Oxidised LDL-Induced FOXS1 Mediates Cholesterol Transport Dysfunction and Aortic Valve Calcification

Abstract

Aortic valve calcification (AVC) is one of the progressive diseases that are lipid-mediated where the inflammatory and osteogenic
processes interfere with the normal architecture of the valves. There is growing evidence indicating that oxidised low-density lipoprotein
(oxLDL), a major intermediary of vascular inflammation, is a major mediator of cellular reprogramming among valvular interstitial cells
(VICs). But, the transcriptional pathways, which connects oxLDL exposure to damaged cholesterol homeostasis and calcification, are not
completely understood. The research paper is a study on how the transcription factor FOXS1 is a downstream effecter of oxLDL
signaling in the regulation of cholesterol transport, and calcific remodeling.
We show that oxLDL exposure induces FOXS1 in human VICs and in the murine aortic valve tissue and suppresses the activity of major
cholesterol efflux controllers, such as ABCA1 and ABCG1. Activation of FOXS1 results in intracellular cholesterol deposition,
upregulation of osteogenic genes including RUNX2 and BMP2 and calcium nodules. FOXS1 knockdown reversed the capacity of
cholesterol efflux, toned down the osteogenic gene expression, as well as calmed down the calcification in cell culture in a significant
manner. Overall, overexpression of FOXS1 increased the rate of leaflet stiffening and microcalcification and silencing of FOXS1
alleviated oxLDL-induced valvular transformations during vivo. The combined results reveal that FOXS1 is an important mediator
between deregulated lipid processing and the osteogenic remodelling of AVC and is an attractive therapeutic area of interest because of
its involvement in the onset of pathological alterations early in the disease.