Regulation of Vascular Inflammation

动脉粥样硬化是一种炎症性疾病。临床研究表明， 炎症预示着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。虽然促炎途径已被证明会增加 在动脉粥样硬化中，抗炎途径的保护作用研究得较少。 我们和其他人以前已经表明，一氧化氮（NO）抑制血管疾病。ApoE敲除小鼠 同样缺乏内皮型一氧化氮合酶（eNOS，或NOS 3）基因的人有更严重的动脉粥样硬化 表达NOS 3的ApoE小鼠更少。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。然而，我们和 其他人最近发现NOS减少移植动脉硬化中的炎症。我们尤其 发现诱导型一氧化氮合酶（iNOS，或NOS 2）抑制了WeibeI-Palade小体的释放 从供体心脏的内皮细胞中提取。由于韦伯-帕拉德机构含有炎症和血栓 介质，抑制WeibeI-Palade体释放可能解释了NO的抗炎作用的一部分， 移植血管病变和其他炎性血管疾病，包括动脉粥样硬化。我们 推测来源于NOS的NO抑制血管炎症，部分是通过抑制韦伯-帕拉德体 胞吐作用 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，确定的机制，其中的微博-Palade机构通常被释放。我们接下来将 定义作为NO目标的胞吐机制的分子。最后，我们将研究 活性氧在调节韦氏体胞吐中的作用。这些研究将描述新的 自由基调节血管炎症的分子机制。

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.