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

英国 DENTAL COBRE：口腔感染：COX-2 和 12/15-L0IN 动脉粥样硬化

• 批准号: 6972170
• 负责人: Charles David Loftin
• 金额: $ 25.98万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-23 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6972170
• 关键词: Bacteroides gingivalis; arachidonate; atherosclerosis; clinical research; enzyme activity; enzyme inhibitors; enzyme linked immunosorbent assay; genetically modified animals; laboratory mouse; lipoxygenase; oral bacteria; periodontitis; polymerase chain reaction; prostaglandin E; prostaglandin endoperoxide synthase

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.

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，表明细菌和病毒病原体与动脉粥样硬化形成之间存在联系。流行病学研究也表明牙周感染和牙齿脱落之间的联系，增加了冠状动脉疾病的风险。最近的研究表明，牙龈卟啉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。牙龈卟啉单胞菌诱导花生四烯酸的环氧合酶（考克斯）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起作用。在两种考克斯同种型中，通常认为诱导型考克斯-2同种型合成前列腺素类，其主要负责产生炎症过程。考克斯-2在病变牙龈组织和动脉粥样硬化病变中表达。由考克斯-2激活产生的前列腺素类之一是前列腺素E2（PGE 2），其在发炎的牙龈组织中升高。药理学考克斯-2抑制剂减少载脂蛋白E-/-（apoE）小鼠动脉粥样硬化病变的大小，表明考克斯-2在动脉粥样硬化病变形成中起作用。此外，骨髓移植的应用已经证明促动脉粥样硬化考克斯-2的来源是浸润的白细胞。12/15-LO在患病牙龈组织和动脉粥样硬化病变中表达。牙龈组织分泌的12-羟基二十碳四烯酸（12-HETE）在体内浓度增加。到 迄今为止，12/15-LO在牙周病中的作用知之甚少，12/15-LO定位于动脉粥样硬化病变中的内皮细胞和巨噬细胞。12/15-LO的表达增加诱导脂蛋白氧化和白细胞迁移到血管壁中。12/15-LO缺乏可显着降低高脂血症小鼠的动脉粥样硬化。此外，15-LO在血管壁中的过度表达诱导动脉粥样硬化。因此，本研究的重点将是确定考克斯-2和12/15-LO在牙龈卟啉单胞菌诱导的牙槽骨丢失和动脉粥样硬化中的作用。我们的假设是牙龈卟啉单胞菌感染诱导血管壁中考克斯-2和12/15-LO的表达和活化，从而促进动脉粥样硬化的发生和进展。为了检验这一假设，以下具体目标是 建议：具体目标1。确定考克斯-2在牙龈卟啉单胞菌诱导的牙周病和牙骨质疏松症中的作用。具体目标2。明确12/15-脂氧合酶在牙龈卟啉单胞菌引起的牙周病和动脉粥样硬化中的作用。本研究为牙周病与动脉粥样硬化的关系提供了有用的信息。这项研究将为开发影响这两种疾病发展和进展的药物治疗提供潜在靶点。