ArticleThe Journal of clinical investigation2017
Disruption of spatiotemporal hypoxic signaling causes congenital heart disease in mice.
Article in The Journal of clinical investigation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
27 citing papers in PubMed, 43 citations in OpenAlex.
- Review
- Recurrent Constellations of Embryonic Malformations (RCEM): Teratogenicity Linked to Transient Hypoxia and Hormone Pregnancy Tests Agrees With RCEM and Suggest a Reactive Oxygen Species Pathogenesis.Birth defects research · 2026Review
- Environmentally dependent developmental induction as a potential driver of heart evolution.The Journal of experimental biology · 2026Review
- Hypoxia Alters Corneal Circadian Rhythms and Disrupts Epithelial, Neural, and Immune Balance.Investigative ophthalmology & visual science · 2025Article
- Endothelial RNF20 suppresses endothelial-to-mesenchymal transition and safeguards physiological angiocrine signaling to prevent congenital heart disease.Nature communications · 2025Article
- Neuraminidase 1 Exacerbated Glycolytic Dysregulation and Cardiotoxicity by Destabilizing SIRT1 through Interactions with NRF2 and HIF1α.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- SMYD1 modulates the proliferation of multipotent cardiac progenitor cells derived from human pluripotent stem cells during myocardial differentiation through GSK3β/β-catenin&ERK signaling.Stem cell research & therapy · 2024Article
- The second heart field: the first 20 years.Mammalian genome : official journal of the International Mammalian Genome Society · 2023Review
- Epigenetics in Congenital Heart Disease.Journal of the American Heart Association · 2022Review
- CCN1 gene polymorphisms associated with congenital heart disease susceptibility in Northwest Chinese population from different high-altitude areas.Environmental science and pollution research international · 2021Article
- Maternal iron deficiency perturbs embryonic cardiovascular development in mice.Nature communications · 2021Article
- Gestational intermittent hyperoxia rescues murine genetic congenital heart disease in part.Scientific reports · 2021Article
- A Non-coding HES1 Variant Predisposes Children to Congenital Heart Disease in Chinese Population.Frontiers in cell and developmental biology · 2021Article
- Cardiac Anomalies in Liveborn and Stillborn Monochorionic Twins.Clinical medicine & research · 2020Article
- Article
- Environmental Risk Factors for Congenital Heart Disease.Cold Spring Harbor perspectives in biology · 2020Review
- Re-enforcing hypoxia-induced polyploid cardiomyocytes enter cytokinesis through activation of β-catenin.Scientific reports · 2019Article
- HIF-1α is required for development of the sympathetic nervous system.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Pioneering function of Isl1 in the epigenetic control of cardiomyocyte cell fate.Cell research · 2019Article
- microRNAs and cardiac stem cells in heart development and disease.Drug discovery today · 2019Review
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.