Published online before print October 7, 2004, doi: 10.1161/01.ATV.0000147534.69062.dc
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© 2004 American Heart Association, Inc.
Brief Reviews |
Potential Role of Endotoxin as a Proinflammatory Mediator of Atherosclerosis
From the Department of Internal Medicine, Divisions of Cardiovascular Diseases (L.L.S., N.L.W.) and Infectious Diseases (G.M.D.), University of Iowa and The VA Medical Center, Iowa City, Iowa.
Correspondence to Dr Lynn L. Stoll, Department of Internal Medicine, Division of Cardiovascular Diseases, E 317C GH, University of Iowa, Iowa City, IA 52242. E-mail stolll{at}mail.medicine.uiowa.edu
Atherosclerosis is increasingly recognized as a chronic inflammatory disease. Although a variety of inflammatory markers (ie, C-reactive protein) have been associated with atherosclerosis and its consequences, it is important to identify principal mediators of the inflammatory responses. One potentially important source of vascular inflammation in atherosclerosis is bacterial endotoxin. Mutations in Toll-like receptor 4 (TLR-4), an integral component of the endotoxin signaling complex, are fairly common in the Caucasian population and have recently been associated with reduced incidence of atherosclerosis and other cardiovascular diseases in some studies. Moreover, epidemiological studies suggest that endotoxemia at levels as low as 50 pg/mL constitutes a strong risk factor for the development of atherosclerosis. Endotoxin concentrations in this range may be produced by a variety of common subclinical Gram-negative infections. In this article, we outline the main elements of the endotoxin signaling receptor complex that initiates proinflammatory signaling (lipopolysaccharide binding protein [LBP], CD14, TLR-4, and MD-2) and discuss how changes in expression of these molecules may affect proatherogenic responses in the vessel wall. We also describe some of the proinflammatory effects of endotoxin that may be relevant to atherosclerosis, and discuss how serum lipoproteins, especially high-density lipoprotein, may modulate endotoxin-induced inflammatory responses. Further, we discuss recent findings suggesting that the lipid-lowering statins may have an additional protective role in blocking at least some of these proinflammatory signaling pathways. Finally, we discuss species diversity with regard to endotoxin signaling that should be considered when extrapolating experimental data from animal models to humans.
Bacterial endotoxin is a potential source of vascular inflammation and may be an important risk factor for atherosclerosis. Here, we discuss the endotoxin signaling pathway, vascular proinflammatory effects of endotoxin and their relevance to atherogenesis, interactions between endotoxin and serum lipoproteins, and possible immunomodulatory effects of statins.
Key Words: inflammation • vascular smooth muscle cells • endothelial cells • lipopolysaccharide • species specificity
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