LXR-beta signalling is a key mediator in the pathogenesis of aortic valve stenosis and its prevention by saringosterol

Abstract

Background: Cholesterol metabolism contributes as a risk factor for aor-tic valve stenosis (AS), but pharmacological approaches remained un-satisfying. The liver-X-receptor (LXR) is a key regulator in cholesterol metabolism, though its clinical use is limited due to unwanted side effects. The seaweed-derived oxysterol saringosterol is an agonist of the LXRβ, promising a more favourable tolerability. Purpose: This study aimed to better understand the pathophysiology of aortic valve stenosis and to assess the potential of saringosterol as a targeted pharmacotherapy. Methods: Tissue samples from aortic valves were collected from patients with AS or aortic valve regurgitation (AR). Transcriptomics were performed and gene ontology (GO) analysis was used to determine pathways and genes that are relevant to AS, and then validated using qPCR. In vivo, mice received a wire-induced aortic valve stenosis and were either fed a diet supplemented with saringosterol or control diet. Haemodynamic characteristics were assessed using echocardiography. Additionally, hep-atic concentrations of saringosterol, expression of LXRβ regulated genes as well as aortic valve thickness and composition were assessed. In vitro, human aortic valve interstitial cells (VIC) were cultured in a procal-cifing medium and stimulated with saringosterol to investigate the underlying molecular mechanisms. Results: Transcriptomic analysis of AS samples revealed the regulation of