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Abstract：
Calcific Aortic Valve Disease (CAVD) is a significant concern for cardiovascular health and is closely associated with chronic kidney disease (CKD). Aortic valve endothelial cells (VECs) play a significant role in the onset and progression of CAVD. Previous research has suggested that uremic toxins, particularly indoxyl sulfate (IS), induce vascular calcification and endothelial dysfunction, but the effect of IS on valve endothelial cells (VECs) and its contribution to CAVD is unclear. Our results show that IS reduced human VEC viability and increased pro-calcific markers RUNX2 and alkaline phosphatase (ALP) expression. Additionally, IS-exposed VECs cultured in pro-osteogenic media showed increased calcification. Mechanistically, IS induced endothelial-to-mesenchymal transition (EndMT), evidenced by the loss of endothelial markers and increased expression of mesenchymal markers. IS triggered VEC inflammation, as revealed by NF-kB activation, and decreased integrin-linked kinase (ILK) expression. ILK overexpression reversed the loss of endothelial phenotype and RUNX2, emphasizing its relevance in the pathogenesis of CAVD in CKD. Conversely, a lower dose of IS intensified some of the effects in EndMT caused by silencing ILK. These findings imply that IS affects valve endothelium directly, contributing to CAVD by inducing EndMT and calcification, with ILK acting as a crucial modulator.
摘要：
钙化性主动脉瓣疾病（CAVD）是心血管健康的重要问题，与慢性肾脏疾病（CKD）密切相关。主动脉瓣内皮细胞（VECs）在CAVD的发生和发展中起重要作用。以前的研究表明尿毒症毒素，特别是硫酸吲哚酚(IS)，诱导血管钙化和内皮功能障碍，但IS对瓣膜内皮细胞（VECs）的影响及其对CAVD的贡献尚不清楚。我们的结果表明，IS降低了人VEC的活力，并增加了前钙化标志物RUNX2和碱性磷酸酶（ALP）的表达。此外,在促成骨培养基中培养的暴露于IS的VEC显示钙化增加。机械上,IS诱导内皮-间质转化（EndMT），内皮标记物的丢失和间充质标记物的表达增加。引发VEC炎症，正如NF-kB激活所揭示的，和减少整合素连接激酶（ILK）的表达。ILK过表达逆转了内皮表型和RUNX2的丧失，强调了其在CKDCAVD发病机制中的相关性。相反，较低剂量的IS增强了沉默ILK对EndMT的一些影响。这些发现暗示IS直接影响瓣膜内皮，通过诱导EndMT和钙化促进CAVD，ILK作为一个关键的调制器。
