Abstract
Cardiac development is a dynamic process, temporally and spatially. When disturbed, it leads to congenital cardiac anomalies that affect approximately 1% of live births. Genetic variants in several loci lead to anomalies, with the transcription factor NKX2-5 being one of the largest. However, there are also non-genetic factors that influence cardiac malformations. We examined the hypothesis that hyperoxia may be beneficial and can rescue genetic cardiac anomalies induced by an Nkx2-5 mutation. Intermittent mild hyperoxia (40% PO2) was applied for 10 h per day to normal wild-type female mice mated with heterozygous Nkx2-5 mutant males from gestational day 8.5 to birth. Hyperoxia therapy reduced excessive trabeculation in Nkx2-5 mutant mice compared to normoxic conditions (ratio of trabecular layer relative to compact layer area, normoxia 1.84 ± 0.07 vs. hyperoxia 1.51 ± 0.04) and frequency of muscular ventricular septal defects per heart (1.53 ± 0.32 vs. 0.68 ± 0.15); however, the incidence of membranous ventricular septal defects in Nkx2-5 mutant hearts was not changed. Nkx2-5 mutant embryonic hearts showed defective coronary vessel organization, which was improved by intermittent mild hyperoxia. The results of our study showed that mild gestational hyperoxia therapy rescued genetic cardiac malformation induced by Nkx2-5 mutation in part.
Highlights
Cardiac development is a dynamic process, temporally and spatially
In our experiments, when wild-type pregnant mice were housed under moderate chronic hypoxia (14% of O 2) conditions from gestational day 10.5 until term, newborn mice showed cardiac anomalies such as excessive trabeculation, ventricular septal defects (VSDs), irregular morphology of interventricular septum as well as atrial septal abnormalities, which overlap with those seen in heterozygous Nkx[2,3,4,5] mutant m ice[18]
We recently demonstrated that continuous gestational mild hypoxia (14% P O2) induces cardiac anomalies in wild-type mice, including excessive trabeculation and peri-membranous and muscular VSDs, which partly overlap with those seen in heterozygous Nkx[2,3,4,5] mutant m ice[18]
Summary
Cardiac development is a dynamic process, temporally and spatially. When disturbed, it leads to congenital cardiac anomalies that affect approximately 1% of live births. The same nucleotide variant can lead to varied types and severity of d isease[9], in humans, and in Nkx2-5+/R52G knock-in mutant mice (hereafter called Nkx[2,3,4,5] mutant) that have the same genetic background through b ackcrossing[8,10,11] These observations strongly suggest non-genetic factors have influence on cardiac malformations. We applied mild hyperoxia, and have demonstrated that intermittent hyperoxia (40% of O 2, 10 h per day) starting from gestational day 8.5 partly rescued cardiac anomaly in terms of reducing the frequencies of muscular VSD and ventricular non-compaction with correction of defective coronary vessel organization in Nkx[2,3,4,5] mutant hearts
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