Pharmacological hypothesis: Nitric oxide-induced inhibition of ADAM-17 activity as well as vesicle release can in turn prevent the production of soluble endothelin-converting enzyme.

Abstract

Endothelin‐1 (ET‐1) and nitric oxide (NO) are two highly potent vasoactive molecules with opposing effects on the vasculature. Endothelin‐converting enzyme (ECE) and nitric oxide synthase (NOS) catalyse the production of ET‐1 and NO, respectively. It is well established that these molecules play a crucial role in the initiation and progression of cardiovascular diseases and have therefore become targets of therapy. Many studies have examined the mechanism(s) by which NO regulates ET‐1 production. Expression and localization of ECE‐1 is a key factor that determines the rate of ET‐1 production. ECE‐1 can either be membrane bound or be released from the cell surface to produce a soluble form. NO has been shown to reduce the expression of both membrane‐bound and soluble ECE‐1. Several studies have examined the mechanism(s) behind NO‐mediated inhibition of ECE expression on the cell membrane. However, the precise mechanism(s) behind NO‐mediated inhibition of soluble ECE production are unknown. We hypothesize that both exogenous and endogenous NO, inhibits the production of soluble ECE‐1 by preventing its release via extracellular vesicles (e.g., exosomes), and/or by inhibiting the activity of A Disintegrin and Metalloprotease‐17 (ADAM17). If this hypothesis is proven correct in future studies, these pathways represent targets for the therapeutic manipulation of soluble ECE‐1 production.