Background:There are sex differences in the pathophysiology of aortic valve (AV) calcification in patients with aortic stenosis, although the molecular and cellular mechanisms have not been elucidated. Aldosterone (Aldo) promotes proteoglycan synthesis in valve interstitial cells (VICs) from mitral valves via the mineralocorticoid receptor (MR). We investigated the influence of sex in the role of Aldo/MR pathway in AV alterations in patients with aortic stenosis.METHODS AND RESULTS:MR was expressed by primary aortic VICs and in AVs from patients with aortic stenosis. MR expression positively correlated with VIC activation markers in AVs from both sexes. However, MR expression was positively associated with molecules involved in AV calcification only in AV from men. Aldo enhanced VIC activation markers in cells from men and women. Interestingly, Aldo increased the expression of calcification markers only in VICs isolated from men. In female VICs, Aldo enhanced fibrotic molecules. MR antagonism (spironolactone) blocked all the above effects. Cytokine arrays showed ICAM (intercellular adhesion molecule)-1 and osteopontin to be specifically increased by Aldo in male VICs. In AVs from men, MR expression positively associated with both ICAM-1 (intercellular adhesion molecule-1) and osteopontin. Only in female VICs, estradiol treatment blocked Aldo-induced VICs activation, inflammation, and fibrosis.Conclusions:These findings demonstrate that the Aldo/MR pathway could play a role in early stages of aortic stenosis by promoting VICs activation, fibrosis, and ulterior calcification. Importantly, Aldo/MR pathway is involved in fibrosis in women and in early AV calcification only in men. Accordingly, MR antagonism emerges as a new sex-specific pharmacological treatment to prevent AV alterations.

中文翻译：

---

醛固酮/盐皮质激素受体通路在钙化性主动脉瓣狭窄中的性别相关信号传导

背景：主动脉瓣狭窄患者主动脉瓣（AV）钙化的病理生理学存在性别差异，但分子和细胞机制尚未阐明。醛固酮 (Aldo) 通过盐皮质激素受体 (MR) 促进二尖瓣间质细胞 (VIC) 中蛋白多糖的合成。我们研究了性别对 Aldo/MR 通路在主动脉瓣狭窄患者 AV 改变中的作用的影响。方法和结果：MR 由原发性主动脉 VIC 和主动脉瓣狭窄患者的 AV 表达。MR 表达与两性 AV 中的 VIC 激活标志物呈正相关。然而，MR 表达与仅在男性 AV 中参与 AV 钙化的分子呈正相关。Aldo 增强了男性和女性细胞中的 VIC 激活标志物。有趣的是，Aldo 仅在从男性分离的 VIC 中增加了钙化标志物的表达。在女性 VIC 中，Aldo 增强了纤维化分子。MR 拮抗剂（螺内酯）阻断了上述所有作用。细胞因子阵列显示 ICAM（细胞间粘附分子）-1 和骨桥蛋白在男性 VIC 中被 Aldo 特异性增加。在男性 AV 中，MR 表达与 ICAM-1（细胞间粘附分子-1）和骨桥蛋白呈正相关。仅在女性 VICs 中，雌二醇治疗阻断了 Aldo 诱导的 VICs 活化、炎症和纤维化。结论：这些研究结果表明，Aldo/MR 通路可能通过促进 VICs 活化、纤维化和后部钙化在主动脉瓣狭窄的早期发挥作用. 重要的是，Aldo/MR 通路参与女性的纤维化和仅男性的早期 AV 钙化。