UKY DENTAL COBRE: ORAL INFECTIONS: COX-2 AND 12/15-L0IN ATHEROSCLEROSIS

动脉粥样硬化和牙周病都是慢性炎症性疾病。在动脉粥样硬化斑块中检测到幽门螺杆菌、血链球菌、牙龈卟啉单胞菌（牙龈卟啉单胞菌）巨细胞病毒和单纯疱疹病毒，提示细菌和病毒病原体与动脉粥样硬化发生有关。流行病学研究也表明，牙周感染和牙齿脱落与冠状动脉疾病风险增加之间存在联系。最近的研究表明，牙龈卟啉卟啉引起的牙周病增加了高脂血症小鼠动脉粥样硬化病变的形成。牙龈假单胞菌诱导花生四烯酸的环氧合酶（COX）和脂氧合酶（LO）代谢，从而产生炎症介质，被认为在牙周病和动脉粥样硬化中都起作用。在两种COX亚型中，一般认为可诱导的COX-2亚型可合成主要负责产生炎症过程的前列腺素。COX-2在患病的牙龈组织和动脉粥样硬化病变中表达。COX-2激活产生的前列腺素之一是前列腺素E2 (PGE2)，它在发炎的牙龈组织中升高。药理COX-2抑制剂可减小载脂蛋白E-/- (apoE)小鼠动脉粥样硬化病变的大小，提示COX-2在动脉粥样硬化病变形成中起作用。此外，骨髓移植的应用表明，促动脉粥样硬化COX-2的来源是浸润的白细胞。12/15-LO在病变牙龈组织和动脉粥样硬化病变中表达。患病的牙龈组织在体内产生高浓度的12-羟基二碳四烯酸（12-HETE）。来

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.