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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 HIF1? 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 HIF1?/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.

SUBMITTER: Yuan X

PROVIDER: S-EPMC5451223 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Disruption of spatiotemporal hypoxic signaling causes congenital heart disease in mice.

Yuan Xuejun X Qi Hui H Li Xiang X Wu Fan F Fang Jian J Bober Eva E Dobreva Gergana G Zhou Yonggang Y Braun Thomas T

The Journal of clinical investigation 20170424 6

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, induct ...[more]

PMID: 28436940

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Project description:To validate a prospectively triggered spiral phase-contrast magnetic resonance (MR) sequence accelerated with sensitivity encoding (SENSE) in a population of children and adults with congenital heart disease.The local research ethics committee approved this study, and written consent was obtained from all patients or guardians. Stroke volumes were quantified in 40 patients (mean age ± standard deviation: 21.4 years ± 13.8, age range: 3.0-61.3 years; 22 male patients aged 3.0-38.0 years [mean age, 17.2 years ± 10.5], 18 female patients aged 4.7-61.3 years [mean age, 26.6 years ± 15.9]) with congenital heart disease in the aorta (n = 40), main pulmonary artery (n = 38), right pulmonary artery (n = 22), and left pulmonary artery (n = 24). Stroke volumes were obtained with (a) breath-hold spiral phase-contrast MR imaging with SENSE, (b) conventional breath-hold cartesian phase-contrast MR imaging, and (c) reference free-breathing phase-contrast MR imaging. Stroke volumes were compared by using repeated-measures analysis of variance, Bland-Altman analysis, and correlation coefficients.Imaging time with the breath-hold spiral phase-contrast MR sequence was significantly lower than that with the conventional breath-hold phase-contrast MR sequence (~5 seconds vs ~16 seconds, respectively; P < .0001). There was excellent agreement in stroke volumes in all vessels between the reference free-breathing sequence (mean volume, 60.3 mL ± 27.3) and the two breath-hold sequences-spiral SENSE phase-contrast MR imaging (mean volume, 59.5 mL ± 27.1; P < .001) and conventional cartesian phase-contrast MR imaging (mean volume, 59.8 mL ± 27.6; P = .268). The limits of agreement were smaller with the spiral breath-hold sequence than with the conventional breath-hold sequence (-4.4 mL, 2.9 mL vs -10.3 mL, 9.3 mL, respectively); correlation was similar (r = 0.998 vs r = 0.984, respectively).Flow volumes can be accurately and reliably quantified by using a spiral SENSE phase-contrast MR sequence, with high spatiotemporal resolution obtained in a short breath hold.

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Disruption of spatiotemporal hypoxic signaling causes congenital heart disease in mice.

Publications

Disruption of spatiotemporal hypoxic signaling causes congenital heart disease in mice.

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