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 aortic valve stenosis (AS), but pharmacological approaches remained unsatisfying. The liver-X-receptor (LXR) is key regulator in cholesterol metabolism, though its clinical use limited due to unwanted side effects. seaweed-derived oxysterol saringosterol an agonist of the LXRβ, promising more favourable tolerability. Purpose This study aimed better understand pathophysiology and assess potential targeted pharmacotherapy. Methods Tissue samples from valves were collected patients with AS or regurgitation (AR). Transcriptomics performed gene ontology (GO) analysis was used determine pathways genes that are relevant AS, then validated using qPCR. In vivo, mice received wire-induced either fed diet supplemented control diet. Haemodynamic characteristics assessed echocardiography. Additionally, hepatic concentrations saringosterol, expression LXRβ regulated well thickness composition assessed. vitro, human interstitial cells (VIC) cultured procalcifing medium stimulated investigate underlying molecular mechanisms. Results Transcriptomic revealed regulation several GO-terms related cholesterol- lipid metabolism. Many identified by suggesting pathophysiological relevance AS. We this assumption performing qPCR most prominent downstream targets ABCA1 ABCG1, both being differentially regulated. treatment six weeks resulted significant accumulation liver tissue induction LXRβ-regulated genes. Furthermore, strikingly reduced development after wire injury echocardiographic histological measurements. differentiation VIC into osteoblastic myofibroblastic phenotypes abolished which procalcifying mediators RUNX-2 ACTA-2 dose-dependent manner. Conclusion LXRβ-signalling analyses altered many involved linked LXRβ. murine model, we demonstrated oral application induced LXRβ-activity mitigated vitro experiments prevents adverse cell VIC, provides mechanistic explanation. Funding Acknowledgement Type funding sources: Public Institution(s). Main source(s): BONFOR Universität Bonn