Research Papers:

Role of DNA methylation in perinatal nicotine-induced development of heart ischemia-sensitive phenotype in rat offspring

Jun Ke, Nianguo Dong, Lei Wang, Yong Li, Chiranjib Dasgupta, Lubo Zhang and Daliao Xiao _

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Oncotarget. 2017; 8:76865-76880. https://doi.org/10.18632/oncotarget.20172

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Jun Ke1,3, Nianguo Dong1, Lei Wang2,3, Yong Li3, Chiranjib Dasgupta3, Lubo Zhang3 and Daliao Xiao3

1Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Department of Traditional Chinese Medicine, People’s Hospital of Shanghai Putuo District, Shanghai, China

3Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA

Correspondence to:

Daliao Xiao, email: [email protected]

Nianguo Dong, email: [email protected]

Keywords: perinatal nicotine, DNA methylation, heart ischemia-sensitive phenotype

Received: May 25, 2017    Accepted: June 30, 2017    Published: August 10, 2017


Background and purpose: 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.

Experimental approach: 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.

Key results: 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.

Conclusions and implications: 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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