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http://hdl.handle.net/11375/28411
Title: | Investigating the Role of Endoplasmic Reticulum Stress-Glycogen Synthase Kinase 3α/β Signalling on Endothelial Activation and the Initiation and Progression of Atherosclerosis |
Other Titles: | GSK3α/β IN ENDOTHELIAL ACTIVATION AND ATHEROSCLEROSIS |
Authors: | Mastrogiacomo, Lauren |
Advisor: | Werstuck, Geoff |
Department: | Medical Sciences (Blood and Cardiovascular) |
Keywords: | Atherosclerosis;Diabetes;Cardiovascular Disease |
Publication Date: | 2023 |
Abstract: | Cardiovascular disease (CVD) is the leading cause of mortality worldwide. CVD risk factors include diabetes, dyslipidemia, hypertension, and obesity. Atherosclerosis is the major underlying cause of CVD. Endothelial cells (ECs) line the vasculature and function to maintain homeostasis and regulate blood vessel dynamics. Endothelial activation is thought to be an early predictor of atherosclerosis initiation. Studies have concluded that CVD risk factors cause endoplasmic reticulum (ER) stress. More recently, from work in macrophage models, it was found that ER stress may signal through the glycogen synthase kinase (GSK)3α/β pathway to promote atherosclerosis. The aim of this thesis is to examine the role of ER stress-GSK3α/β signalling on endothelial activation and atherosclerosis initiation and progression. This thesis contains three data chapters that each describe the results of a standalone study. Chapter 3 focuses on the role of hyperglycemia in EC activation. ApoE-/-Ins2+/akita and ApoE+/-Ins2+/akita mice were used to examine the effects of hyperglycemia on adhesion protein expression, monocyte/macrophage recruitment and atherosclerotic plaque development at the aortic sinus. The fourth chapter investigates a potential mechanism by which hyperglycemia promotes EC activation in vitro using cultured human aortic endothelial cells (HAEC). 4-phenylbutyric acid (4-PBA), an ER stress attenuator and tideglusib, a GSK3α/β inhibitor, were added to cells cultured in elevated glucose media. Adhesion protein expression and monocyte attachment were assessed. The results of these experiments support a role for glucose-induced ER stress signalling through GSK3α/β in the activation of EC. Chapter 5 describes the results of in vivo experiments examining adhesion protein expression, monocyte/macrophage recruitment and atherosclerotic progression in endothelium-selective GSK3α and GSK3β knockout mice. These experiments are the first to support a role for endothelial GSK3α, but not GSK3β, in the progression and development of atherosclerosis. Together these data show that hyperglycemia, and perhaps other cardiovascular risk factors, promote early EC activation by a mechanism involving ER stress signalling through GSK3α. These findings further support the viability of a strategy to specifically target GSK3α as a way to block or impede atherosclerosis. |
URI: | http://hdl.handle.net/11375/28411 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Mastrogiacomo_Lauren_A_2022 Dec_PhD.pdf | 14.67 MB | Adobe PDF | View/Open |
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