The prevalence of calcific aortic valve disease (CAVD) remains substantial while there is currently no medical therapy available. Forkhead box O1 (FOXO1) is known to be involved in the pathogenesis of cardiovascular diseases, including vascular calcification and atherosclerosis; however, its specific role in calcific aortic valve disease remains to be elucidated. In this study, we identified FOXO1 significantly down-regulated in the aortic valve interstitial cells (VICs) of calcified aortic valves by investigating clinical specimens and GEO database analysis. FOXO1 silencing or inhibition promoted VICs osteogenic differentiation in vitro and aortic valve calcification in Apoe mice, respectively. We identified that FOXO1 facilitated the ubiquitination and degradation of RUNX2, which process was mainly mediated by SMAD-specific E3 ubiquitin ligase 2 (SMURF2). Our discoveries unveil a heretofore unacknowledged mechanism involving the FOXO1/SMURF2/RUNX2 axis in CAVD, thereby proposing the potential therapeutic utility of FOXO1 or SMURF2 as viable strategies to impede the progression of CAVD.

中文翻译：

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FOXO1 在钙化主动脉瓣疾病中通过 SMURF2 调节 RUNX2 泛素化


钙化性主动脉瓣疾病（CAVD）的患病率仍然很高，但目前尚无可用的药物治疗方法。叉头盒 O1 (FOXO1) 已知参与心血管疾病的发病机制，包括血管钙化和动脉粥样硬化；然而，其在钙化性主动脉瓣疾病中的具体作用仍有待阐明。在本研究中，我们通过研究临床标本和 GEO 数据库分析，发现钙化主动脉瓣的主动脉瓣间质细胞 (VIC) 中 FOXO1 显着下调。 FOXO1 沉默或抑制分别促进 VIC 体外成骨分化和 Apoe 小鼠主动脉瓣钙化。我们发现 FOXO1 促进 RUNX2 的泛素化和降解，该过程主要由 SMAD 特异性 E3 泛素连接酶 2 (SMURF2) 介导。我们的发现揭示了 CAVD 中涉及 FOXO1/SMURF2/RUNX2 轴的迄今为止未被确认的机制，从而提出 FOXO1 或 SMURF2 作为阻止 CAVD 进展的可行策略的潜在治疗效用。