Abstract
Antenatal hypoxia caused epigenetic reprogramming of methylome and transcriptome in the developing heart and increased the risk of heart disease later in life. Herein, we investigated the impact of gestational hypoxia in proteome and metabolome in the hearts of fetus and adult offspring. Pregnant rats were treated with normoxia or hypoxia (10.5% O2) from day 15 to 21 of gestation. Hearts were isolated from near-term fetuses and 5 month-old offspring, and proteomics and metabolomics profiling was determined. The data demonstrated that antenatal hypoxia altered proteomics and metabolomics profiling in the heart, impacting energy metabolism, lipid metabolism, oxidative stress, and inflammation-related pathways in a developmental and sex dependent manner. Of importance, integrating multi-omics data of transcriptomics, proteomics, and metabolomics profiling revealed reprogramming of the mitochondrion, especially in two clusters: (a) the cluster associated with “mitochondrial translation”/“aminoacyl t-RNA biosynthesis”/“one-carbon pool of folate”/“DNA methylation”; and (b) the cluster with “mitochondrion”/“TCA cycle and respiratory electron transfer”/“acyl-CoA dehydrogenase”/“oxidative phosphorylation”/“complex I”/“troponin myosin cardiac complex”. Our study provides a powerful means of multi-omics data integration and reveals new insights into phenotypic reprogramming of the mitochondrion in the developing heart by fetal hypoxia, contributing to an increase in the heart vulnerability to disease later in life.
Highlights
Many risk factors contribute to the development of heart disease that is a leading cause of death in the adult
The unbiased assessment of multi-omics integration across the transcriptome, proteome, and metabolome revealed the major effect of antenatal hypoxia on the mitochondrion in the heart, especially in two clusters: (a) the first cluster associated with “mitochondrial translation”/“aminoacyl t-RNA biosynthesis”/“one-carbon pool of folate”/“DNA
We provided further novel insights into phenotypic reprogramming of proteome and metabolome in the heart, resulting from antenatal hypoxia-induced epigenotype
Summary
Many risk factors contribute to the development of heart disease that is a leading cause of death in the adult. Large studies including both epidemiological and animal studies indicate that an adverse intrauterine environment and fetal stress play a critical role in an increased risk of ischemic heart disease in adulthood [1,2,3,4,5]. Various conditions can cause prolonged fetal stress of intrauterine hypoxia, including preeclampsia and placental insufficiency, pregnancy at high altitude, maternal anemia, and heart and lung disease, among others. We demonstrated that fetal hypoxia caused gene hypermethylation and repression of protein kinase C epsilon and glucocorticoid receptors in the heart, Cells 2019, 8, 1608; doi:10.3390/cells8121608 www.mdpi.com/journal/cells
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