Epigenetic regulation of aldosterone and salt sensitivity in hypertension

高血压醛固酮和盐敏感性的表观遗传调控

• 批准号: 9027422
• 负责人: JONATHAN S. WILLIAMS
• 金额: $ 65.7万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2021-01-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9027422
• 关键词: Address; Adrenal Glands; Affect; African; African American; Aldosterone; Alleles; Animal Model; Biomedical Research; Biopsy; Blood Pressure; Blood Vessels; CYP11B2 gene; Cardiovascular Diseases; Cardiovascular system; Categories; Caucasians; Cell Line; Cells; Cyclic GMP; DNA; Data; Defect; Development; Diet; Disease; Elements; Enrollment; Environmental Risk Factor; Enzymes; Epigenetic Process; Excretory function; Exhibits; Figs - dietary; Functional disorder; Genes; Genetic; Genetic Transcription; Genotype; Heterogeneity; Heterozygote; Histones; Hormones; Human; Hypertension; Hypotension; Individual; Intake; Kidney; Knockout Mice; Life; Light; Link; Lysine; Meta-Analysis; Mexican; Mineralocorticoid Receptor; Modeling; Mononuclear; Mus; Natriuretic Factors; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiological; Play; Population; Protocols documentation; Publishing; Race; Regulation; Reporting; Research; Risk; Role; Sodium; Sodium Chloride; Structure; Symptoms; Syndrome; Techniques; Variant; Vascular Diseases; Vasodilation; base; blood pressure reduction; blood pressure regulation; chromatin immunoprecipitation; clinically relevant; dietary control; dietary salt; epigenetic regulation; genetic variant; high salt diet; histone methylation; hypertension prevention; knock-down; normotensive; programs; public health relevance; research study; response; risk variant; salt intake; salt sensitive hypertension; saluretic; screening; treatment strategy

 DESCRIPTION (provided by applicant): Genetic and environmental factors contribute to the development of cardiovascular diseases. Establishing the relationship between these two factors is of increasing importance in moving towards more refined treatment strategies (identifying specific "at-risk" sub-populations within a disease category, and developing more specific treatment options). To this end, the proposed research program focuses on the role a gene transcription regulating enzyme, Lysine-specific Demethylase 1 (LSD1) plays in linking an environmental modifier of blood pressure (dietary salt) and a key effector enzyme of volume and blood pressure (aldosterone) in the development of hypertension. Our preliminary data demonstrate that a genetically modified LSD1 deficient animal model expresses a loss of usual dietary salt regulation over aldosterone expression. The resultant phenotype is elevated aldosterone expression in the face of high salt intake, salt-sensitive hypertension, and vascular dysfunction. Of clinical relevance, humans with LSD1 polymorphic variation also display an associated salt sensitivity of blood pressure and altered aldosterone responsiveness. However, only African American and not Caucasian display this altered phenotype. These findings led to the hypothesis that LSD1 plays a role in linking dietary salt to aldosterone action. Loss of LSD1 activity disables the usual suppressive actions of a high salt diet on aldosterone secretion, which in turn leads to salt-sensitivity of blood pressure and vascular dysfunction. The following research protocol will seek to demonstrate that the altered aldosterone and vascular phenotypes present in the LSD1 knockdown mouse early in life are also seen in normotensive humans ("pre-disease") who possess the "at risk" variant allele that represents LSD1 dysfunction. Because this is in a pre-disease state, we expect the abnormal phenotype to be present in both races (prior to development of counteracting mechanisms). We will then show that the affected LSD1 genotype in hypertensive individuals affects African Americans more than Caucasians due to impaired natriuretic capacity in the former (an intact counteracting mechanism). We will conduct a strictly controlled dietary loading experiment and compare by genotype and between race sodium excretion capacity, salt sensitivity of blood pressure, expression of LSD1 in vascular structures, impaired aldosterone and vascular responsiveness. We will demonstrate direct evidence in our animal model that LSD1 affects aldosterone synthase expression in turn leading to development of salt-sensitive hypertension and concomitant vascular dysfunction.

 描述（由申请人提供）：遗传和环境因素导致心血管疾病的发生。建立这两个因素之间的关系对于迈向更精细的治疗策略（识别疾病类别中特定的“高危”亚群，并开发更具体的治疗方案）变得越来越重要。为此，拟议的研究计划重点关注基因转录调节酶赖氨酸特异性脱甲基酶 1 (LSD1) 在高血压发展中将血压环境调节剂（膳食盐）与容量和血压的关键效应酶（醛固酮）联系起来所发挥的作用。我们的初步数据表明，转基因 LSD1 缺陷动物模型表现出对醛固酮表达的日常饮食盐调节的丧失。由此产生的表型是在高盐摄入、盐敏感性高血压和血管功能障碍时醛固酮表达升高。具有临床相关性的是，具有 LSD1 多态性变异的人类还表现出与血压相关的盐敏感性和改变的醛固酮反应性。然而，只有非裔美国人而不是白种人表现出这种改变的表型。这些发现引发了这样的假设：LSD1 在将膳食盐与醛固酮作用联系起来方面发挥着作用。 LSD1活性的丧失会导致高盐饮食对醛固酮分泌的通常抑制作用失效，进而导致血压对盐敏感和血管功能障碍。以下研究方案将试图证明 LSD1 敲低小鼠生命早期存在的醛固酮和血管表型的改变也出现在血压正常的人类（“疾病前期”）中，这些人拥有代表 LSD1 功能障碍的“危险”变异等位基因。因为这是处于疾病前状态，所以我们预计两个种族中都存在异常表型（在对抗机制发展之前）。然后我们将证明，高血压患者中受影响的 LSD1 基因型对非裔美国人的影响比白人更大，因为前者的尿钠排泄能力受损（完整的抵消机制）。我们将进行严格控制的膳食负荷实验，并按基因型和种族之间的钠排泄能力、血压的盐敏感性、血管结构中LSD1的表达、醛固酮受损和血管反应性进行比较。我们将在我们的动物模型中证明 LSD1 影响醛固酮合酶表达进而导致盐敏感性高血压和伴随的血管功能障碍的直接证据。