To Örebro University

Interferon gamma (IFN-γ) regulates the expression of numerous genes, many with known immunomodulatory, angiostatic, and antiviral functions. However, the functions of many of these genes in vascular cells and their implications for atherosclerosis remain to be fully understood.

In this thesis, we investigate the functions of IFN-γ-regulated genes in vascular cells to understand their implications for atherosclerosis. In Paper I, we demonstrate RSAD2, a gene strongly induced by IFN-γ, to regulate the expression of CXCR3 chemokines in vascular smooth muscle cells (VSMCs), which are crucial for monocyte migration in vitro. Both VSMCs and macrophages express RSAD2 within human carotid atherosclerotic lesions where RSAD2 also correlates with CXCL10 and CXCL11. In Paper II, we generated a mousemodel of atherosclerosis lacking one or both alleles for RSAD2 and report that RSAD2-deficient mice exhibit reduced body weight without significant differences in plaque size. In Paper III, we observed tumour necrosis factor alpha (TNF-α) to upregulate the expression of genes encoding laminin-332 (LN332). These genes are downregulated by IFN-γ (unpublished results included in this thesis). Endothelial cells, when cultured on LN332, acquire an atherogenic phenotype and the levels of two of the genes encoding LN332 are elevated in human carotid atherosclerotic lesions where they also correlate with TNF-α. In Paper IV we demonstrate IFN-γ to alter the expression of genes involved in glutamine metabolism in VSMCs. Among these, a significant downregulation is observed for the enzyme, glutaminase, which converts glutamine to glutamate, a precursor required for de novo glutathione synthesis, a molecule that counters oxidative damage. Notably, glutaminase expression is significantly reduced in human carotid atherosclerotic lesions. Furthermore, the expression pattern of genes associated with glutamine metabolism in IFN-γ-stimulated VSMCs closely resembles that observed in human carotid lesions. In summary, this thesis investigates the effects of IFN-γ-regulated genes on vascular cells and demonstrates that IFN-γ may exert both pro- and anti-atherogenic effects in vascular cells.