BACKGROUND Aortic valve disease (AVD) is associated with high mortality and morbidity. To date, there is no pharmacological therapy available to prevent AVD progression. Because valve calcification is the hallmark of AVD and S1P (sphingosine-1-phosphate) plays an important role in osteogenic signaling, we examined the role of S1P signaling in aortic stenosis disease. METHODS AVD progression and its consequences for cardiac function were examined in a murine wire injury-induced AVD model with and without pharmacological and genetic modulation of S1P production, degradation, and receptor signaling. S1P was measured by LC-MS. Calcification of valvular interstitial cells and their response to biomechanical stress were analyzed in the context of S1P signaling. Human explanted aortic valves from patients undergoing aortic valve replacement and cardiovascular magnetic resonance imaging were analyzed for S1P by LC-MS. RESULTS Raising S1P concentrations in mice with injury-induced AVD by pharmacological inhibition of its sole degrading enzyme S1P lyase vastly enhanced AVD progression and impaired cardiac function resembling human disease. In contrast, low S1P levels caused by SphK1 (sphingosine kinase 1) deficiency potently attenuated AVD progression. We found S1P/S1PR2 (S1P receptor 2) signaling to be responsible for the adverse S1P effect because S1PR2-deficient mice were protected against AVD progression and its deterioration by high S1P. It is important to note that pharmacological S1PR2 inhibition administered after wire injury successfully prevented AVD development. Mechanistically, biomechanical stretch stimulated S1P production by SphK1 in human valvular interstitial cells as measured by C17-S1P generation, whereas S1P/S1PR2 signaling induced their osteoblastic differentiation and calcification through osteogenic RUNX2/OPG signaling and the GSK3β-Wnt-β-catenin pathway. In patients with AVD, stenotic valves exposed to high wall shear stress had higher S1P content and increased SphK1 expression. CONCLUSIONS Increased systemic or local S1P levels lead to increased valvular calcification. S1PR2 antagonists and SphK1 inhibitors may offer feasible pharmacological approaches to human AVD in prophylactic, disease-modifying or relapse-preventing manners.

中文翻译：

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靶向鞘氨醇-1-磷酸信号传导以防止主动脉瓣疾病的进展。


背景 主动脉瓣病 （AVD） 与高死亡率和发病率相关。迄今为止，尚无可用于预防 AVD 进展的药物治疗。由于瓣膜钙化是 AVD 的标志，并且 S1P （鞘氨醇-1-磷酸盐） 在成骨信号传导中起重要作用，因此我们研究了 S1P 信号传导在主动脉瓣狭窄疾病中的作用。方法 在小鼠导线损伤诱导的 AVD 模型中检查了 AVD 进展及其对心脏功能的影响，有和没有 S1P 产生、降解和受体信号的药理学和遗传调节。通过 LC-MS 测量 S1P。在 S1P 信号转导的背景下分析瓣膜间质细胞的钙化及其对生物力学应激的反应。通过 LC-MS 分析接受主动脉瓣置换术和心血管磁共振成像的患者的人外植主动脉瓣的 S1P。结果通过药理学抑制其唯一的降解酶 S1P 裂解酶来提高损伤诱导的 AVD 小鼠的 S1P 浓度，极大地促进了 AVD 的进展和类似于人类疾病的心脏功能受损。相比之下，由 SphK1 （鞘氨醇激酶 1） 缺乏引起的低 S1P 水平有效减轻了 AVD 进展。我们发现 S1P/S1PR2 （S1P 受体 2） 信号传导是导致不良 S1P 效应的原因，因为 S1PR2 缺陷小鼠受到保护，免受 AVD 进展及其因高 S1P 而恶化。值得注意的是，电线损伤后给予的药物 S1PR2 抑制成功阻止了 AVD 的发展。 从机制上讲，通过 C17-S1P 生成测量，生物力学拉伸刺激 SphK1 在人瓣膜间质细胞中产生 S1P，而 S1P/S1PR2 信号通过成骨 RUNX2/OPG 信号传导和 GSK3β-Wnt-β-catenin 通路诱导其成骨细胞分化和钙化。在 AVD 患者中，暴露于高壁剪切应力的狭窄瓣膜具有较高的 S1P 含量和 SphK1 表达增加。结论 全身或局部 S1P 水平升高导致瓣膜钙化增加。S1PR2 拮抗剂和 SphK1 抑制剂可能以预防、改善疾病或预防复发的方式为人类 AVD 提供可行的药物方法。