Ah Receptor and Endothelin-Dependent Hypertension

Ah 受体与内皮素依赖性高血压

• 批准号: 7194301
• 负责人: Mary K Walker
• 金额: $ 36.16万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-03 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7194301
• 关键词: Adult; Anabolism; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Aryl Hydrocarbon Receptor; Blood Pressure; Blood Vessels; Cardiac; Cardiovascular Diseases; Cause of Death; Condition; Data; Disease; Elements; Endothelial Cells; Endothelin Receptor; Endothelin-1; Exhibits; Fibrinogen; Gene Expression; Genetic; Genetic Models; Genetic Transcription; Heart Hypertrophy; Hypertension; Hypoxia; In Vitro; Indium; Injury; Kidney; Knockout Mice; Ligands; Luciferases; Lung; Mediating; Messenger RNA; Modeling; Molecular Analysis; Mus; Organ; Oxygen; Pathogenesis; Pathology; Plasma; Production; Qualifying; Reactive Oxygen Species; Regulation; Regulatory Pathway; Renin-Angiotensin System; Repression; Research; Stimulus; Superoxide Dismutase; Systems Biology; Technology; Testing; Tissues; Transcriptional Regulation; Transgenic Mice; Transgenic Organisms; Work; activating transcription factor; enzyme activity; experience; in vivo; innovation; mimetics; mouse Ahr protein; mouse model; novel; promoter; receptor; tempol

DESCRIPTION (provided by applicant): 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-1 is 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-1 expression, 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-1 promoter control and by conducting ET-1 promoter analysis in primary murine endothelial cells. Our results will define a novel regulatory pathway for suppression of hypoxia-induced ET- 1, which could be used to develop new therapies for ET-1-dependent cardiovascular diseases.

描述（由申请人提供）：心血管疾病发生在1/4的成年人中，并且是美国死亡的主要原因。内皮素-1（ET- 1）是与许多这些疾病的发病机制有关的一个因素。ET-1的生物合成受基因转录调控，缺氧是最有效的刺激之一。我们认为，芳烃受体（AhR），配体激活的转录因子，影响氧调节ET-1的表达和调节ET-1依赖性心血管疾病的发病机制。当AhR基因缺失时，在常氧条件下的裸小鼠表现出组织前ET-1 mRNA和血浆ET-1升高，并发展为心脏肥大。然而，当AhR敲除小鼠暴露于轻度缺氧（约1，500 m）时，ET-1被进一步诱导，心脏肥大的进展加速，小鼠变得高血压。此外，AhR敲除小鼠在轻度缺氧下表现出增加的血管紧张素（Ang）II和活性氧，与野生型小鼠相比。这些数据表明，AhR的影响基础和缺氧诱导的ET-1的表达，ET-1和血管紧张素II可能介导的组织病理条件下轻度缺氧。因此，我们将测试的假设，AhR抑制基础和缺氧诱导的ET-1的转录，使AhR的损失增加的敏感性，缺氧诱导的ET-1的表达，导致激活的肾素-血管紧张素系统（RAS），高血压和器官损伤，通过诱导活性氧（ROS）。在目标1中，我们将建立缺氧诱导的ET-1，RAS激活和ROS产生的AhR基因敲除小鼠的组织病理学的贡献。在常氧或轻度缺氧条件下维持的AhR敲除小鼠中的研究将比较RAS基因表达和酶活性;血管、心脏和肾损伤;以及ROS产生。将使用ACE抑制剂/ETA受体拮抗剂组合来研究Ang II和ET-1的贡献，而将使用超氧化物来研究ROS的贡献。歧化酶模拟物，tempol。在目标2中，我们将描述AhR在内皮细胞缺氧诱导的，ET-1介导的RAS激活，高血压，和器官损伤的贡献，通过研究小鼠AhR是删除只在内皮细胞中使用Cre/Lox技术。在目标3中，我们将使用在ET-1启动子控制下表达荧光素酶的转基因小鼠并通过在原代小鼠内皮细胞中进行ET-1启动子分析来建立AhR抑制ET-1转录的机制。我们的研究结果将定义一种抑制缺氧诱导的ET- 1的新型调节途径，可用于开发ET-1依赖性心血管疾病的新疗法。