Atherosclerosis, the most common cause of death in the United States, is a chronic inflammatory disorder. The sources of inflammation, and the mechanisms by which the inflammation leads to vascular disease, however, remain to be elucidated. Levels of circulating endotoxin, a glycolipid component of the outer membrane of Gram-negative bacteria, are markedly elevated during Gram-negative septicemia and lead to acute vascular inflammatory injury. Very recently, endotoxemia at much lower levels (i.e., >50 pg/ml) has been identified as a strong risk factor for atherosclerosis, particularly among smokers. Endotoxemia in apparently healthy subjects may result from chronic or recurrent infection, periodontitis, or breaching of epithelial barrier function. However, the extent of endothelial dysfunction caused by low levels of endotoxin, and its potential role in the pathogenesis of atherosclerosis, remain to be determined. Preliminary data from our laboratocy indicate that relatively low levels of endotoxin (i.e., 1 ng/ml) increase the levels of reactive oxygen species (ROS), induce the pro-inflammatory cytokines interleukin-8 and monocyte chemoattractant peptide-1, and promote U-937 monocyte binding to human coronary artery endothelial cells. Similarly, very low levels of endotoxin ( equal to approximately 30 pg/ml) induce inflammatory responses in human coronary artery smooth muscle cells and human blood vessel explants. These endotoxin-mediated pro-inflammatory effects are blocked by pre-treatment with HMG-CoA reductase inhibitors (statins) and epoxyeicosatrienoic acids (EETs), endothelium-derived metabolites of the polyunsaturated fatty acid arachidonic acid, which has potentially important implications for atherosclerosis and its treatment. Our hypothesis is that subclinical levels of endotoxin cause pro-inflammatory activation of human coronary artery endothelial and smooth muscle cells, and intact human blood vessels, and that these effects can be modulated by statins, EETs and fatty acids.
Four specific aims are proposed, in which we will investigate the mechanisms of endotoxin signaling in vascular cells, the sources and consequences of endotoxin-induced ROS production, the regulation of endotoxin by specific binding proteins and enzymatic degradation, and the capacity of statins, EETs and other fatty acids to modulate endotoxin bioactivity. The proposed studies will provide novel insight into the mechanisms by which endotoxin-mediated vascular inflammation may contribute to atherosclerosis.
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