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: 9415442
• 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/9415442
• 关键词: Address; Adrenal Glands; Affect; African; African American; Aldosterone; 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; Functional disorder; Genes; Genetic; Genetic Transcription; Genotype; Heterogeneity; Heterozygote; Histones; Hormones; Human; Hypertension; Impairment; Individual; Intake; KDM1A gene; Kidney; Knockout Mice; Life; Light; Link; 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 salt; epigenetic regulation; experimental study; genetic variant; high salt diet; histone methylation; hypertension prevention; knock-down; normotensive; programs; public health relevance; 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）：遗传和环境因素有助于心血管疾病的发展。确定这两个因素之间的关系对于迈向更完善的治疗策略（确定疾病类别中特定的“风险”亚群，并制定更具体的治疗方案）越来越重要。为此，拟议的研究计划侧重于基因转录调节酶，赖氨酸特异性脱甲基酶1（LSD 1）在连接血压的环境调节剂（膳食盐）和体积和血压的关键效应酶（醛固酮）在高血压发展中的作用。我们的初步数据表明，遗传修饰的LSD 1缺陷动物模型表达了通常的饮食盐调节醛固酮表达的损失。由此产生的表型是面对高盐摄入、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LSD 1多态性变异的人也显示出相关的血压盐敏感性和改变的醛固酮反应性。然而，只有非洲裔美国人而不是高加索人显示这种改变的表型。这些发现导致了LSD 1在将膳食盐与醛固酮作用联系起来中起作用的假设。LSD 1活性的丧失使高盐饮食对醛固酮分泌的通常抑制作用失效，这反过来导致血压的盐敏感性和血管功能障碍。以下研究方案将试图证明，在生命早期LSD 1敲除小鼠中存在的改变的醛固酮和血管表型也见于具有代表LSD 1功能障碍的“风险”变体等位基因的血压正常的人（“疾病前”）中。因为这是在疾病前的状态，我们预计异常表型存在于两个种族（在发展抵消机制之前）。然后，我们将表明，受影响的LSD1基因型在高血压个体影响非洲裔美国人比白人，由于受损的利钠尿能力在前者（一个完整的抵消机制）。我们将进行严格控制的饮食负荷实验，并通过基因型和种族之间的钠排泄能力，血压的盐敏感性，LSD 1在血管结构中的表达，受损的醛固酮和血管反应性进行比较。我们将在我们的动物模型中证明LSD 1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发展的直接证据。