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 发生在急性或慢性炎症期间，是高度促炎事件 这可能导致不可逆转的组织损伤、器官衰竭和疾病。 了解EC如何在情况下保护自己免受细胞凋亡的影响 应激在制定治疗策略中可能是至关重要的 抑制与急性和/或慢性相关的有害影响 发炎。EC保护的生理机制之一 它们自身的凋亡依赖于一系列细胞因子的表达 细胞保护基因。我们将研究其中一个这样的保护性基因 提出了应激反应基因--血红素加氧酶-L(HO-1)。在……下面 炎症条件HO-1成为分解代谢中的限速酶 以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的细胞保护作用在很大程度上是通过产生 公司体内表达HO-1可抑制急性炎症反应 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预防EC的能力 细胞凋亡。这一点得到了以下观察的支持：HO-1在 体外培养可防止内皮细胞发生凋亡。在这两种情况下， HO-1的细胞保护作用是通过CO的产生来实现的。这个 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)信号转导途径及其作用机制 转录因子核因子-KB的激活。据推测，这一事件导致了 上调核因子-KB依赖的保护性基因的表达 有助于抑制EC细胞凋亡。这项提案旨在分析 HO-1及其衍生物CO保护EC的机制(S) 细胞凋亡。我们建议确定HO-1和CO激活p38的机制 MAPK以及转录因子NF-KB，并确定它们是如何 这些事件有助于防止EC细胞凋亡。我们相信，取得的成果 在这些应用中，首次揭示了有效的抗细胞凋亡 CO的影响，将提供有价值的信息，有助于 开发新的方法来克服与疾病相关的病理状况 急性和/或慢性炎症，包括感染性休克、动脉粥样硬化 和/或立即血管化移植器官的排斥反应。

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.