Maresha Gay


Each year 1 in 9 infants are born preterm in the United States. Preterm infants have a host of complications associated with prematurity, including respiratory distress syndrome. Dexamethasone, a synthetic glucocorticoid is the ‘gold standard’ intervention in the treatment of preterm infants and mothers at risk of preterm birth because it promotes organ maturation, particularly the lungs and aids in surfactant production. However, a growing body of evidence suggests perinatal dexamethasone exposure is associated with health consequences later in life including increased risk of cardiovascular disease. Cardiomyocytes are the functional unit of the heart and are unique in that they don’t have an infinite proliferative capacity. In fact, soon after birth myocytes exit the cell cycle and become terminally differentiated. It is therefore crucial that sufficient proliferation occurs before terminal differentiation takes place to ensure adequate cardiomyocyte endowment in the mature heart. The purpose of this study is to test the hypothesis that neonatal dexamethasone exposure causes premature cardiomyocyte terminal differentiation, to elucidate potential molecular targets, and evaluate the role of epigenetic modifications. In newborn rats, dexamethasone was administered in tapered, clinically relevant doses during the first three days of life. We found that newborn dexamethasone treatment induced premature terminal differentiation in cardiomyocytes resulting in reduced cardiomyocyte number in the mature heart, in a glucocorticoid receptor-dependent manner. In addition we demonstrated that an increase in DNA methylation is of importance in dexamethasone-mediated cardiomyocyte terminal differentiation. To further elucidate the molecular mechanisms involved, the effect of dexamethasone was determined in freshly isolated cardiomyocytes from newborn rats. We demonstrated that dexamethasone has a direct effect and induces hypermethylation of cyclin D2 gene promoter, resulting in epigenetic repression of cyclin D2 protein and mRNA expression in cardiomyocytes. Of importance, inhibition of DNA methylation reversed dexamethasone-mediated down-regulation of cyclin D2 expression and blocked dexamethasone-induced cardiomyocyte terminal differentiation. Furthermore, overexpression of cyclin D2 gene in cardiomyocyte rescued dexamethasone-mediated phenotype. Thus, we demonstrated a cause and effect relation of epigenetic repression of cyclin D2 gene and dexamethasone-mediated cardiomyocyte terminal differentiation in newborn rat hearts. These findings provided new insights in understanding the potential harmful effects of perinatal glucocorticoid treatment on reducing cardiomyocyte endowment in the heart and possible long-term adverse cardiovascular consequences.

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

Mata-Greenwood, Eugenia

Degree Name

Doctor of Philosophy (Medical Science)

Degree Level


Year Degree Awarded


Date (Title Page)




Library of Congress/MESH Subject Headings

Dexamethasone; Neonatalogy; Respiratory Distress Syndrome; Heart -- Growth and Development; Glucocorticoids

Subject - Local

Organ maturation; Surfactant Production; Cardiomyocytes; Terminal differentiation; Epigenetic Modifications



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