Vulnerability of the developing heart to oxygen deprivation as a cause of congenital heart defects.
Bottom Line: 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.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.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.
Affiliation: Department of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, MD (D.K., S.A.F.).Show MeSH
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Mentions: To determine if the stage‐dependent induction of ODD‐Luc activity is reflective of the endogenous response to oxygen deprivation, pregnant mice were exposed to the same hypoxia protocol (8% O2 for 4 hours) and selected transcripts measured by qPCR. Transcripts were selected based on prior experiments in which Stage 25 (ED4) chicken eggs were incubated in 7.5% O2 for 6 hours with or without DMOG, an iron chelator that inhibits PHD activity. Hypoxia‐inducible gene expression in the embryonic chick hearts was measured by gene array and confirmed by real‐time PCR (Table 4). Ccn1+2 were most robustly induced by the hypoxic stress in the E11.5 mouse heart (Figure 7A). Ccn3 was expressed at a low level and not induced (data not shown). There was good correlation between induction of ODD‐Luc and Ccn1+2, Bnip3 and Glut1 in E11.5 versus E15.5 mouse heart. Igfbp1 was induced several‐fold in the embryonic mouse heart (Figure 7A) and liver (Figure 7B) with no relationship to the induction of ODD‐Luc activity. Ccn1+2 were modestly induced in the embryonic mouse liver (Figure 7B), but the induction of Ccn2 at E11.5 was not significant. These genes were not induced in the maternal tissues consistent with the minimal increase in ODD‐Luc activity.
Affiliation: Department of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, MD (D.K., S.A.F.).