Thesis Format
Monograph
Degree
Doctor of Philosophy
Program
Microbiology and Immunology
Supervisor
Heit, Bryan
Abstract
Atherosclerosis is one of the primary causes of cardiovascular disease which is one of the leading causes of death worldwide. It is a chronic inflammatory disease characterized by the formation of lipid-rich plaques comprised of lipoproteins, apoptotic cells, and immune cells within the intima of blood vessels in the heart and other tissues. Intimal macrophages play a central role in the development of atherosclerosis where they lose efferocytic activity – the phagocytic clearance of apoptotic cells – allowing the accumulation of necrotic cells in the atherosclerotic plaque. Our lab found that defects in macrophage efferocytosis occur due to the overexpression of the hematopoietic transcription factor GATA2. In this thesis, we investigated the pathways that regulate GATA2 expression in macrophages and identified the GATA2-regulated genes that promote atherogenesis. We found higher GATA2 expression in the circulating monocytes of ~50% of atherosclerosis patients with higher GATA2 in all patient’s monocyte-derived macrophages. Plasma PDGF-AB/BB and cholesterol are elevated in some patients when PDGF-AB/BB induced GATA2 expression and GATA2 expression strongly correlated with cholesterol level. Moreover, GATA2-expressing macrophages were identified in the plaques of patients, where GATA2 drives the proliferation of these macrophages, thus contributing to plaque development. Although GATA2 can be expressed from two promoters, we determined that only the internal (IG) promoter is used by macrophages. Atherogenic stimuli induce GATA2 expression from the IG promoter via NF-кB, AHR, and STAT1, while pan-activator of the retinoic acid and retinoid X receptors, all-trans-retinoic acid and AP-1 negatively regulates GATA2 expression. Through ChIP-seq, we identified that GATA2 directly regulates several pro-atherogenic genes and genes involved in efferocytosis in plaque macrophages. GATA2 suppressed several genes that limit plaque development including ABCG1, DISP3, and JUN gene expression. GATA2 induced foam cell formation by suppressing ABCG1 and DISP3 expression which are involved in cholesterol homeostasis, and promoting macrophage proliferation by downregulating JUN. This thesis identified that GATA2 promotes atherosclerosis progression by inducing local macrophage proliferation and foam cell formation that accumulates in the plaque. This study provides further insights into the mechanism by which GATA2 promotes atherosclerosis and may identify future therapeutic targets for the treatment of atherosclerosis.
Summary for Lay Audience
Atherosclerosis is caused by the accumulation of cholesterol and dead cells in the heart's blood vessels, which ultimately causes heart disease. Heart macrophages play a central role in the progression of this disease. Normally, macrophages clear the cholesterol and dead cells. However, the excessive accumulation of “bad” cholesterol causes these cells to die, allowing dead cells and cholesterol to build up in the heart blood vessels called atherosclerotic plaque. Our lab discovered that the gene GATA2, which turns other genes on and off, causes macrophages to stop clearing dead cells. In this thesis, we investigated how GATA2 is regulated, which genes are controlled by GATA2 in heart macrophages, and determined how these genes promote the development of atherosclerotic plaque. A major mechanism by which GATA2 was found to drive atherosclerosis was via increasing the number of macrophages in the atherosclerotic plaque by causing these cells to divide. We also found that GATA2 reduces the function of many genes that normally limit atherosclerosis plaque formation. This study provides further understanding of the mechanism by which GATA2 promotes atherosclerosis and may identify future therapeutic targets for treating heart disease.
Recommended Citation
Aktar, Amena, "Overexpression of GATA2 in Atherogenic Macrophages Promotes the Development of Atherosclerosis" (2025). Electronic Thesis and Dissertation Repository. 10740.
https://ir.lib.uwo.ca/etd/10740