Molecular mechanisms in vascular inflammation
Year: 2008
Type: dissertation
Abstract: Vascular inflammation plays an important role in a multitude of major \ndiseases including sepsis and atherosclerosis. Sepsis has been estimated \nto account for more than 100 000 deaths per year in Europe. \nCardiovascular disease, of which atherosclerosis is a common pathological \nbasis, is the leading cause of death in the Western world and predicted \nto become the leading cause of death globally. Inflammation plays a \nsignificant role in the development of atherosclerosis and aggravation of \ninflammation has been linked to precipitation of clinical manifestations \nsuch as myocardial infarction. Therefore, therapeutic modulation of \ninflammation has emerged as a potential treatment strategy in \ncardiovascular disease. \n \n \n \nIn an effort to shed more light on the response to activation of the \narterial innate immunity, the global transcriptional response to \nendotoxin in explanted human arteries was investigated using Affymetrix \nGene Chip® arrays. Transcripts were subsequently selected for further \nstudies on the basis of a combination of strong response to endotoxin and \npotential immunologic functions. The four selected molecules were studied \nin the context of vascular inflammation and atherosclerosis using cell \ncultures, atherosclerosis prone hypercholesterolemic mice and/or clinical \ncohorts. \n \n \n \n1) The conserved inhibitor of viral replication cig5/viperin was found in \nvascular inflammation and atherosclerosis. Cig5/viperin was induced by \nseveral stimuli of the innate immune system and detected in endothelial \ncells in human atherosclerotic lesions. Since cig5/viperin inhibits virus \nreplication, its function in vascular inflammation may relate to \ndisease-associated pathogens and play a role in the vascular innate \nimmune defense. However, viperin levels in human atherosclerosis did not \ncorrelate to anti-cytomegalovirus antibody titers. \n \n \n \n2) The tumor necrosis factor superfamily (TNFSF) member CD137 was found \nto promote a pro-inflammatory phenotype of atherosclerotic lesions. CD137 \nwas detected on T cells and endothelial cells, and its ligand, CD137L, on \nmacrophages in atherosclerotic lesions. Activation of CD137 reduced \nproliferation of smooth muscle cells and upregulated adhesion molecules \non endothelial cells in vitro. A CD137 agonist increased vascular T cell \ninfiltration and immune activation in mice. CD137 mRNA levels in human \natherosclerotic lesions correlated to transcripts associated with lesion \ndestabilisation such as matrix metalloproteinases and pro-inflammatory \nmediators. Taken together, CD137 was associated with processes that are \nlikely to make atherosclerotic lesions more prone to rupture. \n \n \n \n3) The TNFSF member OX40L was found in human atherosclerotic lesions, \nmRNA levels correlated with markers for T cell activation and \ninfiltration and OX40L mRNA was regulated by TNF-alpha in endothelial \ncells in vitro. However, the OX40L genotype did not significantly \ninfluence the risk for carotid artery disease or stroke and did not alter \nknown systemic risk factors for cardiovascular disease. Hence, OX40L may \nbe involved in local immune activation in atherosclerotic lesions, but, \nalthough a certain OX40L genotype has been associated with increased risk \nfor myocardial infarction in women, this genotype did not significantly \ninfluence the risk for stroke. \n \n \n \n4) CXCL16 was found on smooth muscle cells in human atherosclerotic \nlesions and shown to be regulated by interferon gamma in smooth muscle \ncells in vitro. In summary, the investigation of the global \ntranscriptional response to innate immune activation and the subsequent \nhypothesis-based studies suggest functions for immunoregulatory molecules \nnew in the context of vascular inflammation pertaining to host defense \nand recruitment and activation of leukocytes.
Source: Figshare
Author: Peder S. Olofsson
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2103869539