Ah Receptor and Endothelin-Dependent Hypertension

心血管疾病发生在四分之一的成年人中，并且是美国死亡的主要原因。 1)是与许多这些疾病的发病机制有关的一个因素。ET-1生物合成是 受基因转录调控，缺氧是最有效的刺激之一。我们建议芳基 碳氢化合物受体（AhR）是一种配体激活的转录因子，影响ET-1的氧调节 表达并调节ET-1依赖性心血管疾病的发病机制。当AhR 在常氧条件下，基因缺失的无效小鼠表现出升高的组织preproET-1 mRNA， 血浆ET-1，并发展为心肌肥厚。然而，当AhR敲除小鼠暴露于轻度缺氧时， （~ 1，500 m）时，ET-1进一步诱导，心肌肥厚进程加快， 变得高血压。此外，AhR敲除小鼠表现出增加的血管紧张素（Ang）II和反应性血管紧张素（Ang）II受体。 与野生型小鼠相比，在轻度缺氧下的氧种类。这些数据表明，AhR影响基础 和缺氧诱导的ET-1表达，ET-1和Ang II都可能介导组织病理学， 轻度缺氧因此，我们将测试AhR抑制基础和缺氧诱导的ET-1的假设 因此AhR的缺失增加了对缺氧诱导的ET-1表达的敏感性， 通过诱导血管紧张素转换酶激活肾素-血管紧张素系统（RAS）、高血压和器官损伤， 活性氧（ROS）。目的1：建立缺氧诱导的ET-1、RAS在心肌缺血再灌注损伤中的作用 激活和ROS产生对AhR缺失小鼠中的组织病理学的影响。维持AhR敲除小鼠研究 在常氧或轻度缺氧下比较RAS基因表达和酶活性;血管，心脏， 和肾损伤;和ROS产生。Ang II和ET-1的作用将使用 ACE抑制剂/ETA受体拮抗剂组合，而ROS的贡献将使用 超氧化物歧化酶模拟物，tempol。在目标2中，我们将描述AhR在以下方面的贡献： 内皮细胞对缺氧诱导的、ET-1介导的RAS激活、高血压和器官损伤的作用 使用Cre/Lox技术研究仅在内皮细胞中缺失AhR的小鼠。在目标3中，我们 使用表达ET-1的转基因小鼠建立AhR抑制ET-1转录的机制， 荧光素酶在ET-1启动子调控下的表达和在原代小鼠中进行ET-1启动子分析 内皮细胞我们的研究结果将定义一个新的调节途径，抑制缺氧诱导的ET-1。 1，可用于开发治疗ET-1依赖性心血管疾病的新疗法。

Cardiovascular disease occurs in 1 in 4 adults and is the leading cause of death in the U.S. Endothelin-1 (ET- 1) is one factor that has been implicated in the pathogenesis of many of these diseases. ET-1 biosynthesis is regulated by gene transcription and hypoxia is one of the most potent stimuli. We propose that the aryl hydrocarbon receptor (AhR), a ligand activated transcription factor, influences oxygen-regulation of ET-1 expression and modulates the pathogenesis of ET-1-dependent cardiovascular diseases. When the AhR is genetically deleted, null mice under normoxic conditions exhibit elevated tissue preproET-1 mRNA and plasma ET-1, and develop cardiac hypertrophy. However, when AhR null mice are exposed to mild hypoxia (~1,500 m), ET-1is induced further, the progression of cardiac hypertrophy is accelerated, and the mice become hypertensive. Additionally, AhR null mice exhibit increased angiotensin (Ang) II and reactive oxygen species under mild hypoxia, compare to wildtype mice. These data suggest that AhR influences basal and hypoxia-induced ET-1 expression and that both ET-1 and Ang II may mediate tissue pathologies under mild hypoxia. Thus, we will test the hypothesis that AhR suppresses basal and hypoxia-induced ET-1 transcription so that loss of AhR increases the sensitivity to hypoxia-induced ET-1expression, leading to activation of the renin-angiotensin system (RAS), hypertension and organ damage via induction of reactive oxygen species (ROS). In aim 1, we will establish the contribution of hypoxia-induced ET-1, RAS activation, and ROS production to tissue pathologies in AhR null mice. Studies in AhR null mice maintained under normoxia or mild hypoxia will compare RAS gene expression and enzyme activity; vascular, cardiac, and renal injury; and ROS production. The contribution of Ang II and ET-1 will be investigated using an ACE inhibitor/ETA receptor antagonist combination, while the contribution of ROS will be investigated using the superoxide. dismutase mimetic, tempol. In aim 2, we will delineate the contribution of the AhR in endothelial cells to hypoxia-induced, ET-1-mediated RAS activation, hypertension, and organ damage by studying mice where AhR is deleted only in endothelial cells using Cre/Lox technology. In aim 3, we will establish the mechanism by which AhR suppresses ET-1 transcription using transgenic mice that express luciferase under ET-1promoter control and by conducting ET-1promoter analysis in primary murine endothelial cells. Our results will define a novel regulatory pathway for suppression of hypoxia-induced ET- 1, which could be use to develop new therapies for ET-1-dependent cardiovascular diseases.