Heme Oxygenase-1: protection against chronic rejection

Heme Oxygenase-1：防止慢性排斥反应

• 批准号: 7327813
• 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/7327813
• 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

An effective treatment for transplant-associatedarteriosclerosiswould 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-1is 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 (M0)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-1or 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-1and subsequent generation of CO and biliverdin is part of a vascular response to injury that prevents the development of arterioscleroticlesions 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 stduies of these signaling cascades.

一种有效的移植相关性治疗方法可以改善器官的结果 移植非常明显。最近的数据表明诱导血红素加氧酶-1的表达 （HO-1）在移植之前和此后短期内可以抑制动脉硬化。类似的数据是 可用于动脉粥样硬化模型。 HO-11S应力响应酶，将血红素分解为 三种产品：一氧化碳（CO），biliverdin（由biliverdin转化为胆红素 还原酶）和游离铁（导致铁蛋白诱导，一种铁序列蛋白）。 HO-1服务 作为“保护性”基因的抗炎，抗凋亡和抗增殖作用。这些 效果通常可以用CO代替，CO抑制激活的促炎表型 单核细胞/巨噬细胞（M0）并阻止SMC增殖。 biliverdin具有相似的总体作用（抗 炎症性，抗增殖性），尽管Biliverdin和Co部分通过激活不同的 信号传导级联反应的不同组成部分。这些发现表明 CO和Biliverdin具有抗动脉粥样硬化的特性或很可能是抗动脉粥样硬化的特性。我们已经证明Co可以 抑制与移植相关的动脉硬化以及球囊损伤后看到的内膜增生， 后者也被biliverdin封锁。有趣的是，诱导的HO-1OR的表达 CO或Biliverdin/胆红素仅针对供体而导致移植时会产生有益的结果，发现 我们将在拟议的研究中进行调查。在此提案中检验的总体假设是表达 HO-1和随后产生的CO和Biliverdin是对损伤的血管反应的一部分 与移植器官的慢性排斥相关的动脉硬化病的发展。在 CO的情况，我们表明其抗炎和抗增殖作用取决于激活 p38有丝分裂原激活的蛋白激酶（MARK）信号转导途径。如初步所示 研究，biliverdin和p38标记也存在关系。因此看来p38标记 信号级联是一个主要的“信号开关”，可调节这些功能，并调节此功能 途径决定了防止动脉硬化病变发展的保护性表型。我们 提出这些信号级联反应的体外和体内基础。