Cardiovascular Translational Research, Navarrabiomed (Miguel Servet Foundation), Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdiSNA, C/Irunlarrea 3., 31008, Pamplona, Spain.
Research Methodology Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.
Biol Sex Differ. 2023 Oct 24;14(1):72. doi: 10.1186/s13293-023-00556-1.
Aortic stenosis (AS) is characterized by inflammation, fibrosis, osteogenesis and angiogenesis. Men and women develop these mechanisms differently. Galectin-3 (Gal-3) is a pro-inflammatory and pro-osteogenic lectin in AS. In this work, we aim to analyse a potential sex-differential role of Gal-3 in AS.
226 patients (61.50% men) with severe AS undergoing surgical aortic valve (AV) replacement were recruited. In AVs, Gal-3 expression and its relationship with inflammatory, osteogenic and angiogenic markers was assessed. Valve interstitial cells (VICs) were primary cultured to perform in vitro experiments.
Proteomic analysis revealed that intracellular Gal-3 was over-expressed in VICs of male AS patients. Gal-3 secretion was also higher in men's VICs as compared to women's. In human AVs, Gal-3 protein levels were significantly higher in men, with stronger immunostaining in VICs with myofibroblastic phenotype and valve endothelial cells. Gal-3 levels in AVs were positively correlated with inflammatory markers in both sexes. Gal-3 expression was also positively correlated with osteogenic markers mainly in men AVs, and with angiogenic molecules only in this sex. In vitro, Gal-3 treatment induced expression of inflammatory, osteogenic and angiogenic markers in male's VICs, while it only upregulated inflammatory and osteogenic molecules in women-derived cells. Gal-3 blockade with pharmacological inhibitors (modified citrus pectin and G3P-01) prevented the upregulation of inflammatory, osteogenic and angiogenic molecules.
Gal-3 plays a sex-differential role in the setting of AS, and it could be a new sex-specific therapeutic target controlling pathological features of AS in VICs.
主动脉瓣狭窄（AS）的特征是炎症、纤维化、成骨和血管生成。男性和女性在这些机制上的表现不同。半乳糖凝集素-3（Gal-3）是 AS 中的一种促炎和促成骨凝集素。在这项工作中，我们旨在分析 Gal-3 在 AS 中潜在的性别差异作用。
招募了 226 名（61.50%为男性）患有严重 AS 并接受外科主动脉瓣（AV）置换的患者。在 AV 中，评估了 Gal-3 的表达及其与炎症、成骨和血管生成标志物的关系。原代培养瓣膜间质细胞（VIC）以进行体外实验。
蛋白质组学分析显示，男性 AS 患者的 VIC 中细胞内 Gal-3 过度表达。与女性 VIC 相比，男性 VIC 的 Gal-3 分泌也更高。在人 AV 中，Gal-3 蛋白水平在男性中明显较高，在具有成纤维细胞表型和瓣膜内皮细胞的 VIC 中免疫染色更强。AV 中的 Gal-3 水平与两性的炎症标志物呈正相关。Gal-3 表达也与主要在男性 AV 中的成骨标志物呈正相关，而仅在该性别中与血管生成分子呈正相关。在体外，Gal-3 处理诱导男性 VIC 中炎症、成骨和血管生成标志物的表达，而仅在女性细胞中上调炎症和成骨分子。用药理学抑制剂（改性柑橘果胶和 G3P-01）阻断 Gal-3 可防止炎症、成骨和血管生成分子的上调。
Gal-3 在 AS 中发挥性别差异作用，它可能是控制 VIC 中 AS 病理特征的新的性别特异性治疗靶点。
