Soochan Bae

Abstract

Human epidemiological studies have shown a clear association of adverse intrauterine environment and an increased risk of ischemia heart disease in later adult life. Cocaine abuse during pregnancy has been shown to cause abnormities in the heart during fetal and postnatal development, but mechanisms underlying the detrimental effects of cocaine on the developing heart are not fully understood. The central hypothesis is that cocaine exposure during fetal development may cause in utero programming of apoptotic pathways, which may has lasting and prolong effect on heart development postnatally.

In a pregnant rat model, chronic hypoxia increased apoptosis in the fetal heart which may cause a premature exit of the cell cycle of cardiomyocytes and myocyte hypertrophy in the remaining cells. It is likely that multiple mechanisms may be involved in cocaine/hypoxia-induced apoptosis in the fetal heart. In a neonatal and juvenile offspring, prenatal cocaine exposure induced abnormal apoptosis and myocyte hypertrophy in the early postnatal rats. Furthermore, prenatal cocaine exposure significantly increased heart susceptibility to ischemia/reperfusion (I/R) injury in juvenile and adult rats by increasing myocardial infarct size and decreasing postischemic recovery of left ventricular function. Interestingly, the effect of prenatal cocaine exposure on cardiac vulnerability in adult offspring is gender-dependent, with the male heart being more susceptible to increased I/R injury induced by prenatal cocaine exposure. Accordingly, there was a significant decrease in PKCs and phospho-PKCe levels in left ventricle in the male, but not female offspring.

Many studies have reported the sex differences in heart susceptibility to I/R injury, but the mechanisms are not fully understood. Inhibition of PBK/Akt pathway by wortmannin or PKC by chelerjdhrine before ischemia significantly reduced postischemic recovery, and increased infarct size in female but not male hearts. Although the levels of total Akt or PKCs were same between male and female hearts, the ratio of p-Akt/Akt and / p-PKCs/PKCs were significantly higher in female hearts. In addition, there were significantly increases in p-Akt and p-PKCs levels during reperfusion in female but not male hearts. The results suggest that increased p-Akt and p-PKCs play an important role in cardioprotection against I/R injury in females.

LLU Discipline

Pharmacology

Department

Pharmacology

School

Graduate School

First Advisor

Lubo Zhang

Second Advisor

John N. Buchholz

Third Advisor

Carlos A. Casiano

Fourth Advisor

Charles A. Ducasy

Fifth Advisor

Raymond D. Gilbert

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2005

Date (Title Page)

6-2005

Language

English

Library of Congress/MESH Subject Headings

Fetus -- drug effects; Infant, Newborn -- drug effects; Maternal-Fetal Exchange -- drug effects; Substance Abuse -- in pregnancy; Fetal Heart -- drug effects; Fetal Heart -- growth and development

Type

Dissertation

Page Count

xii; 241

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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Included in

Pharmacology Commons

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