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: Luciferase activity was measured in ODD‐Luc mouse tissue homogenates throughout development as a reporter for O2‐dependent PHD activity. Activity normalized to total protein was highest in the E9.5 embryo (Figure 1A). Dissection of individual organs was not feasible at this stage due to their small size. In the embryonic heart, activity was highest at E10.5 and declined 3.5‐fold to E15.5 (P<0.001) and further decreased by 4.6‐fold between E17.5 and maturity (P<0.001; Figure 1B). The liver showed a similar pattern (Figure 1C); the activity was 2.2‐fold higher in E10.5 liver versus heart (P<0.001). The decline in activity in the liver occurred between E10.5 and 13.5. The developmental decline in luciferase activity was specific for the ODD of the modified Luciferase protein as there was no difference between E13.5 and adult heart (P=0.66) when wild type luciferase (WT‐Luc) was expressed from the Rosa26 locus (Figure 1D). Comparisons of WT‐Luc and ODD‐Luc activity suggest that ≈40% of the ODD‐Luc is degraded in E13.5 tissues versus 90% in adult tissues.
Affiliation: Department of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, MD (D.K., S.A.F.).