Epigenetic regulation of aldosterone and salt sensitivity in hypertension

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 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.