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，炎症的血清标记升高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。尽管促炎性途径已显示出增加动脉粥样硬化，但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。与表达NOS3的APOE小鼠相比，也缺乏内皮一氧化氮合酶（ENOS或NOS3）基因的APOE NULL小鼠具有更严重的动脉粥样硬化。在人类中，内皮功能障碍（以无法产生NO的特征）与冠状动脉疾病（CAD）有关。因此，不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）抑制了供体心脏内皮细胞中的微甲状腺释放。由于微生型体含有炎症和血栓形成介质，因此抑制微甲状腺体的释放可能解释了NO在移植血管病和其他炎症血管疾病中NO的抗炎作用的一部分，包括动脉粥样硬化。我们假设NO源自NOS抑制血管炎症，部分是通过抑制微甲状腺体体胞吐作用。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的机制。接下来，我们将定义非胞吐化机制的分子，这些分子是NO的靶标。最后，我们将研究活性氧在调节微生体胞吐作用中的作用。这些研究将表征自由基调节血管炎症的新型分子机制。