Molecular mechanisms in vascular inflammation

Sammanfattning: Vascular inflammation plays an important role in a multitude of major diseases including sepsis and atherosclerosis. Sepsis has been estimated to account for more than 100 000 deaths per year in Europe. Cardiovascular disease, of which atherosclerosis is a common pathological basis, is the leading cause of death in the Western world and predicted to become the leading cause of death globally. Inflammation plays a significant role in the development of atherosclerosis and aggravation of inflammation has been linked to precipitation of clinical manifestations such as myocardial infarction. Therefore, therapeutic modulation of inflammation has emerged as a potential treatment strategy in cardiovascular disease. In an effort to shed more light on the response to activation of the arterial innate immunity, the global transcriptional response to endotoxin in explanted human arteries was investigated using Affymetrix Gene Chip® arrays. Transcripts were subsequently selected for further studies on the basis of a combination of strong response to endotoxin and potential immunologic functions. The four selected molecules were studied in the context of vascular inflammation and atherosclerosis using cell cultures, atherosclerosis prone hypercholesterolemic mice and/or clinical cohorts. 1) The conserved inhibitor of viral replication cig5/viperin was found in vascular inflammation and atherosclerosis. Cig5/viperin was induced by several stimuli of the innate immune system and detected in endothelial cells in human atherosclerotic lesions. Since cig5/viperin inhibits virus replication, its function in vascular inflammation may relate to disease-associated pathogens and play a role in the vascular innate immune defense. However, viperin levels in human atherosclerosis did not correlate to anti-cytomegalovirus antibody titers. 2) The tumor necrosis factor superfamily (TNFSF) member CD137 was found to promote a pro-inflammatory phenotype of atherosclerotic lesions. CD137 was detected on T cells and endothelial cells, and its ligand, CD137L, on macrophages in atherosclerotic lesions. Activation of CD137 reduced proliferation of smooth muscle cells and upregulated adhesion molecules on endothelial cells in vitro. A CD137 agonist increased vascular T cell infiltration and immune activation in mice. CD137 mRNA levels in human atherosclerotic lesions correlated to transcripts associated with lesion destabilisation such as matrix metalloproteinases and pro-inflammatory mediators. Taken together, CD137 was associated with processes that are likely to make atherosclerotic lesions more prone to rupture. 3) The TNFSF member OX40L was found in human atherosclerotic lesions, mRNA levels correlated with markers for T cell activation and infiltration and OX40L mRNA was regulated by TNF-alpha in endothelial cells in vitro. However, the OX40L genotype did not significantly influence the risk for carotid artery disease or stroke and did not alter known systemic risk factors for cardiovascular disease. Hence, OX40L may be involved in local immune activation in atherosclerotic lesions, but, although a certain OX40L genotype has been associated with increased risk for myocardial infarction in women, this genotype did not significantly influence the risk for stroke. 4) CXCL16 was found on smooth muscle cells in human atherosclerotic lesions and shown to be regulated by interferon gamma in smooth muscle cells in vitro. In summary, the investigation of the global transcriptional response to innate immune activation and the subsequent hypothesis-based studies suggest functions for immunoregulatory molecules new in the context of vascular inflammation pertaining to host defense and recruitment and activation of leukocytes.