Regulation of Endothleial Cell Apoptosis by HO-1 and CO

描述（申请人摘要）：内皮细胞（EC）凋亡，如 在急性或慢性炎症期间发生，是高度促炎事件 会导致不可逆的组织损伤器官衰竭和疾病 了解EC如何保护自己免受凋亡的情况下， 压力可能是关键的治疗策略的发展， 抑制与急性和/或慢性 炎症EC保护的生理机制之一是 细胞凋亡的发生依赖于一系列 细胞保护基因我们将在本研究中研究其中一种保护性基因。 推测为应激反应基因血红素加氧酶-1（HO-1）。下 炎症条件HO-1成为catalysts中的限速酶 血红素产生等摩尔量的胆红素，游离铁和气体 分子一氧化碳（CU）。我们的初步研究表明， HO-1的细胞保护作用主要是通过产生 HO-1在体内的表达可以抑制急性炎症反应， 与移植器官的排斥反应有关。据推测， 这种细胞保护作用依赖于HO-1阻止EC的能力 凋亡这一点得到了以下观察结果的支持，即HO-1的表达在细胞中的表达水平低于在细胞中的表达水平。 体外培养可抑制EC凋亡。在这两种情况下的 HO-1的细胞保护作用通过CO的产生介导。 HO-1/CO的抗凋亡作用依赖于p38的激活 丝裂原活化蛋白激酶（MAPK）信号转导通路与 转录因子NF-κ B的激活。据推测，这些事件导致 NF-κ B依赖性保护基因表达的上调， 有助于抑制EC凋亡。该提案旨在分析 HO-1及其衍生物CO保护EC免受 凋亡我们建议确定HO-1和CO激活p38的机制 MAPK以及转录因子NF-κ B的表达，并确定这些 事件有助于阻止EC凋亡。我们认为， 在这些应用中，首次揭示了有效抗细胞凋亡 CO的影响，将提供有价值的信息，这将有助于 开发新的方法来克服与 急性和/或慢性炎症，包括脓毒性休克、动脉粥样硬化 和/或立即血管化的移植器官的排斥。

DESCRIPTION(Applicant's abstract): Endothelial cell (EC) apoptosis, such as it occurs during acute or chronic inflammation, is a highly pro-inflammatory event that can lead to irreversible tissue injury, organ failure and disease. Understanding how EC protect themselves from undergoing apoptosis in situations of stress may be critical in the development of therapeutic strategies aimed suppress the deleterious effects associated with acute and/or chronic inflammation. One of the physiological mechanisms by which EC protect themselves from undergoing apoptosis relies on the expression of a series of cytoprotective genes. We will study one of such protective genes in this proposal, the stress responsive gene heme oxygenase-l (HO-1). Under inflammatory conditions HO-1 becomes the rate limiting enzyme in the catabolism of heme to yield equimolar amounts of bilirubin, free iron and the gaseous molecule carbon monoxide (CU). Our preliminary studies suggest that the cytoprotective effects of HO-1 are largely mediated through the generation of CO. Expression of HO-1 in vivo can suppress acute inflammatory reactions such as those associated with the rejection of a transplanted organ. Presumably, this cytoprotective effect relies on the ability of HO-1 to prevent EC apoptosis. This is supported by the observation that expression of HO-1 in vitro can prevent EC from undergoing apoptosis. In both cases the cytoprotective effect of HO-1 is mediated through the generation of CO. The anti-apoptotic effect of HO-1/CO is dependent on the activation of the p38 mitogen activated protein kinase (MAPK) signal transduction pathway and the activation of the transcription factor NF-KB. Presumably this events lead to the up-regulation of expression of NF-KB dependent protective genes that contribute to suppress EC apoptosis. This proposal aims to analyze the mechanism(s) by which HO-1 and its derivative CO protect EC from undergoing apoptosis. We propose to identify mechanism by which HO-1 and CO activate p38 MAPK as well as the transcription factor NF-KB and to determine how these events contribute to prevent EC apoptosis. We believe that the results gained in these application, which reveal for the first time the potent anti-apoptotic effect of CO, will provide valuable information that will contribute to the development of new approaches to overcome pathologic conditions associated with acute and/or chronic inflammation, including septic shock, atherosclerosis and/or the rejection of immediately vascularized transplanted organs.