart tissue of patients with TOF. RPKM, reads per kilobase of transcript per million mapped reads. (C) Correlation plots revealed no association between the expression of several WNT genes (WNT5A, WNT9B, WNT2, WNT16, and β-catenin) and preoperative O2 saturation levels in a new set of TOF patients (n = 6) with different baseline O2 saturation levels. The expression data (RPKM) were obtained from RNA-Seq of heart tissue of patients with TOF (M. Touma’s unpublished observations [RNA-Seq data set]).