Prenatal Cocaine Exposure and Cardiac Programming

<p>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 <em>in utero</em> programming of apoptotic pathways, which may has lasting and prolong effect on heart development postnatally.</p> <p>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.</p> <p>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. </p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Pharmacology

Year

2005

Author dc:creator

• Bae, Soochan

Contributors dc:contributor

• Lubo Zhang
• John N. Buchholz
• Carlos A. Casiano
• Charles A. Ducasy
• Raymond D. Gilbert

• Pharmacology
• 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

Statement dc: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.

Language dc:language

English

Repository record dc:identifier

https://scholarsrepository.llu.edu/etd/1131

OAI identifier oai:identifier

oai:scholarsrepository.llu.edu:etd-2665