Regulation of macrophage function related to atherosclerosis development
department or school: Medicine, Faculty of
department or school: Medicine, Department of
data provider: DSpace
degree campus: UBCV
creator: Zhang, Peng
issued: 2015-12-31T00:00:00Z
issued: 2015
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Atherosclerosis has been identified as a chronic inflammatory disease resulting from interactions between immune cells and their microenvironment in the walls of susceptible arteries. Macrophages, critical players in innate immunity, participate in major events throughout all stages of atherosclerosis progression. Work in this dissertation is specifically interested in regulation of macrophage functions in the context of atherosclerosis. First, using bone marrow transplantation, we investigated how loss of eukaryotic elongation factor 2 kinase (eEF2K) activity affected atherosclerosis progression. Compared to mice transplanted with wild-type bone marrow, mice transplanted with bone marrow from eEF2K deficient mice had reduced atherosclerosis development after being fed with high-fat diet for 16 weeks. Impaired tumor necrosis factor-α release and subsequent adhesion molecule expression in the eEF2K inactive group may account for the reduction of atherosclerotic plaques. This finding suggested that the eEF2K inhibitor may be clinically useful to treat atherosclerosis. Second, we examined how oxLDL was involved in macrophage plasticity. We found that oxLDL polarized macrophages towards a novel subtype named MoL, which was characterized by high expression levels of heme oxygenase-1 and macrophage inhibitory cytokine-1. MoL cells are polarized, in part, through the activation of the PI3K/Akt pathway. MoL cells specifically up-regulates vascular cell adhesion molecule-1. This finding provided a more comprehensive view of macrophage plasticity in the context of atherosclerosis. Finally, we investigated signal transduction of ceramide 1-phosphate induced vascular endothelial growth factor release in macrophages. Using pharmaceutical inhibitors, we ruled out contributions of p38 MAPK and PKC-ζ signalling, and showed that the PI3K/Akt and MEK/ERK pathways were responsible for this process. Although we have no solid evidence to conclude on the mechanisms by which signals trans…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/53971
note: REGULATION OF MACROPHAGE FUNCTION RELATED TO ATHEROSCLEROSIS DEVELOPMENT by PENG ZHANG B.S., Peking University, 2006 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) June 2015 © Peng Zhang, 2015 ii Abstract Atherosclerosis has been identified as a chronic inflammatory disease resulting from interactions between immune cells and their microenvironment in the walls of susceptible arteries. Macrophages, critical players in innate immunity, participate in major events throughout all stages of atherosclerosis progression. Work in this dissertation is specifically interested in regulation of macrophage functions in the context of atherosclerosis. First, using bone marrow transplantation, we investigated how loss of eukaryotic elongation factor 2 kinase (eEF2K) activity affected atherosclerosis progression. Compared to mice transplanted with wild-type bone marrow, mice transplanted with bone marrow from eEF2K deficient mice had reduced atherosclerosis development after being fed with high-fat diet for 16 weeks. Impaired tumor necrosis factor-α release and subsequent adhesion molecule expression in the eEF2K inactive group may account for the reduction of atherosclerotic plaques. This finding suggested that the eEF2K inhibitor may be clinically useful to treat atherosclerosis. Second, we examined how oxLDL was involved in macrophage plasticity. We found that oxLDL polarized macrophages towards a novel subtype named MoL, which was characterized by high expression levels of heme oxygenase-1 and macrophage inhibitory cytokine-1. MoL cells are polarized, in part, through the activation of the PI3K/Akt pathway. MoL cells specifically up-regulates vascular cell adhesion molecule-1. This finding provided a more comprehensive view of macrophage plasticity in the context of atherosclerosis. Finally, we investig…
has type: Thesis/Dissertation
date issued: 2015-09
is shown at: 10.14288/1.0166327
language: eng
degree discipline: Experimental Medicine
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivs 2.5 Canada
rights URI: http://creativecommons.org/licenses/by-nc-nd/2.5/ca/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/53971