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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070860-02
Application #
6727577
Study Section
Pathology A Study Section (PTHA)
Program Officer
Applebaum-Bowden, Deborah
Project Start
2003-05-01
Project End
2007-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
2
Fiscal Year
2004
Total Cost
$258,125
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Snyder, Gary D; Oberley-Deegan, Rebecca E; Goss, Kelli L et al. (2008) Surfactant protein D is expressed and modulates inflammatory responses in human coronary artery smooth muscle cells. Am J Physiol Heart Circ Physiol 294:H2053-9
Qin, Zhenyu; Reszka, Krzysztof J; Fukai, Tohru et al. (2008) Extracellular superoxide dismutase (ecSOD) in vascular biology: an update on exogenous gene transfer and endogenous regulators of ecSOD. Transl Res 151:68-78
McCormick, Michael L; Gavrila, Dan; Weintraub, Neal L (2007) Role of oxidative stress in the pathogenesis of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 27:461-9
Shaheen, Mazen; Weintraub, Neal L (2007) Osteopontin: a bona fide mediator of abdominal aortic aneurysm? Arterioscler Thromb Vasc Biol 27:439-41
Coyle, Christian H; Martinez, Luis J; Coleman, Mitchell C et al. (2006) Mechanisms of H2O2-induced oxidative stress in endothelial cells. Free Radic Biol Med 40:2206-13
Fang, Xiang; Faraci, Frank M; Kaduce, Terry L et al. (2006) 20-Hydroxyeicosatetraenoic acid is a potent dilator of mouse basilar artery: role of cyclooxygenase. Am J Physiol Heart Circ Physiol 291:H2301-7
Thomas, Manesh; Gavrila, Dan; McCormick, Michael L et al. (2006) Deletion of p47phox attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient mice. Circulation 114:404-13
Fang, Xiang; Hu, Shanming; Xu, Bingkun et al. (2006) 14,15-Dihydroxyeicosatrienoic acid activates peroxisome proliferator-activated receptor-alpha. Am J Physiol Heart Circ Physiol 290:H55-63
Kabra, Rajesh; Welke, Karl F; Kernstine, Kemp H et al. (2005) Bacterial pericarditis due to group F streptococci as a complication of esophagomediastinal fistula. Ann Thorac Surg 79:2132-4
Collins, Xixuan H; Harmon, Shawn D; Kaduce, Terry L et al. (2005) Omega-oxidation of 20-hydroxyeicosatetraenoic acid (20-HETE) in cerebral microvascular smooth muscle and endothelium by alcohol dehydrogenase 4. J Biol Chem 280:33157-64

Showing the most recent 10 out of 17 publications