Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)


Cellular, Molecular and Biomedical Sciences

First Advisor

Jeffrey L. Spees


Physiological cardiac remodeling is a beneficial process by which the heart becomes more efficient. To investigate mechanisms regulating cardiac remodeling, we assayed gene expression of epicardial cells after running exercise, which induces physiological cardiac remodeling. We identified Snord116 and FoxG1 as the most differentially expressed gene and transcription factor, respectively, (both increased) in running animals, compared with healthy, non-running controls. Snord116 is a maternally-imprinted locus containing sequences for small nucleolar RNAs (snoRNAs) and 116hg, a long noncoding RNA (lncRNA). The 116hg lncRNA was reported to regulate the rhythmic diurnal methylation of thousands of genes with epigenetic, metabolic, and circadian functions. FoxG1 controls the proliferation of neural progenitor cells. In cultured epicardial cells, shRNA-mediated FoxG1 knockdown reduced proliferation and Snord116 expression; this indicated a potential role for FoxG1 in epicardial-based cardiac remodeling. Although paternal Snord116 deletion causes Prader Willi Syndrome, a complex disorder with neurologic, metabolic, and cardiovascular pathologies, the role of Snord116 in cardiac cells is poorly understood. To investigate the impact of Snord116 expression on pathological cardiac remodeling, we obtained Snord116 paternal deletion (Snord116p-) mice and monitored cardiac structure and function during aging and after myocardial infarction (MI). We found that Snord116p- mice did not undergo age-induced ventricular wall thickening as was observed in wildtype littermates (WT LM). At 8 weeks post-MI, compared with WT LM, Snord116p- mice had reduced remodeling and scar tissue formation, as well as improved cardiac function. Of note, we demonstrated increased left ventricular levels of beta-hydroxybutyrate dehydrogenase (BDH1), concurrent with elevated 3-hydroxybutyrate (β-OHB) in the blood of Snord116p- animals compared with WT LM, indicating increased myocardial ketone body use. These data suggest Snord116 expression impacts chronic cardiac remodeling potentially through the regulation of myocardial metabolism. To determine whether Snord116 expression affected the cardiomyocyte response to ischemia, we developed a model of ischemia and reperfusion using living myocardial slices. We monitored cardiomyocyte function in slices derived from Snord116p- and WT LM mice of both sexes at baseline, after ischemia, and after a recovery period. We found that loss of Snord116 protected cardiomyocytes from ischemia-induced prolongation of systole and delayed diastolic elongation. Importantly, we found that tissue derived from female animals demonstrated a greater increase in end diastolic force, compared with tissue from males. This work establishes the utility of myocardial slices to investigate sex- and genetic-based regulation of cardiomyocyte function. Our studies established that loss of Snord116 expression reduced pathological cardiac remodeling. One mechanism by which Snord116 expression exerted change on the progression of pathological remodeling was by increasing the ability of cardiomyocytes to withstand ischemic stress. Further work to define the mechanism(s) by which Snord116 loss or inhibition benefits cardiac remodeling could lead to new therapeutics for the treatment of cardiovascular disease.



Number of Pages

188 p.

Available for download on Thursday, October 17, 2024