NITRIC OXIDE & PULMONARY ARTERY ENDOTHELIAL INJURY

一氧化氮

• 批准号: 6667522
• 负责人: A R WHORTON
• 金额: $ 4.85万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6667522
• 关键词: JUN kinase; antioxidants; cytoprotection; cytotoxicity; enzyme activity; free radicals; glutathione; heat shock proteins; mitogen activated protein kinase; nitric oxide; nitric oxide synthase; oxidative stress; pulmonary artery; tissue /cell culture; vascular endothelium; vascular smooth muscle

DESCRIPTION (Applicant's Abstract): It has become increasingly apparent that NO induces a number of adaptive responses in vascular cells which may protect and enhance the survival of these cells. The mechanisms are not clear, however, NO has been shown by us and others to increase expression of HO-1, HSP-70 and increase cellular levels GSH levels in smooth muscle and endothelial cells. In each case these responses are associated with protection of cells from injury elevation of GSH or induction of either HO-1 or HSP-70 blocks injury/apoptosis in response to TNF-alpha, NO, or H2O2. These are likely critical mechanisms for vascular homeostasis and may be involved in protection/survival in inflammation, ischemia/reprefusion, or in cancer where oxidants, cytokines and NO potently affect vascular cells. The mechanisms by which NO GSH levels or elevates regulates expression of these proteins are not clear. In each case either NO or a variety of oxidants have been found to activate mechanisms leading to the response seen. In this regard, NO-mediated signaling is analogous to oxidant signaling and the pathways involved are likely to be similar. In fact, in addition to activation of ras, NO has been found to activate stress activated pathways leading to increased activity of MAP kinase p38 and c-jun NH2-terminal kinases (JNKs) and, activation of these pathways has been shown to be involved in adaptive/protective mechanisms initiated by NO. Since both oxidants and NO appear to activate similar stress responses and appear to activate similar stress activated mechanisms, we propose to test the hypothesis that NO induces adaptive responses in vascular cells through redox activation/regulation of MAP kinase signaling pathways and modifies responses to other agents through similar mechanisms. In this project we will determine the role of MAP kinases in adaptive responses (GSH synthesis, stress protein induction) using vascular smooth muscle and endothelial cells.

描述（申请人的摘要）：已经变得越来越明显的是， NO诱导血管细胞的适应性反应， 并提高这些细胞的存活率。其机制尚不清楚， 然而，我们和其他人已经证明NO增加HO-1表达， HSP-70和增加细胞水平GSH水平在平滑肌和 内皮细胞在每种情况下，这些反应都与 保护细胞免受GSH升高或HO-1诱导的损伤 或HSP-70阻断响应TNF-α、NO或H2 O2的损伤/凋亡。 这些可能是血管稳态的关键机制， 参与炎症、缺血/再灌注中的保护/存活， 癌症，其中氧化剂、细胞因子和NO有效地影响血管细胞。的 NO GSH水平或升高调节这些表达的机制 蛋白质不清楚。在每种情况下，NO或各种氧化剂都具有 被发现激活导致反应的机制。在这 在这方面，NO介导的信号传导类似于氧化剂信号传导， 所涉及的途径可能是相似的。其实除了 已经发现ras、NO的激活激活应激激活途径 导致MAP激酶p38和c-jun NH 2-末端激酶活性增加 （JNK），这些途径的激活已被证明参与了 适应/保护机制启动NO。由于氧化剂和NO 似乎激活了类似的压力反应， 应激激活机制，我们建议测试的假设，NO诱导 通过氧化还原激活/调节血管细胞的适应性反应 MAP激酶信号通路，并通过以下途径改变对其他药物的反应： 类似的机制。在这个项目中，我们将确定MAP激酶的作用， 在使用血管的适应性反应（GSH合成、应激蛋白诱导）中 平滑肌和内皮细胞。