Regulation of the late-pathway of aldosterone biosynthesis

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DESCRIPTION (provided by applicant): Aldosterone has a significant role in the development of hypertension and cardiovascular damage. Primary Aldosteronism, caused by the autonomous and excessive secretion of aldosterone by the adrenal, is the etiology of the high blood pressure in 5-10% of hypertensive patients. Synthesis of aldosterone requires several enzymatic steps, some occurring in the cytosol, others, notably the first and last, in mitochondria. Aldosterone biosynthesis is known to be regulated at two steps in the pathway, an early step requiring the transfer of cholesterol by the StAR protein into the mitochondria where it is hydroxylated and cleaved to produce pregnenolone, and late in the pathway when deoxycorticosterone (DOC) is successively hydroxylated to aldosterone by the product of the CYP11B2 gene, aldosterone synthase, within the mitochondria. Aldosterone synthase is regulated primarily at the transcriptional level. DOC is synthesized from progesterone by the cytosolic enzyme 21-hydroxylase. We present preliminary data indicating that aldosterone biosynthesis is also regulated by the efficient transfer of DOC into the mitochondria by an active process. We proposed to address the following hypotheses: "Regulation of the late pathway of aldosterone biosynthesis involves regulation of the transfer of DOC from the cytosol into the mitochondria" This is an exploratory proposal to address the specific aims: 1. Characterize the mechanism of the regulation of the facilitated transfer of DOC into the mitochondria for conversion into aldosterone by the CYP11B2 enzyme 2. Identify and clone of the factor responsible for facilitating the transfer of DOC into the mitochondria. Relevance to human health: Hypertension is one of the most common diagnoses in adults and contributes to cardiovascular morbidity and mortality, as well as stroke, the primary causes of morbidity and death in America. Patients with aldosteronism have significantly greater cardiovascular, renal and cerebrovascular pathology than those with equivalent increases in blood pressure. Information about the regulation of aldosterone synthesis will lead to more effective therapy for these patients. PUBLIC HEALTH RELEVANCE: Primary Aldosteronism is the most common form of secondary hypertension, accounting for about 7-10% of unselected patients with hypertension. The regulation of aldosterone biosynthesis is incompletely understood, but it is known that the regulation occurs both early and late in the biosynthetic pathway. The late pathway involves the action of the enzyme aldosterone synthase upon DOC within the mitochondria. We have shown that the transfer of DOC into the mitochondria is regulated and propose to isolate the factor involved.