SOCS-1 and endothelial dysfunction in graft arteriosclerosis

移植物动脉硬化(GA)，定义为移植物管道动脉的进行性管腔丧失，是主要的 慢性同种异体心脏移植失败的原因。最近的几条证据表明，细胞因子干扰素-γ 作为一种促动脉硬化因子，干扰素-Y对内皮细胞(EC)的关键功能作用是早期的 血管内皮细胞依赖的松弛功能受损，发生在平滑肌细胞之前并与其有因果关系 (SMC)积累。具体地说，我的同事们报告说，依赖干扰素的人 内皮型一氧化氮合酶在移植物EC中的功能/表达有趣的是，干扰素本身就有作用。 不会影响eNOS。它与另一种促炎症细胞因子--干扰素协同作用，减少eNOS的表达 欧盟委员会也不会放行。然而，干扰素-Y和肿瘤坏死因子协同降低NO的机制 EC的生产情况尚不清楚，这是该项目的主题。我们的数据表明，SOCS1，一个 细胞因子信号蛋白抑制因子是干扰素-γ和肿瘤坏死因子诱导的血管内皮细胞功能障碍的关键介质。 我们提出了以下假设：1)。在静息(和暴露于干扰素-γ)的EC中，SOCS1结合到非活性 (酪氨酸磷酸化)ASK1导致SOCS1和ASK1的相互降解。2)。作为对.的回应 TNF、ASK1从SOCS1中解离，导致ASK1-JNK信号被激活，进而 磷酸化并激活SOCS1。3)。独立激活SOCS1和ASK1-JNK， 协同抑制生长因子(如血管内皮生长因子和胰岛素样生长因子-1)介导的NO释放导致EC功能障碍 和遗传算法的进步。我们提出以下具体目标来检验我们的假设：1)确定 SOCS1诱导内皮细胞降解ASK1的机制(S)及干扰素-γ和肿瘤坏死因子对此的影响 回应。2)确定SOCS1损伤NO功能的机制(S)。3)确定 SOCS1在同种和异种移植模型中的作用。这些研究应有助于发展 控制GA和移植物衰竭以及其他血管疾病的新治疗方法，如 动脉硬化。

Graft arteriosclerosis (GA), defined as progressive loss of lumen in allograft conduit arteries, is the major cause of chronic cardiac allograft failure. Several recent lines of evidence have implicated the cytokine IFN-y as a pro-arteriosclerotic factor and that a key functional effect of IFN-Y on endothelial cells (EC) is an early impairment of EC-dependent relaxation which occurs prior to and is causally linked to smooth muscle cell (SMC) accumulation. Specifically, my colleagues have reported IFN-y-dependent reduction in the function/expression of endothelial nitric oxide synthase (eNOS) in graft EC. Interestingly, IFN-y by itself does not affect eNOS. It acts in concert with INF, another proinflammatoy cytokine, to reduce eNOS expression and NO release by EC. However, the mechanism by which IFN-Y and TNF synergistically reduce NO production by EC is not known, and is the subject of this project. Our data suggest that SOCS1, a member of suppressor of cytokine signaling proteins, is a critical mediator in IFN-y and TNF-induced EC dysfunction. We propose the following hypotheses: 1). In resting (and IFN-y-exposed) EC, SOCS1 binds to inactive (tyrosine phosphorylated) ASK1 leading to mutual degradation of both SOCS1 and ASK1. 2). In response to TNF, ASK1 is dissociated from SOCS1 leading to activation of ASK1-JNK signaling which in turn phosphorylates and activates SOCS1. 3). Activated SOCS1 and ASK1-JNK independently and synergistically inhibit growth factors (e.g. VEGF and IGF-1 )-mediated NO release leading to EC dysfunction and GA progression. We propose the following specific aims to test our hypothesis: 1) Determine the mechanism(s) by which SOCS1 induces ASK1 degradation in EC and how IFN-y and TNF modify this response. 2) Determine the mechanism(s) by which SOCS1 impairs NO function. 3) Determine the role of SOCS1 in EC function in allograft and xenograft models. These studies should facilitate the development of new therapeutic approaches to control GA and graft failure as well as other vascular diseases such as atherosclerosis.