All ETDs from UAB

Advisory Committee Chair

David W Garber

Advisory Committee Members

Vinod Mishra

R D Watson

Document Type

Thesis

Date of Award

2011

Degree Name by School

Master of Science (MS) College of Arts and Sciences

Abstract

Coronary Artery Disease (CAD) is the leading cause of deaths worldwide, including the United States. Atherosclerosis remains the primary cause of CAD, and is a leading target for drug treatments. Despite advances in treatments, many questions remain unanswered pertaining to the mechanisms of the treatments on inflammation and oxidative stress. We hypothesize that peptides 4F and Ac-hE18A-NH2 act as anti-inflammatory factors and reduce oxidative stress. We also hypothesize that these peptides require apolipoprotein A-I (apoA-I) to increase paraoxonase-1 (PON-1) activity. The effects of administering peptides 4F and Ac-hE18A-NH2 on oxidative stress were evaluated through the analysis of plasma from apoA-I-null mice, or C57BL/6J and C3H/HeJ mice fed either normal chow or the atherogenic Paigen diet. Inflammation was detected through Interleukin-6 (IL-6) and serum amyloid A (SAA) levels. Oxidative stress was measured through levels of free 15-F2-Isoprostanes, oxidized lipids, and PON-1 and platelet activating factor acetylhydrolase (PAF-AH) enzymatic activity. Macrophage modulation was examined through immunohistochemistry. Peptide-mediated changes in isoprostane levels, circulating lipid hydroperoxides, PON-1 and PAF-AH activity, or IL-6 levels were not detected. C57BL/6J mice fed the Paigen diet had significantly higher levels of SAA than did C3H mice fed the same diet; treatment with 4F in C57BL/6J mice fed the Paigen diet significantly reduced levels of SAA and decreased aortic sinus macrophage load, but did not change the already lower levels of SAA in C3H mice on the diet. Our results suggest that C3H mice are less susceptible to inflammation on the Paigen diet than C57BL/6J, as seen through concentrations of inflammatory markers. In apoA-I-null mice, cholesterol increased with Ac-hE18A-NH2 treatment after two weeks, suggesting that peptide Ac-hE18A-NH2 may increase apolipoprotein synthesis in these mice; however, PON-1 activity decreased. Treatment of apoA-I null mice with 4F increased PON-1 activity acutely but not chronically, and did not change plasma cholesterol levels. Our results suggest that peptide 4F may require apoA-I to chronically increase PON-1 activity. The information obtained from this study has provided insight into potential mechanisms by which peptide 4F and Ac-hE18A-NH2 affect inflammation and oxidative stress, as well as the role of apoA-I in peptide function.

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