Disruption of spatiotemporal hypoxic signaling causes congenital heart disease in mice
Xuejun Yuan, … , Yonggang Zhou, Thomas Braun
Xuejun Yuan, … , Yonggang Zhou, Thomas Braun
Published April 24, 2017
Citation Information: J Clin Invest. 2017;127(6):2235-2248. https://doi.org/10.1172/JCI88725.
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Research Article Cardiology

Disruption of spatiotemporal hypoxic signaling causes congenital heart disease in mice

Abstract

Congenital heart disease (CHD) represents the most prevalent inborn anomaly. Only a minority of CHD cases are attributed to genetic causes, suggesting a major role of environmental factors. Nonphysiological hypoxia during early pregnancy induces CHD, but the underlying reasons are unknown. Here, we have demonstrated that cells in the mouse heart tube are hypoxic, while cardiac progenitor cells (CPCs) expressing islet 1 (ISL1) in the secondary heart field (SHF) are normoxic. In ISL1+ CPCs, induction of hypoxic responses caused CHD by repressing Isl1 and activating NK2 homeobox 5 (Nkx2.5), resulting in decreased cell proliferation and enhanced cardiomyocyte specification. We found that HIF1α formed a complex with the Notch effector hes family bHLH transcription factor 1 (HES1) and the protein deacetylase sirtuin 1 (SIRT1) at the Isl1 gene. This complex repressed Isl1 in the hypoxic heart tube or following induction of ectopic hypoxic responses. Subsequently, reduced Isl1 expression abrogated ISL1-dependent recruitment of histone deacetylases HDAC1/5, inhibiting Nkx2.5 expression. Inactivation of Sirt1 in ISL1+ CPCs blocked Isl1 suppression via the HIF1α/HES1/SIRT1 complex and prevented CHDs induced by pathological hypoxia. Our results indicate that spatial differences in oxygenation of the developing heart serve as signals to control CPC expansion and cardiac morphogenesis. We propose that physiological hypoxia coordinates homeostasis of CPCs, providing mechanistic explanations for some nongenetic causes of CHD.

Authors

Xuejun Yuan, Hui Qi, Xiang Li, Fan Wu, Jian Fang, Eva Bober, Gergana Dobreva, Yonggang Zhou, Thomas Braun

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Figure 7

Schematic model of the regulation of ISL1+ CPC behavior by hypoxia, transcription factors, and epigenetic modifiers during early heart development.

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Schematic model of the regulation of ISL1+ CPC behavior by hypoxia, tran...
ISL1+ CPCs maintain high Isl1 expression directed by transcription activators such as β-catenin/LEF, FOXO1, and GATA4 in response to inductive signals, but low Nkx2.5 expression levels in the cardiac mesoderm, where O2 concentrations are relatively high, favoring self-renewal and expansion. ISL1 recruits HDACs to the Nkx2.5 promoter in CPCs to repress Nkx2.5 expression and prevent precocious myocyte specification. Migration of ISL1+ cells into the growing physiologically hypoxic (O2 ≤2%) heart tube results in HIF1α-SIRT1-HES1–dependent silencing of Isl1 expression and HIF1α-p300–dependent stimulation of Nkx2.5 expression, promoting cardiomyocyte specification. In the absence of SIRT1, repression of Isl1 transcription is relieved, resulting in increased Isl1 levels and enhanced proliferation of CPCs. As a consequence, ISL1-mediated Nkx2.5 repression is augmented and the transition of CPCs from an ISL1+NKX2.5– to an ISL1–NKX2.5+ state is hindered, compromising cardiomyocyte specification. TF, transcription factors.