Date of Award

7-1-2004

Degree Type

Restricted Access Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Biochemistry and Molecular Biology

Department

Graduate School of Biomedical Sciences

First Advisor

Lad Dory

Second Advisor

Robert Easom

Third Advisor

Alakananda Basu

Abstract

Anson Pierce, Characterization of a Novel Extracellular Superoxide Dismutase Allele Discovered in Mouse Models of Atherosclerosis. Doctor of Philosophy (Biochemistry and Molecular Biology), July 2004, 128 pp., 3 tables, 22 illustrations, references, 230 titles. Many diseases display some involvement with oxidative mechanisms and could potentially benefit from antioxidant therapy designed to restore the balance between reductive and oxidative factors. Data presented in this dissertation explore and establish the protective effect hyperbaric oxygen (HBO) has on the development of atherosclerosis, an oxidation-driven inflammatory disease mediated through low-density lipoproteins in the vasculature. Atherosclerosis in the apolipoprotein E-/- (apoE-/-) mouse is drastically reduced after 10 weeks of HBO treatment. Macrophages in HBO treated mice have an increased antioxidant capacity and reduced ability to generate oxidants. From this work, a new polymorphism of a key antioxidant enzyme, extracellular superoxide dismutase (ecSOD), is identified and characterized in mice. The new polymorphism is termed the “short” allele, and has the potential to alter the regulation of ecSOD mRNA and protein, as well as enzyme activity. Examination of its effect on the ecSOD phenotype in mice shows dramatic changes in enzyme levels and activity. In the plasma compartment ecSOD activity and mass are elevated, and indicate based on heparin injection studies that a change in ecSOD distribution results in tissues of mice expressing the short allele. Systematic examination of ecSOD in tissues of mice shows that its distribution is altered such that it is more accessible to heparin; this is most evident in the liver and kidney of mice expressing the short allele. The finding that HBO is protective against atherosclerosis highlights a potentially promising approach to treatment for this devastating disease, sheds light on the role oxidative processes play in atherosclerosis, and identifies potential targets for antioxidant therapy. This study also shows for the first time that two alleles for a major antioxidant enzyme exist in mice that display markedly different effects on the ecSOD phenotype, a finding that underlines the importance of genetic homogeneity in mouse models and adds to our knowledge concerning the role antioxidants play in human health and disease.

Comments

Anson Pierce, Characterization of a Novel Extracellular Superoxide Dismutase Allele Discovered in Mouse Models of Atherosclerosis. Doctor of Philosophy (Biochemistry and Molecular Biology), July 2004, 128 pp., 3 tables, 22 illustrations, references, 230 titles W 4 P615C 2004

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