Regulation of Vascular Inflammation

血管炎症的调节

• 批准号: 7426027
• 负责人: CHARLES J LOWENSTEIN
• 金额: $ 5.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7426027
• 关键词: Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Applications Grants; Arteriosclerosis; Atherosclerosis; Biological; Clinical Research; Coronary Arteriosclerosis; Coronary heart disease; Cytoplasmic Granules; Cytotoxic T-Lymphocytes; Data; Disease; Endothelial Cells; Exocytosis; Functional disorder; Grant; Heart; Human; Hydrogen Peroxide; Inflammation; Inflammatory; Injury; Knockout Mice; Mediating; Mediator of activation protein; Molecular; Mus; NOS2A gene; NOS3 gene; Nitric Oxide; Pathway interactions; Platelet aggregation; Play; Reactive Oxygen Species; Regulation; Risk; Role; SNAP receptor; Serum Markers; System; Transplantation; Vascular Diseases; Weibel-Palade Bodies; atherogenesis; human NOS2A protein; human NOS3 protein; injured; killings; neurotransmission; novel; vascular inflammation

Atherosclerosis is an inflammatory disease. Clinical studies show that elevated serum markers of inflammation predict an increased risk for atherosclerosis. Animal studies show that inflammatory mediators play a role in atherogenesis. Although pro-inflammatory pathways have been shown to increase atherosclerosis, the protective roles of anti-inflammatory pathways are less well studied. We and others have previously shown that nitric oxide (NO) inhibits vascular diseases. ApoE null mice that also lack the endothelial nitric oxide synthase (eNOS, or NOS3) gene have more severe atherosclerosis than ApoE mice that express NOS3. In humans, endothelial dysfunction (characterized by an inability to produce NO) is associated with coronary artery disease (CAD). Thus, NO may protect the vasculature from atherosclerosis. The molecular mechanisms by which NO inhibits atherosclerosis are unknown. However, we and others recently discovered that NOS decreases inflammation in transplant arteriosclerosis. In particular, we found that the inducible nitric oxide synthase (iNOS, or NOS2) inhibits the release of WeibeI-Palade bodies from endothelial cells in donor hearts. Since WeibeI-Palade bodies contain inflammatory and thrombotic mediators, inhibition of WeibeI-Palade body release may explain part of the anti-inflammatory effects of NO in transplant vasculopathy and other inflammatory vascular diseases, including atherosclerosis. We hypothesize that NO derived from NOS inhibits vascular inflammation, in part by inhibiting WeibeI-Palade body exocytosis. We now propose to explore the molecular mechanisms by which NO inhibits WeibeI-Palade body release. Preliminary Data show that NO blocks WeibeI-Palade body release from cultured endothelial cells. We will begin by determining the mechanisms by which WeibeI-Palade bodies are normally released. We will next define the molecules of the exocytosis machinery that are targets of NO. Finally, we will examine the role of reactive oxygen species in regulating WeibeI-Palade body exocytosis. These studies will characterize novel molecular mechanisms by which radicals regulate vascular inflammation.

动脉粥样硬化是一种炎症性疾病。临床研究表明，血清标志物升高 炎症预示着动脉粥样硬化风险的增加。动物研究表明，炎症介质 在动脉粥样硬化形成中起作用。尽管促炎途径已经被证明增加了 在动脉粥样硬化中，抗炎途径的保护作用研究较少。 我们和其他人之前已经证明，一氧化氮(NO)可以抑制血管疾病。APOE基因缺失小鼠 同样缺乏内皮型一氧化氮合酶(eNOS，或NOS3)基因的人动脉粥样硬化更严重 而不是表达NOS3的载脂蛋白E小鼠。在人类中，内皮功能障碍(特征是无法 产生NO)与冠心病(CAD)有关。因此，NO可能保护血管系统免受 动脉硬化。 NO抑制动脉粥样硬化的分子机制尚不清楚。然而，我们和 其他人最近发现，一氧化氮合酶可以减轻移植动脉硬化的炎症反应。特别是，我们 发现诱导型一氧化氮合酶(iNOS，或NOS2)抑制韦贝氏小体的释放 来自供体心脏的内皮细胞。由于Webei-Palade小体含有炎症和血栓 中介物、抑制胃体释放可能是NO抗炎作用的部分原因 移植血管病变和其他炎症性血管疾病，包括动脉粥样硬化。我们 假设一氧化氮合酶产生的一氧化氮抑制血管炎症，部分是通过抑制魏贝帕拉德小体 胞吐。 我们现在建议探索NO抑制韦伯-帕拉德体内释放的分子机制。 初步数据显示，NO可阻断培养的内皮细胞释放维贝-帕莱德小体。我们会 首先确定通常情况下韦贝帕拉德遗体释放的机制。接下来，我们将 定义作为NO靶标的胞吐机制的分子。最后，我们将研究一下 活性氧在调节韦氏小体胞吐中的作用这些研究将成为小说的特征 自由基调节血管炎症的分子机制。