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Systems Biology Analysis of Macrophage Foam Cells: Finding a Novel Function for Peroxiredoxin I

Conway, James Patrick

Abstract Details

2007, Doctor of Philosophy, Case Western Reserve University, Physiology and Biophysics.
Atherosclerosis is a type of cardiovascular disease that is characterized by localized thickening of the arteries at sites referred to as atheromas. The earliest events leading to atheroma formation involve the oxidative modification of low-density lipoprotein in the arterial intima, and the uptake of oxidatively-modified low-density lipoprotein by intimal macrophages. This unregulated uptake results in lipid-laden macrophage-derived foam cells, which aggregate at potential sites of atheroma development known as fatty streaks. We hypothesized that the transition from macrophage to foam cell is characterized by differential expression that, as a whole, is pro-atherogenic. A proteomic and transcriptomic analysis identified several proteins and mRNA transcripts that were differentially-regulated following acute and chronic exposure to oxLDL, including mediators of antioxidant and immune response. Further, chronic oxLDL exposure led to a decrease in oxLDL-induced toxicity, which coincided with an increased antioxidant response when compared to macrophages treated with a single exposure to oxLDL. Data obtained from the analysis of differential expression in foam cells provided a foundation for the second stage of this project. Peroxiredoxin I was identified as a protein that is upregulated in macrophages following exposure to oxLDL, which led to the hypothesis that the upregulation of peroxiredoxin I could protect against toxicity induced by oxLDL-generated reactive oxygen species. It was determined that peroxiredoxin I can decrease oxLDL-induced toxicity when induced prior to oxLDL-exposure. This effect coincides with a decrease in reactive oxygen species, verifying the antioxidant role of peroxiredoxin I. Additionally, alternative functionality for peroxiredoxin I was tested, and it was determined that the activation of p38 MAPK is dependent on peroxiredoxin I expression. The sum of this data suggests that peroxiredoxin I contributes to cell survival and signaling, which affects macrophage foam cell function and survival.
Mike Kinter (Advisor)
171 p.

Recommended Citations

Citations

  • Conway, J. P. (2007). Systems Biology Analysis of Macrophage Foam Cells: Finding a Novel Function for Peroxiredoxin I [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1156961185

    APA Style (7th edition)

  • Conway, James. Systems Biology Analysis of Macrophage Foam Cells: Finding a Novel Function for Peroxiredoxin I. 2007. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1156961185.

    MLA Style (8th edition)

  • Conway, James. "Systems Biology Analysis of Macrophage Foam Cells: Finding a Novel Function for Peroxiredoxin I." Doctoral dissertation, Case Western Reserve University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1156961185

    Chicago Manual of Style (17th edition)