Heme Oxygenase-1: protection against chronic rejection

Heme Oxygenase-1：防止慢性排斥反应

• 批准号: 7035144
• 负责人: FRITZ H BACH
• 金额: $ 42.5万
• 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/7035144
• 关键词: apoptosis; arteriosclerosis; bilirubin; carbon monoxide; cardiovascular injury; cardiovascular transplantation; cell proliferation; gene expression; genetically modified animals; heme oxygenase; inflammation; iron; laboratory mouse; mitogen activated protein kinase; pathologic process; stem cells; transplant rejection

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）：移植相关动脉硬化的有效治疗将非常显著地改善器官移植的结果。最近的数据表明，诱导血红素氧合酶-1（HO-1）的表达移植前和移植后的一段短时间内可以抑制动脉硬化。类似的数据也可用于动脉粥样硬化模型。HO-1是一种应激反应酶，可将血红素分解为三种产物：气体一氧化碳（CO）、胆绿素（通过胆绿素还原酶转化为胆红素）和游离铁（导致铁蛋白（一种铁螯合蛋白）的诱导）。HO-1由于其抗炎、抗凋亡和抗增殖作用而充当“保护性”基因。这些作用最常被CO替代，CO抑制活化单核细胞/巨噬细胞的促炎表型并阻断SMC增殖。胆绿素具有相似的总体效果（抗炎、抗增殖），尽管胆绿素和CO通过激活不同的信号级联和影响病理反应的不同组分部分地实现其效果。这些发现表明，CO和胆绿素具有抗动脉粥样硬化的性质，或者很可能具有抗动脉粥样硬化的性质。我们已经证明，一氧化碳可以抑制移植相关的动脉硬化以及球囊损伤后的内膜增生，后者也被胆绿素阻断。有趣的是，HO-1的诱导表达或CO或胆绿素/胆红素的管理，只有供体导致有益的结果时，移植移植，我们将在拟议的研究调查的发现。在这个提议中测试的总体假设是HO-1的表达和随后产生的CO和胆绿素是血管对损伤的反应的一部分，其防止与移植器官的慢性排斥相关的动脉炎病变的发展。在CO的情况下，我们已经表明，其抗炎和抗增殖作用依赖于p38丝裂原活化蛋白激酶（MARK）信号转导通路的激活。如初步研究所示，胆绿素和p38 MARK也有关系。因此，似乎p38 MARK信号级联是调节这些功能的主要“信号开关”，并且该途径的调节决定了防止动脉粥样硬化病变发展的保护性表型。我们建议在体外和体内研究这些信号级联。