The Role of Ets-1 in Vascular Inflammation

说明(申请人提供)：血管紧张素II(Ang II)是一种重要的调节血管炎症和血管重塑的介质，在许多疾病中包括高血压、动脉粥样硬化和糖尿病。Angii对血管壁功能和形态的影响是由于基因表达的明显变化，至少部分依赖于转录因子NF-kB和AP-1的激活。ETS-1是ETS家族的典型成员。我们的结果表明，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因子。ETS-1在PDGF-BB、血管紧张素II和凝血酶的作用下上调。小鼠长期应用血管紧张素转换酶抑制剂可促进血管重塑，血管重塑始于炎症细胞的募集，随后是中膜肥大和血管周围纤维化。与对照小鼠相比，Ets-1缺陷小鼠的血管重塑明显减少。我们已经确定趋化因子MCP-1是ETS-1的主要下游靶点。Ets-1基因缺陷小鼠血管炎症部位MCP-1表达显著减少。我们还将NAD(P)H同工酶phox47确定为ETS-1的下游靶点。这一提议的总体假设是，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所必需的。这些研究的目的是：1)在转录、转录后和翻译后水平上表征Ets-1是如何被Ang II调控的。2)研究ETS-1在调节血管紧张素Ⅱ和其他炎症刺激下的ROS，特别是NAD(P)H氧化酶同工酶phox47中的作用。3)测试全身性应用显性-阴性形式的ETS-1以阻断血管炎症的疗效3)通过在血管平滑肌细胞中产生条件性基因敲除来确定ETS-1作为特定细胞类型的血管炎症和重塑的介导物的作用。这项建议的长期目标不仅是了解血管炎症的分子机制，而且由此确定抑制这一过程的潜在的新的治疗方法。公共卫生相关性：血管炎症是几种血管疾病的重要组成部分，包括高血压、冠心病和糖尿病。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.