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已检测到幽门螺杆菌、血链球菌、牙龈疫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的发生有关。流行病学研究还表明，牙周感染和牙齿脱落之间存在联系，从而增加了患冠状动脉疾病的风险。最近的研究表明，牙龈假单胞菌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，导致炎症介质的产生，被认为在牙周病和动脉粥样硬化中都发挥了作用。在两种COX异构体中，一般认为可诱导的COX-2异构体合成前列腺素类化合物，而前列腺素类化合物主要负责产生炎症过程。COX-2在病变牙龈组织和动脉粥样硬化病变中表达。由COX-2激活产生的前列腺素E_2(PGE_2)是前列腺素E_2(PGE_2)，它在炎症的牙龈组织中升高。药物COX-2抑制剂可减少载脂蛋白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的形成中起一定作用。此外，骨髓移植的使用已经证明，促动脉粥样硬化的环氧合酶-2的来源是浸润性白细胞。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会产生浓度升高的12-羟基二十碳四烯酸(12-HETE)。至 目前对12/15-LO在牙周疾病中的作用知之甚少，12/15-LO在动脉粥样硬化病变中定位于内皮细胞和巨噬细胞。12/15-LO的高表达诱导脂蛋白氧化和白细胞向血管壁迁移。12/15-LO缺乏症可显著减轻高脂血症小鼠的动脉粥样硬化。此外，15-LO在血管壁的过度表达会导致动脉粥样硬化。因此，这项资助的重点将是确定COX-2和12/15-LO在牙龈假单胞菌诱导的牙槽骨丢失和动脉粥样硬化中的作用。我们的假设是牙龈假单胞菌感染诱导COX-2和12/15-LO在血管壁的表达和激活，从而促进动脉粥样硬化的发生发展。为了验证这一假设，以下是具体目标 建议：具体目的：1.确定COX-2在牙周炎和牙周病中的作用。明确12/15-脂氧合酶在牙周炎和动脉粥样硬化中的作用。这项拟议的研究将提供有关牙周病和动脉粥样硬化之间关系的有用信息。这项研究将为影响这两种疾病的发展和进展的药物治疗的发展提供潜在的靶点。

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.