Fetal programming by nicotine increases cardiac susceptibility to ischemic injury

Fetal programming is the area of study that focuses on the prenatal origins of adult onset disorders. Previous studies have associated an adverse prenatal environment with the onset of physiologic and metabolic diseases during adulthood. Fetal malnutrition, hypoxia, and exposure to drugs---such as cocaine and nicotine---have been associated with adult disease states. Cigarette smoking is the number one cause of preventable death in the developed world. Among the many dangerous chemicals found in tobacco products is nicotine, the compound responsible for the addictive nature of tobacco use. Nicotine use during pregnancy is a known cause of fetal morbidity and mortality. Dispite prevealent warnings of its adverse effects, addiction to this chemical causes many to continue using tobacco products, even during pregnancy. Nicotine is able to bind to nicotinic acetylcholine receptors (nAChR), resulting in increased systemic norepinephrine levels. Norepinephrine has previously been observed to downregulate protien kinase C epsilon (PKCepsilon) expression in cardiomyocytes. PKCepsilon is a member of a family of serine/threonine kinases that are involved in a number of cellular signalling pathways. PKCepsilon has been confirmed to play a vital role in the process of cardiac preconditioning against ischemia/reperfusion injury. This study utilized a rat animal model to demonstrate the effect of prenatal nicotine exposure on adult cardiac functionality. This study aimed to determine whether prenatal nicotine exposure affects cardiac response to ischemia/reperfusion injury in adult offspring; the molecular mechanisms of nicotine's effect on PKC expression pattern in the fetal heart; and the molecular mechanisms of nicotine's effect on PKC expression pattern in the adult heart . Pregnant rats were treated with nicotine comparable to that of a heavy smoker beginning on day four of gestation until postnatal day ten. The animals exposed to nicotine during gestation were studied at the fetal and adult stages. The ability of the heart to recover for ischemia-reperfusion injury was studied using the langendorff apparatus. This study demonstrated that prenatal nicotine exposure significantly reduces cardiac recovery from ischemia-reperfusion injury. The expression of PKCepsilon protein and mRNA levels were observed to decrease in fetal and adult cardiac tissue exposed to nicotine in utero. DNA methylation studies showed that prenatal nicotine exposure decreases PKCepsilon expression by increasing DNA methylation at the EGR-1 transciption factor binding site of the promoter region in both fetal and adult cardiac tissue. Nicotine was determined to affect cardiac PKCepsilon expression via norepinephrine. This study demonstrates that prenatal nicotine exposure significantly reduces recovery from ischemia-reperfusion injury. This decreased recovery is associated with a significant decrease in PKCepsilon expression in cardiac tissue initiated by epigenetic modification of the PKCepsilon gene promoter.