Oxidized LDL-induced FOXS1 mediates cholesterol transport dysfunction and inflammasome activation to drive aortic valve calcification

作者：Chen Jiang, Dingyi Yao, Qiang Shen, Rui Tian, Lin Fan, Zheng Qiang, Xingyu Qian, Zongtao Liu, Yuming Huang, Nianguo Dong · 发表于：Cardiovascular Research · 年份：2025 · DOI：10.1093/cvr/cvaf159 · 被引用次数：9 · 研究领域：Cardiac Valve Diseases and Treatments、Congenital heart defects research、Aortic Disease and Treatment Approaches

AIMS: Calcific aortic valve disease (CAVD) is becoming more prevalent with the population ageing; however, there is currently no medical therapy available. During early lipid deposition, low-density lipoprotein (LDL) mediates chronic inflammation and accelerates calcification progression. However, the mechanism still needs to be further explored. METHODS AND RESULTS: The study identified the transcription factor FOXS in human valvular interstitial cells (VICs) as a pivotal regulator in aortic valve calcification. Bulk RNA-seq and qRT-PCR analysis were conducted to establish that FOXS1 is induced by oxidized LDL (oxLDL) in VICs. To elucidate the role of FOXS1 in osteogenic differentiation, small interfering RNA and recombinant adenovirus were utilized to modulate FOXS1 expression in VICs. High-fat diet (HFD)-fed Apoe-/-Foxs1-/- mice served as an in vivo model to investigate the role of FOXS1 in aortic valve calcification. Analysis from bulk RNA-seq, qRT-PCR, and western blot indicated significant activation of FOXS1 by oxLDL in VICs, with silencing of FOXS1 inhibiting oxLDL-induced osteogenic differentiation. Deletion of FOXS1 markedly reduced aortic valve calcification in HFD-fed Apoe-/- mice, as shown by decreased calcium deposition in the aortic valve leaflets. RNA-seq and chromatin immunoprecipitation sequencing were performed to reveal the regulatory mechanisms of FOXS1, uncovering direct interactions with the promoter of BSCL2, which subsequently inhibits the expression ...