Abstract
Fetal nicotine exposure increased risk of developing cardiovascular disease later in life. The present study tested the hypothesis that perinatal nicotine-induced programming of heart ischemia-sensitive phenotype is mediated by enhanced reactive oxygen species (ROS) in offspring. Nicotine was administered to pregnant rats via subcutaneous osmotic minipumps from day 4 of gestation to day 10 after birth, in the absence or presence of a ROS inhibitor, N-acetyl-cysteine (NAC) in drinking water. Experiments were conducted in 8 month old age male offspring. Isolated hearts were perfused in a Langendorff preparation. Perinatal nicotine treatment significantly increased ischemia and reperfusion-induced left ventricular injury, and decreased post-ischemic recovery of left ventricular function and coronary flow rate. In addition, nicotine enhanced cardiac ROS production and significantly attenuated protein kinase Cε (PKCε) protein abundance in the heart. Although nicotine had no effect on total cardiac glycogen synthase kinase-3β (GSK3β) protein expression, it significantly increased the phosphorylation of GSK3β at serine 9 residue in the heart. NAC inhibited nicotine-mediated increase in ROS production, recovered PKCε gene expression and abrogated increased phosphorylation of GSK3β. Of importance, NAC blocked perinatal nicotine-induced increase in ischemia and reperfusion injury in the heart. These findings provide novel evidence that increased oxidative stress plays a causal role in perinatal nicotine-induced developmental programming of ischemic sensitive phenotype in the heart, and suggest potential therapeutic targets of anti-oxidative stress in the treatment of ischemic heart disease.
Highlights
Tobacco smoking is one of the leading causes of preventable morbidity and mortality worldwide, accounting for nearly $200 billion in health care costs each year within the United States alone [1]
After global ischemia in adult offspring, which was associated with an increased reactive oxygen species (ROS) production in the hearts; (2) antenatal antioxidant treatment prevented nicotine-mediated increase in ischemia/reperfusion-induced heart injury and improved post-ischemic recovery of left ventricle (LV) function in the offspring; (3) perinatal nicotine exposure significantly decreased coronary flow rate as compared with the saline control group during post-ischemic recovery in the adult hearts, which was reversed by antenatal antioxidant treatment; (4) perinatal nicotine exposure suppressed cardiac protein kinase Cε (PKCε) expression as compared with the saline treated group
Antenatal antioxidant treatment eliminated the difference in cardiac PKCε expression between the nicotine-treated and saline control groups; (5) perinatal exposure to nicotine had no effect on total cardiac glycogen synthase kinase-3β (GSK3β) protein expression but significantly enhanced the phosphorylation of GSK3β as compared with the saline control, which was eliminated by antenatal antioxidant treatment
Summary
Tobacco smoking is one of the leading causes of preventable morbidity and mortality worldwide, accounting for nearly $200 billion in health care costs each year within the United States alone [1]. Epidemiological studies have clearly shown an increased risk of cardiovascular disease in children born to women who smoked during pregnancy [2,3,4,5]. Antenatal Antioxidant and Ischemic Heart major active components in cigarettes, nicotine may contribute to maternal smoking-induced developmental programming of cardiovascular dysfunction in offspring. Recent studies have shown that exposure to electronic cigarette (e-cigarette), a nicotine delivery system, causes a cardiac development defect in zebrafish and human embryonic stem cells in vivo and in vitro [9]. Previous studies in our laboratory demonstrated that perinatal nicotine exposure reprogrammed cardiovascular function and caused a development of heart ischemia-sensitive phenotype in adult offspring [10,11,12,13,14,15].
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