Endocrine Abstracts (2017) 50 S11.1 | DOI: 10.1530/endoabs.50.S11.1

ACTH: an underappreciated driver of hypertension

Eleanor Davies

Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.

Hypertension is one of the most common risk factors for cardiovascular disease and is well known to have a substantial heritable component. The mineralocorticoid aldosterone plays a key role in the regulation of BP and excess production can lead to hypertension. Therefore, much attention has focused on the genes mediating its biosynthesis.

The terminal stage of aldosterone production is catalysed by the aldosterone synthase enzyme, encoded by the CYP11B2 gene. We have shown that this gene is highly polymorphic and that variation in its regulatory regions associate with altered aldosterone production and hypertension due to changes in transcriptional and post-transcriptional gene regulation. Interestingly, polymorphic variation at two key loci involved in the biosynthesis of cortisol, CYP11B1 and CYP17A1, are also associated with increased aldosterone production and hypertension.

While the influence of CYP11B2 expression over aldosterone secretion is obvious, it not immediately clear how CYP11B1 and CYP17A1 affect the aldosterone phenotype, given their lack of expression in the aldosterone-producing adrenal zona glomerulosa. However, one hypothesis, which we have long proposed, concerns the role of ACTH. Although often overlooked as a significant long-term regulator of aldosterone, we have evidence that common genetic polymorphisms at this trio of steroidogenic genes affects ACTH secretion and action, with consequences for the aldosterone response. We believe this relationship between ACTH and the biosynthesis of corticosteroids, including aldosterone, is a key factor in the development of hypertension. The relative frequency of the polymorphisms we have identified implies a widespread genetic predisposition to high blood pressure. Therefore, understanding the genetic influences underlying ACTH and its regulation of aldosterone secretion could ultimately lead to improved control of blood pressure and the differential diagnosis of hypertension.

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