Expression profiling of human macrophages and atherosclerotic plaques to identify genes and mechanisms that modulate the development of atherosclerosis
Year: 2008
Type: dissertation
Study design: Observational Study
Abstract: Macrophages play an important role in atherosclerosis, a disease that affects large and\nmedium size arteries and causes clinical manifestations such as myocardial infarction or\nstroke. The aim of this thesis was to identify genes that are important in the development of\natherosclerosis. Genes that have their major site of expression in macrophages or in\natherosclerotic plaques, or are differently expressed in macrophages from subjects with\natherosclerosis compared with macrophages from control subjects may affect atherogenesis.\nBy comparing DNA microarray expression profiles of macrophages and atherosclerotic\nplaques with expression profiles from major tissues and cell types, macrophage and plaque\nspecific genes were identified. The macrophage specific anti-inflammatory cytokine\ninterleukin 1 receptor antagonist (IL1RN) was down regulated by oxidized low-density\nlipoprotein (LDL), suggesting a novel pro-inflammatory role of oxidized LDL.\nImmunohistochemistry showed that the plaque specific gene chemokine CC motif ligand 18\n(CCL18) co-localized with macrophages in the plaques. In addition, macrophages from\nsubjects with atherosclerosis had more than two-fold higher gene expression of CCL18 than\nmacrophages from subjects without atherosclerosis. CCL18 is chemotactic for leukocytes and\nmay therefore contribute to plaque inflammation. A promoter region polymorphism of the\nCCL18 gene was associated with increased macrophage CCL18 gene expression, but not with\nan increased risk of coronary heart disease (CHD).\nComparison of macrophage expression profiles from subjects with atherosclerosis and control\nsubjects identified 27 genes with an altered expression. Among these genes, CD44 and insulin\nreceptor substrate 2 (IRS2) were both expressed at higher levels in macrophages from subjects\nwith atherosclerosis compared with macrophages from control subjects.\nImmunohistochemistry showed that IRS2, an intracellular signaling molecule important in\nmetabolism, was expressed in macrophages and endothelial cells in human carotid plaques.\nThe C allele of the -765C→T SNP in the promoter region of the IRS2 gene was associated\nwith increased macrophage expression of IRS2, and subjects homozygous for the C allele had\n40% increased risk of coronary heart disease. The receptor CD44 mediates adhesion of\nmonocytes to the vascular wall, a crucial step in atherosclerosis. CD44 expression correlated\nwith secretion of interleukin 6 (IL-6) in macrophages, and IL-6 augmented CD44 expression\nin macrophages. In addition, CD44 deficient mice had lower circulating IL-6 than wild type\nmice. This suggests a positive feed-back loop between IL-6 and CD44, and that CD44 may\naffect atherosclerosis progression by modulating the inflammatory response.\nIn conclusion, IRS2 might be a new susceptibility gene for atherosclerosis and CHD. CCL18,\nIL1RN and CD44 may play important roles in the development of atherosclerosis.
Author: Daniel Hägg
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1506882367