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Foetal nicotine exposure causes PKC? gene repression by promoter methylation in rat hearts.

ABSTRACT: foetal nicotine exposure results in decreased protein kinase C epsilon (PKC?) expression and increased cardiac vulnerability to ischaemia and reperfusion injury in adult rat offspring. The present study tested the hypothesis that maternal nicotine administration causes increased promoter methylation of the PKC? gene resulting in PKC? repression in the heart.nicotine treatment of pregnant rats starting at day 4 of gestation increased the methylation of the Egr-1 binding site at the PKC? gene promoter and decreased PKC? protein and mRNA abundance in near-term foetal hearts. Methylation of the Egr-1 binding site reduced Egr-1 binding to the PKC? promoter in the heart. Site-specific deletion of the Egr-1 binding site significantly decreased PKC? promoter activity. The effects of nicotine were sustained in the heart of adult offspring. Ex vivo studies found no direct effect of nicotine on PKC? gene expression. However, maternal nicotine administration increased norepinephrine content in the foetal heart. Treatment of isolated foetal hearts with norepinephrine resulted in the same effects of increased methylation of the Egr-1 binding site and PKC? gene repression in the heart. 5-Aza-2'-deoxycytidine inhibited the norepinephrine-induced increase in methylation of the Egr-1 binding site and restored Egr-1 binding and PKC? gene expression to the control levels.this study demonstrates that prolonged nicotine exposure increases the sympathetic neurotransmitter release in the foetal heart and causes programming of PKC? gene repression through promoter methylation, linking maternal smoking to pathophysiological consequences in the offspring heart.

SUBMITTER: Lawrence J

PROVIDER: S-EPMC3002869 | biostudies-other | 2011 Jan

REPOSITORIES: biostudies-other

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Foetal nicotine exposure causes PKCε gene repression by promoter methylation in rat hearts.

Lawrence Jennifer J Chen Man M Xiong Fuxia F Xiao Daliao D Zhang Haitao H Buchholz John N JN Zhang Lubo L

Cardiovascular research 20100823 1

<h4>Aims</h4>foetal nicotine exposure results in decreased protein kinase C epsilon (PKCε) expression and increased cardiac vulnerability to ischaemia and reperfusion injury in adult rat offspring. The present study tested the hypothesis that maternal nicotine administration causes increased promoter methylation of the PKCε gene resulting in PKCε repression in the heart.<h4>Methods and results</h4>nicotine treatment of pregnant rats starting at day 4 of gestation increased the methylation of the ...[more]

PMID: 20733009

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Project description:Epidemiological studies demonstrate a clear association of adverse intrauterine environment with an increased risk of ischemic heart disease in adulthood. Hypoxia is a common stress to the fetus and results in decreased protein kinase C epsilon (PKCepsilon) expression in the heart and increased cardiac vulnerability to ischemia and reperfusion injury in adult offspring in rats.The present study tested the hypothesis that fetal hypoxia-induced methylation of cytosine-phosphate-guanine dinucleotides at the PKCepsilon promoter is repressive and contributes to PKCepsilon gene repression in the heart of adult offspring.Hypoxic treatment of pregnant rats from days 15 to 21 of gestation resulted in significant decreases in PKCepsilon protein and mRNA in fetal hearts. Similar results were obtained in ex vivo hypoxic treatment of isolated fetal hearts and rat embryonic ventricular myocyte cell line H9c2. Increased methylation of PKCepsilon promoter at SP1 binding sites, -346 and -268, were demonstrated in both fetal hearts of maternal hypoxia and H9c2 cells treated with 1% O(2) for 24 hours. Whereas hypoxia had no significant effect on the binding affinity of SP1 to the unmethylated sites in H9c2 cells, hearts of fetuses and adult offspring, methylation of both SP1 sites reduced SP1 binding. The addition of 5-aza-2'-deoxycytidine blocked the hypoxia-induced increase in methylation of both SP1 binding sites and restored PKCepsilon mRNA and protein to the control levels. In hearts of both fetuses and adult offspring, hypoxia-induced methylation of SP1 sites was significantly greater in males than in females, and decreased PKCepsilon mRNA was seen only in males. In fetal hearts, there was significantly higher abundance of estrogen receptor alpha and beta isoforms in females than in males. Both estrogen receptor alpha and beta interacted with the SP1 binding sites in the fetal heart, which may explain the sex differences in SP1 methylation in the fetal heart. Additionally, selective activation of PKCepsilon restored the hypoxia-induced cardiac vulnerability to ischemic injury in offspring.The findings demonstrate a direct effect of hypoxia on epigenetic modification of DNA methylation and programming of cardiac PKCepsilon gene repression in a sex-dependent manner, linking fetal hypoxia and pathophysiological consequences in the hearts of adult offspring.

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Foetal nicotine exposure causes PKC? gene repression by promoter methylation in rat hearts.

Publications

Foetal nicotine exposure causes PKCε gene repression by promoter methylation in rat hearts.

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