Title

Regulation of Vascular Endothelial Function by Oxidative Stress and Dietary Antioxidants

Date of Completion

January 2011

Keywords

Health Sciences, Nutrition

Degree

Ph.D.

Abstract

Cardiovascular disease (CVD) is the leading cause of death in the U.S., accounting for ∼810,000 deaths annually. The involvement of oxidative/nitrative stress and pro-inflammatory responses in CVD pathogenesis suggests that improvement in antioxidant defenses could be a viable strategy to decrease CVD risk. Furthermore, oxidative stress is also implicated in vascular endothelial dysfunction (VED), an early indicator of CVD risk. Thus, it is important to better define the redox-sensitive events leading to VED and investigate the contribution of antioxidant defenses in regulating vascular endothelial function. Therefore, the central hypothesis of this dissertation is that greater oxidative/nitrative stress and pro-inflammatory responses induce VED and that improvements in antioxidant status can protect against these responses to maintain proper vascular endothelial function. By assessing vascular endothelial function using flow-mediated dilation of the brachial artery (FMD), low vitamin C status was observed to be associated with pro-inflammatory responses and VED in healthy college-aged men. To better define the role of antioxidants in vascular endothelial function and to examine if improvements in antioxidant status can protect against VED, the effect of short-term γ-tocopherol supplementation (500 mg γ-tocopherol/d, 70% γ-tocopherol, 5 d) in regulating redox-sensitive responses and attenuating VED was investigated in an in vivo model of oxidative stress by administering an oral glucose challenge in healthy young men. γ-Tocopherol supplementation attenuated postprandial hyperglycemia-mediated lipid peroxidation and increases in the ratio of asymmetric dimethylarginine to arginine (ADMA/arginine), an index of CVD risk, thus possibly mitigating disruptions in nitric oxide production by endothelial nitric oxide synthase. Consistent with these observations, y-tocopherol effectively restored FMD responses that were otherwise impaired following glucose ingestion. In conclusion, this dissertation demonstrates the role of vitamin C and E in maintaining proper fasting and postprandial vascular endothelial function in healthy individuals. Therefore, efforts to increase vitamin C and γ-tocopherol status such as greater fruit and vegetable consumption and γ-tocopherol supplementation may be effective dietary strategies to maintain proper vascular endothelial function and cardiovascular health in healthy individuals. Ultimately, the findings of this dissertation contribute to current efforts to eliminate CVD as the leading cause of mortality and morbidity in the U.S. ^