Aldosterone, Histone Demethylase and Cardiovascular Disease

醛固酮、组蛋白去甲基化酶与心血管疾病

• 批准号: 7923955
• 负责人: GORDON H WILLIAMS
• 金额: $ 62.16万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7923955
• 关键词: Abdomen; Address; Adrenal Cortex; Adrenal Glands; Aldosterone; Alleles; Androgens; Angiotensin II; Angiotensinogen; Animal Model; Animals; Blood Pressure; Blood Vessels; California; Candidate Disease Gene; Cardiac; Cardiovascular Diseases; Cells; Characteristics; Clinical Research; Corticotropin; Data; Defect; Deltastab; Diet; Endothelial Cells; Enzyme Interaction; Enzymes; Estrogens; Functional disorder; Gene Expression; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genomics; Genotype; Goals; Gonadal Steroid Hormones; Heterozygote; Hispanics; Histones; Hormonal; Hormones; Human; Hypertension; In Vitro; Individual; Injury; Intake; Kidney; Knockout Mice; Link; Lysine; Mediating; Messenger RNA; Metabolism; Methylation; Mineralocorticoid Receptor; Minor; Modeling; Molecular; Nucleotides; Pathway interactions; Peptidyl-Dipeptidase A; Phenotype; Polymorphic Microsatellite Marker; Population; Potassium; Proteins; Protocols documentation; Receptor Activation; Receptor, Angiotensin, Type 1; Research Personnel; Research Project Grants; Role; Small Interfering RNA; Sodium; Sodium Chloride; Steroid Receptors; Steroids; Structure; Techniques; Testing; Tissues; Transcription Coactivator; Translational Research; Universities; Urine; Variant; base; cohort; db/db mouse; design; in vivo; knock-down; neutrophil; normotensive; programs; public health relevance; response; salt sensitive; text searching

DESCRIPTION (provided by applicant): For the past 20 years, we have studied the genetic underpinnings of hormonal factors leading to hypertension (HTN) in the HyperPATH cohort. From these studies, we have identified several associations between single nucleotide polymorphic (SNP) markers on candidate genes and specific intermediate phenotypes of the HTN. This proposal will focus on one of these identified phenotype/genotype associations. The intermediate phenotype is derived from the aldosterone (ALDO) response to angiotensin II (ANGII) on a sodium-restricted intake. This phenotype is heritable in the hypertensive population, is bimodally distributed in the hypertensive but not normotensive population and the hypertensive intermediate phenotype consists of those subjects in the lower mode that comprise 25% of hypertensives and <2% of normotensives. Associated with this subset is an enhanced sodium sensitivity of blood pressure and a defect in the vasculature, specifically the renovasculature. The genetic mechanisms responsible for these effects are unclear. One candidate is the recently described, first identified, histone demethylase that is linked to and whose action is modified by steroids---lysine-specific demethylase 1 (LSD1). A positive association between SNPs in LSD1 and ALDO response to ANGII was only observed in hypertensives and not normotensives. We then extended our studies in two ways: assessing LSD1 SNPs relationship to other phenotypic characteristics in humans (the minor allele also was associated with low urine ALDO levels on a high salt diet and sodium sensitivity of BP) and studying in experimental animals the relationship between LSD1, ALDO, the mineralocorticoid receptor (MR), and vascular injury. Our preliminary data suggest that LSD1: is present in vascular and cardiac tissue; is regulated by NA intake; is decreased by ALDO with the reversal by administering an MR antagonist; and is reduced in a CV injury model with parallel increases in its level and reduction in CV damage with MR blockade. The overall goal of the present proposal is to expand on these preliminary findings by characterizing the mechanisms underlying the interactions between LSD1, ALDO and the vasculature and their involvement in the pathophysiology of cardiovascular disease. Three approaches will be used. 1) We will assess phenotypic associations to polymorphism in the LSD1 gene to other genes and in the HyperPATH cohort and in a different cohort. 2) We will define LSD1's role in ALDO secretion. 3) We will extend our mechanistic studies of LSD1 from the adrenal to the vasculature. Thus, these positive results have formed the basis of the present proposal: a translational research project based on preliminary results from both the bench and the clinical research center. We will use in vivo and in vitro studies on vessels and adrenals in both humans (from our HyperPATH cohort) and animals (the LSD1 heterozygote knockout mouse where the LSD1 levels are 50% of that in the wild type). Vascular reactivity of vessels, molecular biologic and cell biologic techniques will be used. PUBLIC HEALTH RELEVANCE: Aldosterone is a hormone secreted by the adrenal gland whose function traditionally has been assumed to be to modify the kidney's ability to excrete potassium and sodium. However, recently aldosterone also has been implicated in having a major, adverse impact on the vasculature and by extension cardiovascular disease by uncertain mechanisms. This project is designed to assess one of those mechanisms thereby providing entrie to developing more directed therapy to treat cardiovascular diseases.

描述（由申请人提供）：在过去的20年里，我们研究了HyperPATH队列中导致高血压（HTN）的激素因素的遗传基础。从这些研究中，我们已经确定了候选基因上的单核苷酸多态性（SNP）标记与HTN特定中间表型之间的几种关联。本提案将重点关注这些已确定的表型/基因型关联之一。中间表型来源于钠限制摄入时醛固酮（ALDO）对血管紧张素II （ANGII）的反应。这种表型在高血压人群中是可遗传的，在高血压人群而非正常人群中呈双峰分布，高血压中间表型由低模式的受试者组成，包括25%的高血压患者和低于2%的正常人群。与该亚群相关的是血压钠敏感性增强和脉管系统缺陷，特别是肾脉管系统。造成这些影响的遗传机制尚不清楚。其中一个候选是最近被描述并首次发现的组蛋白去甲基化酶，它与赖氨酸特异性去甲基化酶1 （LSD1）相连，其作用被类固醇修饰。LSD1 snp与ALDO对ANGII反应之间的正相关仅在高血压患者中观察到，而在正常血压患者中没有。然后，我们以两种方式扩展了我们的研究：评估LSD1 snp与人类其他表型特征的关系（次要等位基因也与高盐饮食中的低尿ALDO水平和BP的钠敏感性有关），并在实验动物中研究LSD1、ALDO、矿化皮质激素受体（MR）和血管损伤之间的关系。我们的初步数据表明LSD1：存在于血管和心脏组织中；受NA摄入量的调节；通过给予MR拮抗剂逆转，ALDO降低；并在CV损伤模型中减少，MR阻断后其水平平行增加，CV损伤减少。本提案的总体目标是通过描述LSD1、ALDO和脉管系统之间相互作用的机制及其参与心血管疾病的病理生理来扩展这些初步发现。将采用三种方法。1)我们将评估LSD1基因多态性与其他基因、HyperPATH队列和不同队列的表型关联。2)我们将明确LSD1在ALDO分泌中的作用。3)我们将把LSD1的机制研究从肾上腺扩展到血管。因此，这些积极的结果构成了本提案的基础：一个基于实验台和临床研究中心初步结果的转化研究项目。我们将对人类（来自HyperPATH队列）和动物（LSD1杂合子敲除小鼠，其LSD1水平是野生型的50%）的血管和肾上腺进行体内和体外研究。将使用血管反应性、分子生物学和细胞生物学技术。公共卫生相关性：醛固酮是一种由肾上腺分泌的激素，其功能传统上被认为是改变肾脏排泄钾和钠的能力。然而，最近醛固酮也被认为通过不确定的机制对血管系统和心血管疾病产生重大的不利影响。该项目旨在评估其中一种机制，从而为开发更直接的治疗心血管疾病的方法提供入口。