NITRIC OXIDE & PULMONARY ARTERY ENDOTHELIAL INJURY

一氧化氮

• 批准号: 7113720
• 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
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7113720
• 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(申请人摘要)：越来越明显的是 NO在血管细胞中诱导许多适应性反应，这可能保护 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可以增加HO-1的表达， HSP-70和升高细胞内GSH水平的作用 内皮细胞。在每种情况下，这些响应都与 保护细胞免受GSH升高或HO-1诱导的损伤 或HSP-70可阻断肿瘤坏死因子-α、一氧化氮或过氧化氢所致的损伤/凋亡。 这些可能是血管内稳态的关键机制，并可能是 参与炎症、缺血/再灌流中的保护/存活，或 氧化剂、细胞因子和一氧化氮有效影响血管细胞的癌症。这个 一氧化氮GSH水平或升高调节这些基因表达的机制 蛋白质还不清楚。在每种情况下，都没有或多种氧化剂 被发现激活了导致所见反应的机制。在这 NO介导的信号转导类似于氧化剂信号转导，而 涉及的途径很可能是相似的。事实上，除了 已发现激活ras、NO可以激活应激激活通路 导致MAP激酶p38和c-jun NH2末端激酶活性增加 (JNKs)和，这些通路的激活已被证明参与了 由NO启动的适应/保护机制。因为氧化剂和一氧化氮 似乎激活了类似的应激反应，并似乎激活了类似的 应激激活机制，我们建议检验NO诱导的假设 血管细胞氧化还原激活/调节的适应性反应 MAP激酶信号通路并通过以下途径修改对其他介质的响应 类似的机制。在这个项目中，我们将确定MAP激酶的角色 在适应性反应(GSH合成，应激蛋白诱导)中使用血管 血管内皮细胞和平滑肌细胞。