Electronic Theses and Dissertations

Date of Award


Document Type


Degree Name

Ph.D. in Pharmaceutical Sciences


Pharmaceutics and Drug Delivery

First Advisor

James A. Stewart, Jr.

Relational Format



Diabetic individuals have an increased risk for developing cardiovascular disease due to stiffening of the left ventricle, which is thought to occur, in part, by increased AGE/RAGE signaling. Advanced glycation end products (AGEs) accumulate within the body over time, and under hyperglycemic conditions, the formation and accumulation of AGEs is accelerated. AGEs exert their effect by binding to their receptor (RAGE) and can induce myofibroblast differentiation, oxidative stress, cell-extracellular matrix contraction, and cell migration. Previous findings from our lab have demonstrated that preventing the production of Rap1a, a Ras-like GTPase signaling protein, in cardiac fibroblasts will decrease type 2 diabetes complications induced by AGE/RAGE activation. Rap1a acts as a molecular switch and couples extracellular signals to intracellular events. Currently, there are very few known roles of Rap1a within the body and even less is known about the impact of Rap1a on the AGE/RAGE cascade in diabetes. Therefore, we hypothesis that Rap1a crosses the AGE/RAGE cascade to alter expression of AGE/RAGE-associated signaling proteins in cardiac fibroblasts in type 2 diabetic mice. We accomplished this by 1) determining the role of Rap1a on mediating changes to the AGE/RAGE signaling cascade and 2) assessing the impact of Rap1a signaling on cellular functions associated with myofibroblast differentiation. The results from this project showed that Rap1a overlapped the AGE/RAGE cascade to promote/maintain a myofibroblast population and increased oxidative stress in cardiac fibroblasts under diabetic conditions. Rap1a also contributed to cardiac fibroblast function through reducing fibroblast migration and contributed to AGE/RAGE-mediated fibroblast matrix contraction. Therefore, it appears that regulating the level of Rap1a activity during critical times may be an appropriate approach for reducing the impact AGE/RAGE signaling in type 2 diabetes.



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