Abstract
Background and purposeMaternal cigarette smoking increases the risk of cardiovascular disease in offspring. Recently, we have demonstrated that perinatal nicotine exposure alters heart development and increases heart susceptibility to ischemia/reperfusion (I/R) injury in rat offspring. The present study tested the hypothesis that DNA methylation plays a key role in the nicotine-induced development of heart ischemia-sensitive phenotype in offspring.Experimental approachNicotine was administered to pregnant rats via subcutaneous osmotic minipumps from gestational day 4 until postnatal day 10. After birth, the postnatal offspring were treated with the DNA methylation inhibitor, 5-aza-2’-deoxycytidine (5-Aza) or saline from postnatal day 3 to day 10. Experiments were conducted in 1 month old offspring.Key resultsPerinatal nicotine increased I/R-induced left ventricular (LV) injury, and decreased post-ischemic recovery of the LV function and coronary flow rate in both male and female offspring. Nicotine differentially increased DNMT3a expression and global DNA methylation levels in LV tissues. Treatment with 5-Aza inhibited nicotine-induced an increase in DNMT3a and global DNA methylation, and blocked the nicotine-induced increase in I/R injury and dysfunction in the heart. In addition, nicotine attenuated protein kinases Cε and large-conductance Ca(2+)-activated K(+) (BKca) channel β1 subunit protein abundances in the heart, which were reversed by 5-Aza treatment.Conclusions and implicationsThe present findings provide novel evidence that the increased DNA methylation plays a causal role in nicotine-induced development of heart ischemic sensitive phenotype, and suggest a potential therapeutic target of DNA demethylation for the fetal programming of heart ischemic disease later in life.
Highlights
Growing evidence suggests a key role of intrauterine adverse environment in determining the risk of disease in postnatal life
The present findings provide novel evidence that the increased DNA methylation plays a causal role in nicotine-induced development of heart ischemic sensitive phenotype, and suggest a potential therapeutic target of DNA demethylation for the fetal programming of heart ischemic disease later in life
Our previous studies have shown that perinatal nicotine exposure causes an aberrant programmed cardiovascular function and development of heart ischemia-sensitive phenotype in offspring [8, 10, 11]
Summary
Growing evidence suggests a key role of intrauterine adverse environment in determining the risk of disease in postnatal life. Maternal cigarette smoking during gestation is one of the most common causes of fetal growth restriction and a major risk factor in the development of cardiovascular disease in offspring [1, 2]. Our previous studies have shown an aberrant programmed cardiovascular function and development of heart ischemia-sensitive phenotype in response to intrauterine nicotine exposure [8, 10, 11]. The molecular epigenetic mechanisms underlying the perinatal nicotine-induced development of heart ischemia-sensitive phenotypes are not fully understood. We have demonstrated that perinatal nicotine exposure alters heart development and increases heart susceptibility to ischemia/reperfusion (I/R) injury in rat offspring. The present study tested the hypothesis that DNA methylation plays a key role in the nicotine-induced development of heart ischemia-sensitive phenotype in offspring.
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