Heme Oxygenase-1: protection against chronic rejection

有效治疗移植相关性动脉粥样硬化可改善器官移植的效果 移植非常重要。最近的数据表明，血红素氧合酶-1的诱导表达， 在移植前和移植后的短时间内，HO-1可以抑制动脉硬化。类似的数据还有 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（由胆绿素转化为胆红素 还原酶）和游离铁（导致铁蛋白（一种铁螯合蛋白）的诱导）。HO-1服务 由于其抗炎、抗凋亡和抗增殖作用而作为“保护性”基因。这些 这种作用最常被CO替代，其抑制活化的 单核细胞/巨噬细胞（M0）和阻断SMC增殖。胆绿素具有类似的总体效果（抗- 炎性、抗增殖），尽管胆绿素和CO部分地通过激活不同的 信号级联并影响病理反应的不同组分。这些发现表明 一氧化碳和胆绿素具有抗动脉粥样硬化的特性。我们已经证明，CO可以 抑制移植相关动脉硬化以及球囊损伤后可见的内膜增生， 后者也被胆绿素阻断。有趣的是，HO-1的诱导表达或给药 一氧化碳或胆绿素/胆红素只给供体导致有益的结果时，移植，一项发现， 我们将在拟议的研究中进行调查。在这个提议中测试的总体假设是， HO-1和随后产生的CO和胆绿素是血管对损伤的反应的一部分， 与移植器官的慢性排斥反应有关的动脉粥样硬化病变的发展。在 CO的情况下，我们已经表明，其抗炎和抗增殖作用取决于激活 p38丝裂原活化蛋白激酶（MARK）信号转导通路。如图所示， 研究表明，胆绿素与p38 MARK也有一定的关系。因此，p38标记似乎 信号级联是调节这些功能的主要“信号开关”， 该途径决定了防止动脉炎病变发展的保护性表型。我们 提出了这些信号级联的体外和体内研究。

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.