Advisor(s)
Adam Wende
Gregory Payne
Committee Member(s)
Jarrod Barnes
John Chatham
Rakesh Patel
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Pathology
Date of Award
10-9-2025
Abstract
With diabetes prevalence around the world nearing 10%, and half of the US population having either diabetes or pre-diabetes, many epidemiological studies show diabetic patients have both increased risk for developing major cardiovascular disease (CVD), and increased mortality rates due to CVD. Additionally, within this field, studies have shown that indi-viduals with previously higher HbA1C levels have higher long-lasting risk for major ad-verse cardiac events compared to those with previously lower HbA1C levels—establishing the concept of “metabolic memory”. Within the diabetic milieu, cardiac protein O-GlcNAcylation (O-linked B-N-acetyl-glucosamine) is important for cardiac pathology de-velopment. Specifically, our lab generated a cardiomyocyte specific, inducible dominant-negative O-GlcNAcase (dnOGA) mouse (dnOGAh) to study specific cardiac O-GlcNAc enhancement. And upon chronic enhancement of cardiac O-GlcNAcylation, we observed cardiac pathology like that seen in diabetic hearts. With the clinical and pathophysiological background of diabetic hearts, metabolic memory and O-GlcNAc, the current thesis: tests the hypothesis that transient increase in cardiac O-GlcNAcylation exacerbates adverse cardiac remodeling under pressure overload (O-GlcNAc memory). Additionally, it aims to provide initial guidelines and best practic-es/considerations for multi-transgenic models to begin the study of pathologic mechanisms in hearts with altered cardiac O-GlcNAcylation. We validated a new dnOGAh ON/OFF-TAC paradigm for the study of O-GlcNAc memory with pressure overload, and observed exacerbated adverse cardiac remodeling (hypertrophy, fibrosis and dysfunction); transcriptomic analysis identified several altered pathways that could be drivers of the exacerbated pathology. Additionally, we generated and validated a new dnON4K mouse, crossing our dnOGAh and a germline knockout of Nox4 mouse; however, after chronic dnOGA induction, we observed no increase in ex-pected cardiac hypertrophy or O-GlcNAcylation. Follow up experiments support the pos-sibility of mouse strain differences contributing to the variability in results. Overall, results provide a roadmap and considerations for future research models on altered cardiac protein O-GlcNAcylation. Taken together, studies in the current thesis support the role of O-GlcNAc in dia-betic heart pathology (specifically in metabolic memory) and provide initial steps in study-ing the mechanisms underlying cardiac pathology development under altered O-GlcNAcylation. Moreover, findings further biomedical research to better understand and treat differential CVD in diabetic patient hearts.
ProQuest ID
Recommended Citation
Chang, Samuel Formosa, "Insights Into Cardiac O-Glcnacylation As A Link Between The Diabetic State And Increased Cardiovascular Disease Susceptibility And Pathology" (2025). All ETDs from UAB. 7361.
https://digitalcommons.library.uab.edu/etd-collection/7361
