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Published on: November 20, 2015
Foetal nicotine exposure causes PKCε gene repression by promoter methylation in rat hearts
Jennifer Lawrence1, Man Chen, Fuxia Xiong
1Department of Physiology and Pharmacology, Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
Insights
Maternal nicotine exposure reprograms the fetal heart, decreasing protein kinase C epsilon (PKCε) by methylating its gene promoter. This epigenetic change links smoking during pregnancy to heart problems in offspring.
Area of Science:
- Cardiovascular Science
- Developmental Biology
- Epigenetics
Background:
- Fetal nicotine exposure reduces protein kinase C epsilon (PKCε) expression, increasing offspring cardiac vulnerability.
- The precise mechanism linking maternal nicotine to PKCε repression and heart dysfunction remained unclear.
Purpose of the Study:
- To investigate if maternal nicotine administration induces PKCε gene promoter methylation, leading to PKCε repression in the fetal heart.
- To elucidate the role of norepinephrine and Egr-1 in nicotine-induced epigenetic modifications of the PKCε gene.
Main Methods:
- Pregnant rats received nicotine; fetal heart PKCε expression, methylation, and Egr-1 binding were analyzed.
- Ex vivo studies assessed direct nicotine effects and norepinephrine's role.
- Site-specific gene deletion and 5-Aza-2'-deoxycytidine treatments were employed.
Main Results:
- Maternal nicotine increased PKCε promoter methylation and decreased PKCε expression in fetal hearts.
- Nicotine elevated fetal heart norepinephrine, which mimicked these effects.
- Epigenetic changes were sustained in adult offspring hearts.
Conclusions:
- Maternal nicotine exposure leads to PKCε gene repression via promoter methylation, mediated by increased sympathetic neurotransmitter release.
- This study links maternal smoking to programming of cardiac pathophysiology in offspring.
Aims:
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.
Methods And Results:
nicotine treatment of pregnant rats starting at day 4 of gestation increased the methylation of the Egr-1 binding site at the PKCε gene promoter and decreased PKCε protein and mRNA abundance in near-term foetal hearts. Methylation of the Egr-1 binding site reduced Egr-1 binding to the PKCε promoter in the heart. Site-specific deletion of the Egr-1 binding site significantly decreased PKCε promoter activity. The effects of nicotine were sustained in the heart of adult offspring. Ex vivo studies found no direct effect of nicotine on PKCε 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 PKCε 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 PKCε gene expression to the control levels.
Conclusion:
this study demonstrates that prolonged nicotine exposure increases the sympathetic neurotransmitter release in the foetal heart and causes programming of PKCε gene repression through promoter methylation, linking maternal smoking to pathophysiological consequences in the offspring heart.
