期刊
CARDIOVASCULAR RESEARCH
卷 93, 期 2, 页码 302-310出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvr322
关键词
Hypoxia; Heart; Protein kinase C; Epigenetic; Oxidative stress
资金
- National Institutes of Health [HL82779, HL83966, HL89012, HL110125, DA032510, 5R25GM060507]
- California Tobacco-Related Disease Research Program Award [18KT-0024]
- Div Of Biological Infrastructure
- Direct For Biological Sciences [923559] Funding Source: National Science Foundation
Aims Hypoxia causes protein kinase C epsilon (PKC epsilon) gene repression in foetal hearts, resulting in heightened cardiac susceptibility to ischaemic injury in offspring. We tested the hypothesis that hypoxia inducible factor 1 (HIF-1) and/or reactive oxygen species (ROS) mediate hypoxia-induced PKC epsilon gene repression. Methods and results Hypoxia induced in vivo to pregnant rats, ex vivo to isolated foetal rat hearts, and in vitro in the rat embryonic ventricular myocyte cell line H9c2 resulted in a comparable decrease in PKC epsilon protein and mRNA abundance in foetal hearts and H9c2 cells, which was associated with a significant increase in CpG methylation of the SP1-binding sites at the PKC epsilon promoter. In H9c2 cells and foetal hearts, hypoxia caused nuclear accumulation of HIF-1 alpha, which was inhibited by 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole and 2-methoxy estradiol. The HIF-1 alpha inhibitors had no significant effect on hypoxia-induced PKC epsilon mRNA repression. Hypoxia produced a time-dependent increase in ROS production in H9c2 cells and foetal hearts that was blocked by ROS scavengers N-acetyl-cysteine or tempol. In accordance, N-acetyl-cysteine and tempol, but not apocynin, inhibited the hypoxic effect and restored PKC epsilon protein and mRNA expression to the control values in foetal hearts and H9c2 cells. The ROS scavengers blocked hypoxia-induced CpG methylation of the SP1-binding sites, restored SP1 binding to the PKC epsilon promoter, and abrogated the hypoxia-induced increase in the susceptibility of the heart to ischaemic injury in offspring. Conclusions The results demonstrate that hypoxia induces epigenetic repression of the PKC epsilon gene through a NADPH oxidase-independent ROS-mediated pathway in the foetal heart, leading to heightened heart vulnerability to ischaemic injury in offspring.
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