Regulation of Vascular Inflammation

血管炎症的调节

• 批准号: 6889495
• 负责人: CHARLES J LOWENSTEIN
• 金额: $ 24.53万
• 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/6889495
• 关键词: SDS polyacrylamide gel electrophoresis; atherosclerosis; binding proteins; cell surface receptors; coronary disorder; enzyme linked immunosorbent assay; exocytosis; fibrinolytic agents; free radical oxygen; genetically modified animals; granule; hydrogen peroxide; inflammation; laboratory mouse; nitric oxide; nitric oxide synthase; nitroso compounds; polymerase chain reaction; vascular endothelium

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：动脉粥样硬化是一种炎症性疾病。临床研究表明，血清炎症标志物升高可预测动脉粥样硬化风险增加。动物研究表明，炎症介质在动脉粥样硬化形成中起作用。虽然促炎通路已被证明会增加动脉粥样硬化，但抗炎通路的保护作用研究较少。我们和其他人以前已经表明，一氧化氮（NO）抑制血管疾病。同样缺乏内皮型一氧化氮合酶（eNOS或NOS 3）基因的ApoE缺失小鼠比表达NOS 3的ApoE小鼠具有更严重的动脉粥样硬化。在人类中，内皮功能障碍（特征在于不能产生NO）与冠状动脉疾病（CAD）相关。因此，NO可以保护血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。然而，我们和其他人最近发现NOS减少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NOS 2）抑制释放的魏贝I-Palade体从内皮细胞在供体心脏。由于WeibeI-Palade体含有炎症和血栓介质，因此抑制WeibeI-Palade体释放可以解释NO在移植血管病变和其他炎性血管疾病（包括动脉粥样硬化）中的部分抗炎作用。我们推测，NO来源于NOS抑制血管炎症，部分是通过抑制韦伯-帕拉德体胞吐。我们现在建议探索NO抑制WeibeI-Palade体释放的分子机制。初步数据显示，NO阻断了培养的内皮细胞释放的WeibeI-Palade体。我们将开始通过确定的机制，其中通常释放的微博宫机构。接下来我们将定义作为NO靶点的胞吐机制的分子。最后，我们将研究活性氧在调节韦氏体胞吐中的作用。这些研究将表征自由基调节血管炎症的新分子机制。