Abstract
We conducted large scale gene expression analysis of the response of macrophages to exposure to oxidized low density lipoprotein (Ox-LDL). Much of the vessel wall lesion of atherosclerosis is composed of macrophages that have become engorged with cholesterol. These resulting "foam cells" contribute to the progression of vascular disease through several pathways. As a potential model of foam cell formation, we treated THP-1 cells with 12-O-tetradecanoylphorbol 13-acetate to differentiate them into a macrophage-like phenotype and subsequently treated them with oxidized low density lipoprotein for various time periods. RNA from Ox-LDL treated and time-matched control untreated cells was hybridized to microarrays containing 9808 human genes. 268 genes were found to be at least 2-fold regulated at one or more time points. These regulation patterns were classified into seven clusters of expression profiles. The data is discussed in terms of the overall pattern of gene expression, the thematic classification of the responding genes, and the clustering of functional groups in distinct expression patterns. The magnitude and the temporal patterns of gene expression identified known and novel molecular components of the cellular response that are implicated in the growth, survival, migratory, inflammatory, and matrix remodeling activity of vessel wall macrophages. In particular, the role of nuclear receptors in mediating the gene expression modulation by Ox-LDL is highlighted.
Highlights
Atherosclerosis, and the resulting coronary heart disease and cerebral stroke, represent the most common cause of death in industrialized nations
Extensively oxidized oxidized low density lipoprotein (Ox-low density lipoprotein (LDL)) becomes a ligand for scavenger receptor A and the other receptors that contribute to foam cell formation by facilitating uptake of lipoprotein particles
Our preliminary experiments have established that comparing RNA from Ox-LDL-treated cells to cells from time 0 revealed many changes that were due to PMA effects and masked specific Ox-LDL changes
Summary
Atherosclerosis, and the resulting coronary heart disease and cerebral stroke, represent the most common cause of death in industrialized nations. Cholesterol content is tightly controlled by feedback regulation of low density lipoprotein (LDL) receptors and biosynthetic enzymes [1] Consistent with their roles as scavenger cells, macrophages contain several receptors that, in addition to facilitating the removal of apoptotic cells and cell debris, facilitate the loading of oxidatively modified LDL. Numerous studies have described a variety of foam cell responses that would contribute to the growth and rupture of the vessel wall plaques of atherosclerosis These include the production of multiple growth factors and cytokines, which promote the proliferation and adherence of neighboring cells; chemokines, which can attract further circulating monocytes into the growing plaque; proteins that cause remodeling of the extracellular matrix; and tissue factors, which can trigger thrombosis [3, 4]. RNA from Ox-LDL and non-exposed cells was labeled and applied to microarrays to assay the relative expression of 9808 human genes in response to the stimulus. 268 genes were significantly affected by Ox-LDL exposure, providing insights into the patterns of transcriptional response and identifying individual genes whose regulation can alter the survival and migration of macrophages and their effects on surrounding tissue and circulating leukocytes
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