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UBC Theses and Dissertations

Therapeutic use of a mutant Caveolin-1 peptide to reduce atherosclerosis induced by hypercholesterolemia and diabetes Sharma, Arpeeta


Endothelial dysfunction is a well-established response to cardiovascular risk factors, such as hypercholesterolemia and diabetes, and is the critical first step of atherogenesis. Nitric oxide (NO), the key regulator of endothelial function, is greatly diminished in atherosclerotic disease settings resulting in augmented oxidative stress and endothelial activation, a process that involves upregulation of endothelial adhesion molecules and increased leukocyte-endothelial interactions, all of which are major steps in the pathogenesis of atherosclerosis. Pharmacological inhibition of endothelial nitric oxide synthase (eNOS), the main vascular source of protective NO, induces endothelial dysfunction and promotes atherosclerosis. While there is little doubt that endothelial dysfunction is directly linked to atherosclerosis and cardiovascular disease in patients, whether the endogenous pool of eNOS and associated NO release can be considered a direct, therapeutically relevant primary target for atheroprotection is unknown. Caveolin-1 (Cav-1), the major coat protein of plasma membrane caveolae, binds to and inhibits endogenous eNOS. Previously, we have reported that a Cav-1-derived cell permeable peptide with an inactivated eNOS inhibitory domain, known as CavNOxin is able to increase basal NO release without interfering with the biological activities of Cav-1. Herein the current thesis, I hypothesize that ‘antagonizing’ the eNOS/Cav-1 interaction to specifically relieve eNOS from the inhibitory clamp of Cav-1, through the intracellular delivery of CavNOxin, is a potentially novel and unexplored anti-atherosclerotic therapeutic strategy. I show that CavNOxin is able to significantly attenuate hypercholesterolemia- and diabetes-induced atherosclerosis. In contrast, mice lacking eNOS showed resistance to CavNOxin treatment, indicating eNOS specificity. Mechanistically, I show that CavNOxin reduces oxidative stress, expression of pro-atherogenic mediators (in particular VCAM-1) and leukocyte-endothelial interactions. These data are the first to document the use of an eNOS-specific activator to directly reduce oxidative stress and increase atheroprotective endothelial function specifically through endogenous eNOS. In addition, this study provides target validation for the eNOS/Cav-1 interaction, which is highly endothelium-specific, as a strategy for the development of anti-atherosclerotic compounds.

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