SOCS-1 and endothelial dysfunction in graft arteriosclerosis

SOCS-1 与移植动脉硬化中的内皮功能障碍

• 批准号: 7297619
• 负责人: WANG MIN
• 金额: $ 38.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7297619
• 关键词: arteriosclerosis; biological signal transduction; blood vessel transplantation; delayed hypersensitivity; enzyme activity; enzyme induction /repression; genetically modified animals; homologous transplantation; human subject; interferon gamma; intermolecular interaction; laboratory mouse; mitogen activated protein kinase; nitric oxide synthase; phosphorylation; protein binding; protein degradation; protein signal sequence; protein structure function; transplant rejection; tumor necrosis factor alpha; vascular endothelium; xenotransplantation

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.

移植动脉硬化（GA）定义为同种异体移植导管动脉中管腔的逐渐损失，是主要的 慢性心脏同种异体移植衰竭的原因。最近的几条证据暗示了细胞因子IFN-Y 作为促脑膜硬化因素，IFN-Y对内皮细胞（EC）的关键功能作用是早期 损害EC依赖性放松，该松弛发生在此之前，并且与平滑肌细胞有因果关系 （SMC）积累。具体而言，我的同事报告了IFN-y依赖性降低 移植EC中内皮一氧化氮合酶（ENOS）的功能/表达。有趣的是，ifn-y本身确实 不影响eNOS。它与另一种促炎细胞因子Inf共同起作用，以降低eNOS表达 并且没有EC的释放。但是，IFN-Y和TNF协同降低否的机制 EC的生产尚不清楚，也是该项目的主题。我们的数据表明SOCS1是 细胞因子信号蛋白的抑制剂是IFN-Y和TNF诱导的EC功能障碍的关键介体。 我们提出以下假设：1）。在静止（和IFN暴露）EC中，SOCS1与无活性结合 （酪氨酸磷酸化）ASK1导致SOCS1和Ask1的相互降解。 2）。响应 TNF，Ask1与SOCS1分离，导致ask1-jnk信号的激活又 磷酸化并激活SOCS1。 3）。独立激活SOCS1和ASK1-JNK 协同抑制生长因子（例如VEGF和IGF-1）介导的无释放导致EC功能障碍 和GA的进展。我们提出以下特定目的来检验我们的假设：1）确定 SOCS1在EC中诱导ask1降解以及IFN-Y和TNF如何修改的机制 回复。 2）确定SOCS1损害无功能的机制。 3）确定 同种异体移植和异种移植模型中的EC功能中的SOCS1。这些研究应促进 控制GA和移植失败以及其他血管疾病的新治疗方法，例如 动脉粥样硬化。