Heme Oxygenase-1: protection against chronic rejection

描述(申请人提供)：对移植相关动脉硬化的有效治疗将极大地改善器官移植的结果。最近的数据表明，在移植前和移植后的短时间内诱导血红素加氧酶-1(HO-1)的表达可以抑制动脉硬化。类似的数据也适用于动脉粥样硬化的模型。HO-1是一种应激反应酶，可将血红素分解为三种产物：一氧化碳(CO)、胆绿素(由胆绿素还原酶转化为胆红素)和游离铁(导致铁隔离蛋白铁蛋白的诱导)。HO-1具有抗炎、抗凋亡和抗增殖作用，是一种“保护性”基因。这些作用最常被一氧化碳取代，一氧化碳抑制活化的单核/巨噬细胞的致炎表型，并阻断SMC的增殖。胆绿素具有相似的整体作用(抗炎、抗增殖)，尽管胆绿素和CO部分是通过激活不同的信号级联和影响病理反应的不同成分来实现其作用的。这些发现表明，CO和胆绿素具有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的诱导表达或仅对供者给予CO或胆绿素/胆红素会在移植物移植时产生有益的结果，这一发现我们将在拟议的研究中进行调查。在这项建议中检验的总体假设是，HO-1的表达以及随后产生的CO和胆绿素是血管对损伤的反应的一部分，以防止与移植器官的慢性排斥反应相关的动脉硬化性病变的发展。在CO的情况下，我们已经证明它的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。初步研究表明，胆绿素与p38Mark也有关系。因此，p38Mark信号级联似乎是调节这些功能的一个主要的“信号开关”，该通路的调节决定了防止动脉硬化病变发展的保护性表型。我们建议对这些信号级联进行体外和体内研究。

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.