Atherosclerosis and periodontal disease are both chronic inflammatory diseases. Heliobacter pylori, Streptococcus sanguis, Phyromonas gingivalis (P. gingivalis) cytomegalovirus, and herpes simplex virus have been detected in atheroselerotic plaques, suggesting a link between bacterial and viral pathogens and atherogenesis. Epidemiologic studies have also suggested a link between periodontal infections and tooth loss with an increased risk for coronary artery disease. More recent studies have suggested that periodontal disease induced by P. gingivalis increases atherosclerotic lesion formation in hyperlipidemic mice. P. gingivalis induction of cyclooxygenase (COX) and lipoxygenase (LO) metabolism of arachidonic acid resulting in the production of inflammatory mediators, is suggested to play a role in both periodontal disease and atherosclerosis. Of the two COX isoforms, it is generally considered that the inducible COX-2 isoform synthesizes the prostanoids that are primarily responsible for generating inflammatory processes. COX-2 is expressed in diseased gingival tissue and atherosclerotic lesions. One of the prostanoids produced by COX-2 activation is prostaglandin E2 (PGE2) which is elevated in inflamed gingival tissues. Pharmacological COX-2 inhibitors reduce the size of atherosclerotic lesions in apolipoprotein E-/- (apoE) mice, suggesting that COX-2 plays a role in atherosclerotic lesion formation. Additionally, the use of bone marrow transplantation has demonstrated that the source of pro-atherogenic COX-2 is the infiltrating leukocytes. 12/15-LO is expressed in diseased gingival tissues and atherosclerotic lesions. Diseased gingival tissues produce increased concentrations of 12-hydroxyeicosatetraenoic acid (12-HETE) in vivo. To date little is known about the role of 12/15-LO in periodontal disease, 12/15-LO is localized to endothelial cells and macrophages in atherosclerofic lesions. Increased expression of 12/15-LO induces oxidation of lipoproteins and migration of leukocytes into the vascular wall. 12/15-LO deficiency markedly decreases atherosclerosis in hyperlipidemic mice. Moreover, 15-LO overexpression in the vascular wall induces atherosclerosis. Therefore, the focus of this grant will be to determine the role of COX-2 and 12/15-LO in P. gingivalis-induced alveolar bone loss and atherosclerosis. Our hypothesis is that P. gingivalis infection induces COX-2 and 12/15-LO expression and activation in the vascular wall thereby promoting the development and progression of atherogenesis. To test this hypothesis, the following specific aims are proposed:
Specific Aim 1. Determine the role of COX-2 in P. gingivalis-induced periodontal disease and athcrosderosis.
Specific Aim 2. Define the role of 12/15-lipoxygenase in P. gingivalis-induced periodontal disease and atherosclerosis. The proposed research will supply useful information about the relationship between periodontal disease and atheroselerosis. This research will provide insight into potential targets for the development of pharmacologic treatments influencing the development and progression of both of these diseases.
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