Epigenetic regulation of aldosterone and salt sensitivity in hypertension

 描述(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精细的治疗战略(确定疾病类别中的特定“高危”亚群，并制定更具体的治疗选择)越来越重要。为此，建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(LSD1)在连接血压的环境调节剂(食盐)和体积和血压的关键影响酶(醛固酮)在高血压发生中的作用。我们的初步数据表明，转基因LSD1缺陷动物模型表现出通常饮食盐调节对醛固酮表达的丧失。由此产生的表型是面对高盐摄入量、盐敏感型高血压和血管功能障碍时醛固酮表达增加。与临床相关的是，携带LSD1多态变异的人还表现出与血压的盐敏感性和醛固酮反应改变相关的症状。然而，只有非裔美国人而不是高加索人表现出这种改变的表型。这些发现导致了一种假设，即LSD1在将饮食盐与醛固酮作用联系起来方面发挥了作用。LSD1活性的丧失会使高盐饮食通常对醛固酮分泌的抑制作用失效，这反过来会导致血压对盐敏感和血管功能障碍。下面的研究方案将试图证明，在LSD1基因敲除小鼠生命早期存在的改变的醛固酮和血管表型也可以在血压正常的人类(疾病前期)中看到，这些人拥有代表LSD1功能障碍的“处于危险”的变异等位基因。因为这是疾病前的状态，我们预计异常表型在两个种族中都存在(在对抗机制发展之前)。然后，我们将展示高血压患者中受影响的LSD1基因对非裔美国人的影响比对高加索人的影响更大，这是由于前者的利钠能力受损(一种完整的抵消机制)。我们将进行严格控制的膳食负荷实验，并按基因和种族比较钠排泄量、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。我们将在我们的动物模型中证明，LSD1影响醛固酮合成酶的表达，进而导致盐敏感型高血压的发展和伴随的血管功能障碍。

 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.