Regulation of Vascular Inflammation

描述(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，血清炎症标志物的升高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。虽然促炎途径已被证明会增加动脉粥样硬化，但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。同样缺乏内皮型一氧化氮合酶(eNOS，或NOS3)基因的APOE基因缺失的小鼠比表达NOS3的ApoE小鼠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为特征)与冠状动脉疾病(CAD)有关。因此，NO可能对动脉粥样硬化的血管系统具有保护作用。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)抑制供体心脏内皮细胞释放韦贝氏小体。由于WebeI-Palade小体含有炎症和血栓介质，抑制WebeI-Palade小体的释放可能解释了NO在移植血管病变和其他炎症性血管疾病(包括动脉粥样硬化)中的抗炎作用的部分原因。我们推测，来自一氧化氮合酶的一氧化氮抑制血管炎症，部分是通过抑制韦氏小体的胞吐作用。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。我们将首先确定韦伯-帕拉德遗体通常被释放的机制。接下来，我们将定义作为NO靶点的胞吐机制的分子。最后，我们将研究活性氧物种在调节韦贝帕拉德小体胞吐中的作用。这些研究将描述自由基调节血管炎症的新的分子机制。

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.