Role of DNA methylation in perinatal nicotine-induced development of heart ischemia-sensitive phenotype in rat offspring.
Role of DNA methylation in perinatal nicotine-induced development of heart ischemia-sensitive phenotype in rat offspring.
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DOI：
10.18632/oncotarget.20172
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发表时间：
2017-09-29
期刊：
影响因子：
--
通讯作者：
Xiao D
中科院分区：
文献类型：
--
作者：
Ke J;Dong N;Wang L;Li Y;Dasgupta C;Zhang L;Xiao D
母亲吸烟会增加后代患心血管疾病的风险。最近，我们已经证明，围产期尼古丁暴露改变心脏发育和增加心脏缺血/再灌注（I/R）损伤的易感性大鼠后代。本研究验证了DNA甲基化在尼古丁诱导的后代心脏缺血敏感表型发展中起关键作用的假设。从妊娠第4天至出生后第10天，通过皮下渗透微型泵向妊娠大鼠给予尼古丁。出生后，从出生后第3天至第10天，用DNA甲基化抑制剂、5-氮杂-2 '-脱氧胞苷（5-Aza）或生理盐水处理出生后后代。实验在1个月大的后代中进行。围产期尼古丁增加了I/R诱导的左心室（LV）损伤，并降低了缺血后LV功能和冠状动脉流速的恢复。尼古丁差异增加DNMT 3a的表达和整体DNA甲基化水平在LV组织。5-Aza治疗可抑制尼古丁诱导的DNMT 3a和整体DNA甲基化的增加，并阻断尼古丁诱导的I/R损伤和心脏功能障碍的增加。此外，尼古丁减弱了心脏中蛋白激酶Cε和大电导Ca（2+）激活的K（+）（BKca）通道β1亚基蛋白的丰度，5-Aza处理可逆转这一点。目前的研究结果提供了新的证据表明，增加的DNA甲基化在尼古丁诱导的心脏缺血敏感表型的发展中起着因果作用，并提出了一个潜在的治疗靶点的DNA去甲基化的心脏缺血性疾病的胎儿编程以后的生活。
Maternal 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. Nicotine 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. Perinatal 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. 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.
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影响因子：
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作者：
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作者：
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DOI：
10.1073/pnas.191369098
发表时间：
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影响因子：
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