Dataset related to the article "Circulating cytokines as triggers of endothelial dysfunction and sex-specific interstitial cell response in fibrocalcific aortic valve disease"

This record contains raw data related to the article "Circulating cytokines as triggers of endothelial dysfunction and sex-specific interstitial cell response in fibrocalcific aortic valve disease" AbstractGraphic abstractBackground: Fibrocalcific aortic valve disease (FCAVD) is a progressive and multifactorial pathology that remains asymptomatic in its early stages and lacks effective pharmacological therapies. Aortic valve sclerosis (AVSc), the initial phase of FCAVD, is marked by leaflet thickening and early calcium deposition without significant hemodynamic changes. While local inflammation is known to drive valvular remodeling, recent studies suggest that systemic inflammation may also play a critical role, potentially interacting with endothelial (VEC) and interstitial cells (VIC) and thus promoting disease progression. Notably, sex differences in fibrocalcific processes have been identified, yet their mechanistic basis remains understudied. Thus, we hypothesize that systemic inflammation exacerbates endothelial dysfunction and accelerates fibrocalcific remodeling, with distinct processes in men and women, and aim to investigate how these mechanisms contribute to disease progression. Methods: A total of 238 individuals were enrolled across three groups: controls (CTRL n = 80), AVSc (n = 78), and severe aortic stenosis (AS n = 80). A broad panel of circulating cytokines was measured and analyzed with respect to sex and disease stage. To assess the functional impact of key cytokines, in vitro experiments were conducted using human VECs and VICs treated with interleukin-1β (IL-1β) and interferon-β (IFNβ). Cellular responses were evaluated via morphological analyses, gene and protein expression assays, and calcification potential under normal and pro-osteogenic conditions. Results: Cytokine profiling revealed that AVSc patients exhibited significantly elevated levels of IL-1β compared to both CTRL and AS, with IL-1β being consistently higher in males across all stages. In vitro, IL-1β triggered endothelial-to-mesenchymal transition in VECs, promoting a pro-fibrotic and inflammatory phenotype. Sex-stratified analysis of VICs showed that IFNβ enhanced RUNX2 expression and calcification in a dose-dependent manner, with female-derived VICs being more responsive. Conversely, IFNβ exerted anti-fibrotic effects by reducing COL1A1 and ACTA2 expression, more markedly in female cells, particularly at the protein level. Conclusion: Our findings reveal a previously overlooked role of systemic inflammation, primarily driven by IL-1β and IFNβ, in promoting early endothelial activation and sex-specific fibrocalcific remodeling in FCAVD. These cytokines not only serve as markers of disease but also actively influence cell-specific responses, shaping the distinct aortic valve fibrocalcific patterns observed in men and women. Unraveling these mechanisms could open new avenues for developing early monitoring of circulating IL-1β and IFNβ, while informing sex-specific therapeutic strategies to modulate cytokine signaling to slow or prevent FCAVD progression. This dataset is not public. It’s available upon reasonable requesto to the corresponding author.本数据集包含与论文《循环细胞因子作为纤维钙化性主动脉瓣疾病中内皮功能障碍与性别特异性间质细胞应答的触发因子》相关的原始实验数据。 摘要及图表摘要 背景：纤维钙化性主动脉瓣疾病（Fibrocalcific aortic valve disease, FCAVD）是一种进展性多因素病理状态，早期阶段无明显临床症状，且目前尚无有效的药物治疗方案。主动脉瓣硬化（Aortic valve sclerosis, AVSc）作为FCAVD的初始阶段，以瓣膜叶增厚与早期钙沉积为特征，尚未出现显著的血流动力学改变。现有研究已明确局部炎症可驱动瓣膜重构，而近期研究提示系统性炎症同样发挥关键作用，其可能通过与内皮细胞（Vascular endothelial cell, VEC）及瓣膜间质细胞（Valvular interstitial cell, VIC）相互作用，进而促进疾病进展。值得注意的是，学界已发现纤维钙化过程存在性别差异，但其机制基础仍有待深入研究。据此，本研究提出假说：系统性炎症会加重内皮功能障碍并加速纤维钙化性瓣膜重构，且该过程在男性与女性中存在显著差异；本研究旨在探究上述机制如何推动疾病进展。 方法：本研究共纳入238名受试者，分为三组：对照组（CTRL, n=80）、主动脉瓣硬化组（AVSc, n=78）以及重度主动脉瓣狭窄组（Severe aortic stenosis, AS, n=80）。通过检测循环细胞因子的广谱检测面板，并结合受试者性别与疾病分期进行分析。为评估关键细胞因子的功能影响，本研究采用经白细胞介素-1β（Interleukin-1β, IL-1β）与干扰素-β（Interferon-β, IFNβ）处理的人源VEC与VIC开展体外实验。通过形态学分析、基因与蛋白表达检测，以及正常与成骨诱导条件下的钙化潜能评估，对细胞应答进行分析。 结果：细胞因子谱分析显示，与对照组与重度AS组相比，AVSc患者的IL-1β水平显著升高，且在所有疾病分期中，男性受试者的IL-1β水平均持续更高。体外实验表明，IL-1β可诱导VEC发生内皮-间质转化，促进促纤维化与促炎症表型的形成。针对VIC的性别分层分析显示，IFNβ可呈剂量依赖性上调RUNX2的表达并增强钙化能力，且女性来源的VIC应答更为显著。与之相反，IFNβ可通过降低COL1A1与ACTA2的表达发挥抗纤维化作用，该效应在女性细胞中更为明显，尤其在蛋白水平层面。 结论：本研究结果揭示了此前被忽视的系统性炎症的作用——其主要由IL-1β与IFNβ介导，可促进FCAVD早期内皮激活以及性别特异性的纤维钙化性瓣膜重构。上述细胞因子不仅可作为疾病标志物，还可主动调控细胞特异性应答，进而塑造男女两性中各具特征的主动脉瓣纤维钙化模式。阐明上述机制可为开发循环IL-1β与IFNβ的早期监测手段提供新思路，同时也可为制定靶向调控细胞因子信号通路的性别特异性治疗策略提供依据，以延缓甚至阻止FCAVD的疾病进展。 本数据集暂未公开，若有合理需求可向通讯作者申请获取。