Heme Oxygenase-1: protection against chronic rejection

Heme Oxygenase-1：防止慢性排斥反应

• 批准号: 7166066
• 负责人: FRITZ H BACH
• 金额: $ 41.27万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7166066
• 关键词: Abbreviations; Affect; Allogenic; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Aortic Segment; Apoptosis; Apoptotic; Arteriosclerosis; Atherosclerosis; Bilirubin; Biliverdin reductase; Biliverdine; Blood Vessels; Bone Marrow; Bone Marrow Transplantation; Carbon Monoxide; Cell Adhesion Molecules; Cells; Chronic; Data; Development; Endothelial Cells; Enzymes; Ferritin; Gases; Generations; Genes; Genetic; Genetic Polymorphism; Graft Rejection; Heme; Hyperplasia; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Intestines; Iron; Length; Lesion; MAPK14 gene; Mediating; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Organ Transplantation; Pathogenesis; Pathologic; Pathology; Pathway interactions; Personal Satisfaction; Phenotype; Play; Property; Proteins; Relative (related person); Reperfusion Injury; Research Personnel; Role; Sclerosis; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Smooth Muscle Myocytes; Stem cells; Stress; Testing; Transplantation; expectation; heme oxygenase-1; human MAPK14 protein; improved; in vivo; macrophage; migration; monocyte; mouse Smc1l1 protein; mouse Smc1l2 protein; prevent; programs; promoter; protective effect; response; response to injury

DESCRIPTION (provided by applicant): An effective treatment for transplant-associated arteriosclerosis would improve the results of organ transplantation very significantly. Recent data suggest that the induced expression of heme oxygenase-1 (HO-1) before the transplant and for a short period thereafter can suppress arteriosclerosis. Similar data are available for models of atherosclerosis. HO-1 is a stress responsive enzyme that catabolyzes heme into three products: the gas carbon monoxide (CO), biliverdin (which is converted to bilirubin by biliverdin reductase) and free iron (which leads to the induction of ferritin, an iron-sequestering protein). HO-1 serves as a "protective" gene by virtue of its anti-inflammatory, anti-apoptotic and anti-proliferative actions. These effects can most often be substituted for by CO which inhibits the pro-inflammatory phenotype of activated monocyte/macrophages and blocks SMC proliferation. Biliverdin has similar overall effects (anti- inflammatory, anti-proliferative), although biliverdin and CO in part achieve their effects by activating different signaling cascades and impacting different components of a pathologic response. These findings show that CO and biliverdin have properties that are, or might well be, anti-atherogenic. We have shown that CO can suppress transplant-associated arteriosclerosis as well as the intimal hyperplasia seen after balloon injury, the latter also being blocked by biliverdin. Interestingly, the induced expression of HO-1 or the administration of CO or biliverdin/bilirubin only to the donor leads to beneficial results when a graft is transplanted, a finding we shall investigate in the proposed studies. The overall hypothesis tested in this proposal is that expression of HO-1 and subsequent generation of CO and biliverdin is part of a vascular response to injury that prevents the development of arteriosclerotic lesions associated with chronic rejection of transplanted organs. In the case of CO, we have shown that its anti-inflammatory and anti-proliferative effects depend on the activation of the p38 mitogen-activated protein kinases (MARK) signal transduction pathway. As shown in Preliminary Studies, there is a relationship of biliverdin and p38 MARK as well. It thus appears that the p38 MARK signaling cascade is a major "signaling switch" that regulates these functions and that modulation of this pathway dictates the protective phenotype that prevents the development of the arteriosclerotic lesion. We propose in vitro and in vivo studies of these signaling cascades.

描述（由申请人提供）：用于移植相关的动脉硬化的有效治疗方法将非常明显地改善器官移植的结果。最近的数据表明，在移植前和短期内诱导的血红素加氧酶-1（HO-1）的表达可以抑制动脉硬化。类似的数据可用于动脉粥样硬化模型。 HO-1是一种应激反应式酶，将血红素分解为三种产品：一氧化碳（CO），双脂蛋白（通过比列氏蛋白还原酶转化为胆红素）和游离铁（导致铁蛋白诱导的铁蛋白，一种铁序列蛋白）。 HO-1凭借其抗炎，抗凋亡和抗增殖作用作为“保护性”基因。这些效应通常可以用CO代替，CO抑制活化的单核细胞/巨噬细胞的促炎表型，并阻止SMC增殖。 biliverdin具有相似的总体作用（抗炎性，抗增殖性），尽管biliverdin and CO在某种程度上通过激活不同的信号级联反应并影响病理反应的不同成分来实现其作用。这些发现表明，CO和Biliverdin具有抗动脉粥样硬化或很可能是抗动脉粥样硬化的特性。我们已经表明，CO可以抑制与移植相关的动脉粥样硬化以及球囊损伤后观察到的内膜增生，后者也被biliverdin封闭。有趣的是，在移植移植移植时，诱导的HO-1表达或CO或Biliverdin/胆红素仅对供体的施用导致有益结果，我们将在拟议的研究中进行调查。在该提案中检验的总体假设是，HO-1的表达以及随后产生CO和Biliverdin是对损伤的血管反应的一部分，可防止与慢性抑制移植器官相关的动脉硬化病变的发展。在CO的情况下，我们已经表明其抗炎和抗增殖作用取决于p38丝裂原激活蛋白激酶（MARK）信号转导途径的激活。如初步研究所示，双列氏蛋白和p38标记也存在关系。因此，看来p38 mark信号级联是一个主要的“信号开关”，可调节这些功能，并且该途径的调节决定了阻止动脉硬化病变发展的保护性表型。我们提出了这些信号级联反应的体外和体内研究。