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Citations to this article

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 Article has an altmetric score of 3

Disruption of spatiotemporal hypoxic signaling causes congenital heart disease in mice

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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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Total citations by year

Year: 2024 2022 2021 2020 2019 2018 Total
Citations: 1 2 3 2 4 7 19
Citation information
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Citations to this article (19)

Title and authors Publication Year
SMYD1 modulates the proliferation of multipotent cardiac progenitor cells derived from human pluripotent stem cells during myocardial differentiation through GSK3β/β-catenin&ERK signaling.
Chang Y, Bai R, Zhang Y, Lu WJ, Ma S, Zhu M, Lan F, Jiang Y
Stem cell research & therapy 2024
Epigenetics in Congenital Heart Disease
G Wang, B Wang, P Yang
Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease 2022
The second heart field: the first 20 years.
Zhao K, Yang Z
Mammalian genome : official journal of the International Mammalian Genome Society 2022
Gestational intermittent hyperoxia rescues murine genetic congenital heart disease in part
CF Doll, NJ Pereira, MS Hashimi, TJ Grindrod, FF Alkassis, LX Cai, U Milovanovic, AI Sandino, H Kasahara
Scientific Reports 2021
Maternal iron deficiency perturbs embryonic cardiovascular development in mice
JI Kalisch-Smith, N Ved, D Szumska, J Munro, M Troup, SE Harris, H Rodriguez-Caro, A Jacquemot, JJ Miller, EM Stuart, M Wolna, E Hardman, F Prin, E Lana-Elola, R Aoidi, EM Fisher, VL Tybulewicz, TJ Mohun, S Lakhal-Littleton, SD Val, E Giannoulatou, DB Sparrow
Nature Communications 2021
A Non-coding HES1 Variant Predisposes Children to Congenital Heart Disease in Chinese Population
Y Song, W Chen, Z Huang, G Tian, M Li, Z Zhao, Z Feng, F Wu, M Qian, X Ma, W Sheng, G Huang
Frontiers in Cell and Developmental Biology 2021
Fetal Hypoxia Impacts on Proliferation and Differentiation of Sca-1+ Cardiac Progenitor Cells and Maturation of Cardiomyocytes: A Role of MicroRNA-210
X Meng, P Zhang, L Zhang
Genes & development 2020
Cardiac Anomalies in Liveborn and Stillborn Monochorionic Twins
E McPherson, C Korlesky, S Hebbring
Clinical medicine & research 2020
HIF-1α is required for development of the sympathetic nervous system
R Bohuslavova, R Cerychova, F Papousek, V Olejnickova, M Bartos, A Görlach, F Kolar, D Sedmera, GL Semenza, G Pavlinkova
Proceedings of the National Academy of Sciences 2019
Pioneering function of Isl1 in the epigenetic control of cardiomyocyte cell fate
R Gao, X Liang, S Cheedipudi, J Cordero, X Jiang, Q Zhang, L Caputo, S Günther, C Kuenne, Y Ren, S Bhattacharya, X Yuan, G Barreto, Y Chen, T Braun, SM Evans, Y Sun, G Dobreva
Cell Research 2019
Re-enforcing hypoxia-induced polyploid cardiomyocytes enter cytokinesis through activation of β-catenin
YH Jiang, Y Zhu, S Chen, HL Wang, Y Zhou, FQ Tang, Z Jian, YB Xiao
Scientific Reports 2019
Environmental Risk Factors for Congenital Heart Disease
J Kalisch-Smith, N Ved, D Sparrow
Cold Spring Harbor perspectives in biology 2019
Gestational Hypoxia and Developmental Plasticity
CA Ducsay, R Goyal, WJ Pearce, S Wilson, XQ Hu, L Zhang
Physiological reviews 2018
Sirtuins in the Cardiovascular System: Potential Targets in Pediatric Cardiology
A Ianni, X Yuan, E Bober, T Braun
Pediatric Cardiology 2018
microRNAs and cardiac stem cells in heart development and disease
B Li, X Meng, L Zhang
Drug Discovery Today 2018
Sirt7 inhibits Sirt1-mediated activation of Suv39h1
P Kumari, D Popescu, S Yue, E Bober, A Ianni, T Braun
Cell cycle (Georgetown, Tex.) 2018
Recent Advances in Placenta–Heart Interactions
CL Maslen
Frontiers in physiology 2018
Mechanism Sharing Between Genetic and Gestational Hypoxia-Induced Cardiac Anomalies
O Moumne, R Chowdhurry, C Doll, N Pereira, M Hashimi, T Grindrod, JJ Dollar, A Riva, H Kasahara
Frontiers in Cardiovascular Medicine 2018
Single cell RNA-seq and ATAC-seq analysis of cardiac progenitor cell transition states and lineage settlement
G Jia, J Preussner, , S Guenther, X Yuan, M Yekelchyk, C Kuenne, M Looso, Y Zhou, S Teichmann, T Braun
Nature Communications 2018

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