Abstract

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[sic] prevealent[sic] 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 proteins kinase C epsilon (PKCε) expression in cardiomyocytes. PKCε is a member of a family of serine/threonine kinases that are involved in a number of cellular signaling pathways. PKCε has been confirmed to play a vital role in the 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[sic] apparatus. This study demonstrated that prenatal nicotine exposure significantly reduces cardiac recovery from ischemia-reperfusion injury. The expression of PKCε 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 PKCε expression by increasing DNA methylation at the EGR-1 transciption[sic] factor binding site of the promoter region in both fetal and adult cardiac tissue. Nicotine was detemined[sic] to affect cardiac PKCε 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 PKCε expression in cardiac tissue initiated by epigenetic modification of the PKCε gene promoter.

LLU Discipline

Microbiology and Molecular Genetics

School

Graduate Studies

First Advisor

Lubo Zhang

Second Advisor

John N. Buchholz

Third Advisor

Carlos A. Casiano

Fourth Advisor

Charles A. Ducsay

Fifth Advisor

DaLiao Xiao

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2010

Date (Title Page)

6-2010

Language

English

Library of Congress/MESH Subject Headings

Coronary Disease; Coronary Circulation -- drug effects; Pregnancy; Fetal Development; Disease Susceptibility; Maternal-Fetal Exchange -- physiology; Cardiovascular System; Heart -- physiopathology; Heart Ventricles -- drug effects; Reperfusion Injury -- physiopathology; Ischemia -- complications; Myocardial Infarction -- complications; Nicotine -- toxicity; Nicotinic Agonists -- pharmacology; Nitric Oxide -- metabolism; Animals, Laboratory; Rats, Sprague-Dawley

Type

Dissertation

Page Count

xiii; 93

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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