Vulnerability of the developing heart to oxygen deprivation as a cause of congenital heart defects

18Citations
Citations of this article
35Readers
Mendeley users who have this article in their library.

Abstract

Background-The heart develops under reduced and varying oxygen concentrations, yet there is little understanding of oxygen metabolism in the normal and mal-development of the heart. Here we used a novel reagent, the ODD-Luc hypoxia reporter mouse (oxygen degradation domain, ODD) of Hif-1α fused to Luciferase (Luc), to assay the activity of the oxygen sensor, prolyl hydroxylase, and oxygen reserve, in the developing heart. We tested the role of hypoxia-dependent responses in heart development by targeted inactivation of Hif-1α. Methods and Results-ODD-Luciferase activity was 14-fold higher in mouse embryonic day 10.5 (E10.5) versus adult heart and liver tissue lysates. ODD-Luc activity decreased in 2 stages, the first corresponding with the formation of a functional cardiovascular system for oxygen delivery at E15.5, and the second after birth consistent with complete oxygenation of the blood and tissues. Reduction of maternal inspired oxygen to 8% for 4 hours caused minimal induction of luciferase activity in the maternal tissues but robust induction in the embryonic tissues in proportion to the basal activity, indicating a lack of oxygen reserve, and corresponding induction of a hypoxia-dependent gene program. Bioluminescent imaging of intact embryos demonstrated highest activity in the outflow portion of the E13.5 heart. Hif-1α inactivation or prolonged hypoxia caused outflow and septation defects only when targeted to this specific developmental window. Conclusions-Low oxygen concentrations and lack of oxygen reserve during a critical phase of heart organogenesis may provide a basis for vulnerability to the development of common septation and conotruncal heart defects.

Cite

CITATION STYLE

APA

Kenchegowda, D., Liu, H., Thompson, K., Luo, L., Martin, S. S., & Fisher, S. A. (2014). Vulnerability of the developing heart to oxygen deprivation as a cause of congenital heart defects. Journal of the American Heart Association, 3(3). https://doi.org/10.1161/JAHA.114.000841

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free