The Role of Ets-1 in Vascular Inflammation

描述（由申请人提供）：血管紧张素II （Ang II）是高血压、动脉粥样硬化和糖尿病等多种疾病中血管炎症和重构的重要介质。AngII对血管壁功能和形态的影响是基因表达明显变化的结果，这至少部分依赖于转录因子NF-kB和AP-1的激活。ETS -1是ETS家族的原型成员。我们的研究结果表明，Ets-1是血管平滑肌细胞、内皮细胞和T细胞对炎症刺激的炎症反应的关键调节剂。Ets-1在PDGF-BB、血管紧张素II和凝血酶的作用下上调。在小鼠体内长期输注AngII可促进血管重构，这种重构始于炎症细胞的募集，随后是血管内侧肥大和血管周围纤维化。与对照小鼠相比，Ets-1缺陷小鼠对AngII的反应表现出血管重塑的明显减少。我们已经确定趋化因子MCP-1是Ets-1的主要下游靶标。Ets-1缺陷小鼠血管炎症部位MCP-1表达明显降低。我们还发现NAD(P)H同工酶phox47是Ets-1的下游靶标。该提案的总体假设是，ETS转录因子ETS -1是血管炎症的关键介质，因此在许多血管疾病中介导炎症反应是必需的。这些研究的目标是：1)表征Ets-1如何在转录、转录后和翻译后水平上受到Ang II的调控。2)表征Ets-1在AngII和其他炎症刺激反应中调控活性氧（ROS），特别是NAD(P)H氧化酶同工酶phox47的作用。3)测试全身给药优势阴性形式的Ets-1阻断血管炎症的治疗效果3)通过在血管平滑肌细胞中产生条件敲除，确定Ets-1作为特定细胞类型血管炎症和重塑的介质的作用。这项建议的长期目标不仅是了解血管炎症的分子机制，而且因此确定抑制这一过程的潜在新治疗方法。公共卫生相关性：血管炎症是包括高血压、冠心病和糖尿病在内的几种血管疾病的重要组成部分。该项目的目标是进一步确定Ets-1转录因子在调节血管炎症中的作用，并评估该转录因子的显性阴性形式在人类疾病小鼠模型中阻断血管炎症的几个阶段的治疗潜力。

DESCRIPTION (provided by applicant): Angiotensin II (Ang II) is a critical mediator of vascular inflammation and remodeling in a number of diseases including hypertension, atherosclerosis and diabetes. AngII effects on vascular wall function and morphology occur as a result of distinct changes in gene expression, that are at least in part dependent on the activation of the transcription factors NF-kB, and AP-1. Ets-1 is the prototypic member of the ETS family. Our results suggest that Ets-1 is a critical modulator of inflammatory responses in the vascular smooth muscle cells, endothelial cells and T cells, in response to inflammatory stimuli. Ets-1 is upregulated in response to PDGF-BB, Angiotensin II, and thrombin. Chronic infusion of AngII in mice promotes vascular remodeling that begins with the recruitment of inflammatory cells, followed by medial hypertrophy and perivascular fibrosis. Ets-1 deficient mice exhibit marked reductions in vascular remodeling compared to control mice in response to AngII. We have identified the chemokine MCP-1 as a major downstream target for Ets-1. Ets-1 deficient mice exhibit marked reduction in the expression of MCP-1 at sites of vascular inflammation. We have also identified the NAD(P)H isoenzyme phox47 as a downstream target of Ets-1. The overall hypothesis for this proposal is that the ETS transcription factor Ets-1 is a critical mediator of vascular inflammation and is therefore required for mediating inflammatory responses in a number of vascular diseases. The goals of these studies are to: 1) Characterize how Ets-1 is regulated by Ang II at the transcriptional, post-transcriptional, and post-translational levels. 2) Characterize the role of Ets-1 in the regulation of reactive oxygen species (ROS) and in particular the NAD(P)H oxidase isoenzyme phox47 in response to AngII and other inflammatory stimuli. 3) Test the therapeutic effect of systemic administration of dominant-negative forms of Ets-1 to block vascular inflammation 3) Determine the role of Ets-1 as a mediator of vascular inflammation and remodeling in specific cell types by generating conditional knockouts in vascular smooth muscle cells. The long-term goals of this proposal are not only to understand the molecular mechanisms of vascular inflammation but to thereby identify potential novel therapeutic approaches toward inhibiting this process. PUBLIC HEALTH RELEVANCE: Vascular inflammation is a critical component of several vascular diseases including hypertension, coronary heart disease, and diabetes mellitus. The goals of this project are to further define the role of the Ets-1 transcription factor in regulating vascular inflammation, and evaluate the therapeutic potential of dominant negative forms of this transcription factor to block several stages of vascular inflammation in mouse models of human disease.