Supplemental Digital Content is available in the text. Oxidative stress and inflammation play key roles in development of pulmonary arterial hypertension (PAH). We previously reported that an endothelial cell (EC)-specific cyclophilin A overexpression mouse developed many characteristics of PAH. In other models of cardiovascular disease, cyclophilin A stimulates smooth muscle proliferation and vascular inflammation, but mechanisms responsible for PAH have not been defined. In particular, the contribution of endothelial-to-mesenchymal transition in cyclophilin A-mediated PAH has not been studied. We identified increased levels of cyclophilin A in endothelial and neointimal cells of pulmonary arteries in patients with PAH and animal pulmonary hypertension models. In the EC-specific cyclophilin A overexpression mouse that exhibited features characteristic of PAH, lineage tracing showed high level expression of mesenchymal markers in pulmonary ECs. A significant number of mesenchymal cells in media and perivascular regions of pulmonary arterioles and alveoli were derived from ECs. Pulmonary ECs isolated from these mice showed phenotypic changes characteristic of endothelial-to-mesenchymal transition in culture. Cultured pulmonary ECs stimulated with extracellular cyclophilin A and acetylated cyclophilin A demonstrated functional changes associated with endothelial-to-mesenchymal transition such as increased cytokine release, migration, proliferation, and mitochondrial dysfunction. Acetylated cyclophilin A stimulated greater increases for most features of endothelial-to-mesenchymal transition. In conclusion, extracellular cyclophilin A (especially acetylated form) contributes to PAH by mechanisms involving increased endothelial-to-mesenchymal transition, cytokine release, EC migration, proliferation, and mitochondrial dysfunction; strengthening the basis for studying cyclophilin A inhibition as a therapy for PAH.

中文翻译：

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内皮-间充质转化和炎症在亲环蛋白 A 诱导的肺动脉高压中起关键作用

补充数字内容在文本中可用。氧化应激和炎症在肺动脉高压 (PAH) 的发展中起关键作用。我们以前报道过内皮细胞 (EC) 特异性亲环蛋白 A 过表达小鼠发展了许多多环芳烃的特征。在其他心血管疾病模型中，亲环蛋白 A 会刺激平滑肌增殖和血管炎症，但尚未确定导致 PAH 的机制。特别是，尚未研究内皮细胞间质转化在亲环素 A 介导的 PAH 中的作用。我们发现 PAH 患者和动物肺动脉高压模型的肺动脉内皮细胞和新生内膜细胞中亲环素 A 水平升高。在表现出 PAH 特征的 EC 特异性亲环蛋白 A 过表达小鼠中，谱系追踪显示肺 EC 中间充质标记物的高水平表达。肺小动脉和肺泡的中层和血管周围区域中的大量间充质细胞来自内皮细胞。从这些小鼠中分离出的肺内皮细胞显示出培养物中内皮-间充质转化的特征性表型变化。用细胞外亲环蛋白 A 和乙酰化亲环蛋白 A 刺激培养的肺内皮细胞表现出与内皮-间充质转化相关的功能变化，例如细胞因子释放、迁移、增殖和线粒体功能障碍的增加。乙酰化亲环蛋白 A 刺激了内皮-间充质转化的大多数特征的更大增加。综上所述，细胞外亲环蛋白 A（尤其是乙酰化形式）通过增加内皮间质转化、细胞因子释放、EC 迁移、增殖和线粒体功能障碍的机制促进 PAH；加强研究亲环素 A 抑制作为 PAH 疗法的基础。