Heart disease is the leading cause of death worldwide. Numerous epidemiological and animal studies have indicated that an adverse intrauterine environment is associated with increased risk for cardiovascular disease. Therefore proper cardiac development is imperative in optimizing cardiac function throughout life. A key process in determining

cardiomyocyte endowment, and thus cardiac function, is the period of terminal differentiation. This involves the maturation of cardiomyocytes and is essential to heart development, however acceleration of this process may alter cardiomyocyte endowment. Hypoxia/anoxia is a major perinatal stressor that often afflicts the fetus as well as the premature infant, and leads to the production of endothelin-1. Our study aims to test the hypothesis that perinatal hypoxia exposure induces a premature terminal differentiation of cardiomyocytes, focusing on the role of endothelin-1 and the underlying epigenetic and molecular mechanisms. We established two rat models for this study: 1) ex vivo endothelin-1 treatment of fetal cardiomyocytes, and 2) in vivo anoxia episodic treatment of neonatal rats. In the first part of our study, we demonstrated that endothelin-1 exposure promoted premature terminal differentiation of cardiomyocytes. Furthermore, this effect was associated with an increase in global DNA methylation. Our next section of the study simulated the major clinical problem of premature birth and the anoxic episodes that often accompany it. We demonstrated that early neonatal anoxic episodes decrease cardiomyocyte proliferation during the first two weeks of life. Moreover, this loss of proliferation ultimately resulted in a decrease in cardiomyocyte endowment by day 14 when the heart is essentially mature. Furthermore, the ETA-receptor appears to be a key mediator of these effects. Lastly, our third section identified several proteins in the fetal cardiomyocyte that were altered due to endothelin-1. Many of the proteins are associated with proliferation and survival and may help elucidate a molecular mechanism for endothelin-1-induced cardiomyocyte maturation. These findings provide new insights in the understanding of hypoxia-induced terminal differentiation of cardiomyocytes and the role of endothelin-1 as well as the epigenetic and molecular mechanisms involved. This study provides supporting evidence of the detrimental effects of perinatal hypoxia/anoxia on cardiac development, and thus function for a lifetime.

LLU Discipline



Basic Sciences


School of Medicine

First Advisor

Zhang, Lubo

Second Advisor

Blood, Arlin B.

Third Advisor

Buchholz, John N.

Fourth Advisor

Ducsay, Charles A.

Fifth Advisor

Duerksen-Hughes, Penelope

Degree Name

Doctor of Philosophy (PhD)

Degree Level


Year Degree Awarded


Date (Title Page)




Library of Congress/MESH Subject Headings

Fetal Anoxia; Perinatology; Child Development; Cardiovascular Disease

Subject - Local

Heart Disease; Cardiomyocyte Endowment; Perinatal Hypoxia; Perinatal Development; Endothelin-1



Page Count


Digital Format


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.


Loma Linda University Electronic Theses and Dissertations

Collection Website



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