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，血清标记的升高 炎症预测动脉粥样硬化的风险增加。动物研究表明炎症介质 在动脉粥样硬化中起作用。尽管促炎途径已显示出增加 动脉粥样硬化，抗炎途径的保护作用较少。 我们和其他人先前已经表明，一氧化氮（NO）抑制了血管疾病。 apoe null小鼠 还缺乏内皮一氧化氮合酶（ENOS或NOS3）基因具有更严重的动脉粥样硬化 比表达NOS3的APOE小鼠。在人类中，内皮功能障碍（以无法 农产品NO）与冠状动脉疾病（CAD）有关。因此，没有可能保护脉管系统免受 动脉粥样硬化。 NO抑制动脉粥样硬化的分子机制尚不清楚。但是，我们和 其他人最近发现，NOS减少了移植动脉硬化的炎症。特别是我们 发现诱导型一氧化氮合酶（INOS或NOS2）抑制了微生体的释放 从供体心中的内皮细胞。由于微生果胶体含有炎症和血栓形成 介体，抑制微生体释放可能解释了NO的抗炎作用的一部分 移植血管病和其他炎症性血管疾病，包括动脉粥样硬化。我们 假设没有源自NOS的NO抑制血管炎症，部分是通过抑制微生的体型 胞吞作用。 现在，我们建议探索NO抑制Weibei-Palade体释放的分子机制。 初步数据表明，没有块从培养的内皮细胞中释放出微生的身体。我们将 首先确定通常释放微生物体的机制。我们接下来 定义胞吐作用机制的分子，该分子是NO的靶标。最后，我们将研究 活性氧在调节微生体胞吞作用中。这些研究将表征新颖 自由基调节血管炎症的分子机制。