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Lipophilic Compound-Mediated Gene Expression and Implications for Reactive Oxygen Species (ROS)-Related Diseases
AuthorNakamura, Yukiko Kawashima
AdvisorOmaye, Stanley T
Natural Resources and Environmental Science
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Cardiovascular disease (CVD) is a major cause of death in developed countries, and most cardiovascular events are secondary to atherosclerosis. Atherosclerosis is viewed as a chronic inflammatory disease with underlying abnormality in redox-mediated signals in the vasculature. Excessive reactive oxygen species (ROS) generation is implicated in CVD. ROS play a role in oxidizing biomolecules, i.e., low-density lipoprotein (LDL), and in altering gene expression, i.e., proinflammatory and atherogenic gene expression. The antioxidant defense system consists of endogenous and exogenous antioxidants. It prevents ROS generation, subsequent oxidative chain reactions, and ROS-induced signaling/gene expression. Conjugated linoleic acid (CLA) isomers and vitamin E have shown antioxidant and anti-atherogenic effects in a limited number of studies. Recent studies have suggested that these two compounds are possible activators of peroxisome proliferator activated receptor gamma (PPARγ), a nuclear transcription factor. Synthetic PPARγ activators have exhibited anti-inflammatory and anti-atherogenic effects by inducing the antioxidant enzymes, Cu/Zn superoxide dismutase (SOD) and catalase. These results indicate that the link exists between these lipophilic compounds, expression of antioxidant enzymes, and PPARγ activation. This research consists of three review papers and two experimental studies. The objectives of the review papers were to review the roles of ROS and the antioxidant defense system and the potentials of nutritional interventions, CLA isomers and vitamin E, for modulating ROS generation and ROS-related diseases, such as atherosclerosis. The objectives of the two studies were to examine the potentials of nutritional interventions: the effects of the lipid soluble compounds, CLA isomers and α-tocopherol, on 1) gene regulation of the antioxidant enzymes, Cu/Zn SOD and catalase, and on 2) ROS generation in human umbilical vein endothelial cells. In the CLA review papers, it was concluded that there are multiple factors to be considered for accurate extrapolation and interpretation of the human and animal studies of CLA isomers, such as inter-/intra-species-genetic differences, tissue specificities, age and health status, dose/concentration, isomer types and their purity, and duration of supplementation. With regard to vitamin E, the effects of vitamin E may be multifunctional: prooxidant and/or antioxidant, inhibitor of ROS-generating enzyme activities, and inducer and/or inhibitor of gene and protein expression, depending on microenvironments. We also conclude that the modulation of ROS-related diseases by CLA isomers and vitamin E may involve the control of redox status by regulating genes whose products influence ROS generation through redox-sensitive transcription factors, such as PPARγ and NF-κB. The results of our experimental studies support the hypothesis that expression of the antioxidant enzymes is mediated by CLA isomers and α-tocopherol through PPARγ and/or NF-κB. The expression mediated by these compounds appears to be concentration-dependent. The expression of antioxidant enzymes was positively correlated with lipid peroxidation (indicator of ROS generation) exhibiting either stimulatory (prooxidant) or inhibitory (antioxidant) effects on atherogenesis. These results suggest that the amounts of supplemental CLA isomers and α-tocopherol should be tailored and prescribed to elicit beneficial effects, i.e., minimum ROS generation, at individual levels for preventive and therapeutic strategies.