Cardiovascular Translational Research, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), C/Irunlarrea 3, 31008, Pamplona, Spain.
Department of Vascular Physiopathology, Hospital Nacional de Parapléjicos, Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), Toledo, Spain.
Cardiovasc Diabetol. 2023 Oct 17;22(1):280. doi: 10.1186/s12933-023-02009-w.
Diabetes mellitus (DM) accelerates the progression of aortic stenosis (AS), but how their underlying molecular mechanisms interact is not clear. Moreover, whether DM contributes to clinically relevant sex-differences in AS is unknown. In this work we aim to characterize the sex-specific profile of major pathological mechanisms fundamental to aortic valve (AV) degeneration in AS patients with or without concomitant DM.
283 patients with severe AS undergoing surgical valve replacement (27.6% DM, 59.4% men) were recruited. Expression of pathological markers related to AS were thoroughly assessed in AVs and valve interstitial cells (VICs) according to sex and presence of DM. Complementary in vitro experiments in VICs in the presence of high-glucose levels (25 mM) for 24, 48 and 72 h were performed.
Oxidative stress and metabolic dysfunction markers were increased in AVs from diabetic AS patients compared to non-diabetic patients in both sexes. However, disbalanced oxidative stress and enhanced inflammation were more predominant in AVs from male AS diabetic patients. Osteogenic markers were exclusively increased in the AVs of diabetic women. Basal characterization of VICs confirmed that oxidative stress, inflammation, calcification, and metabolic alteration profiles were increased in diabetic VICs with sex-specific differences. VICs cultured in hyperglycemic-like conditions triggered inflammatory responses in men, whereas in women rapid and higher production of pro-osteogenic molecules.
DM produces sex-specific pathological phenotypes in AV of AS patients. Importantly, women with diabetes are more prone to develop AV calcification. DM should be considered as a risk factor in AS especially in women.
糖尿病（DM）会加速主动脉瓣狭窄（AS）的进展，但它们的潜在分子机制如何相互作用尚不清楚。此外，DM 是否导致 AS 中与临床相关的性别差异尚不清楚。在这项工作中，我们旨在描述伴或不伴 DM 的 AS 患者主动脉瓣（AV）退行性变的主要病理机制的性别特异性特征。
招募了 283 名接受外科瓣膜置换术的严重 AS 患者（27.6%为 DM，59.4%为男性）。根据性别和 DM 的存在，在 AV 和瓣膜间质细胞（VIC）中全面评估与 AS 相关的病理标志物的表达。在存在 25 mM 高葡萄糖水平的情况下，对 VIC 进行了 24、48 和 72 小时的补充体外实验。
与非糖尿病患者相比，两性 DM 合并 AS 患者的 AV 中氧化应激和代谢功能障碍标志物增加。然而，在男性 DM 合并 AS 患者的 AV 中，失衡的氧化应激和增强的炎症更为明显。成骨标志物仅在糖尿病女性的 AV 中增加。VIC 的基础特征证实，氧化应激、炎症、钙化和代谢改变谱在具有性别特异性差异的糖尿病 VIC 中增加。在高血糖样条件下培养的 VIC 会引发男性的炎症反应，而在女性中则会迅速产生更高水平的促成骨分子。
DM 会导致 AS 患者的 AV 产生性别特异性的病理表型。重要的是，患有糖尿病的女性更容易发生 AV 钙化。DM 应被视为 AS 的一个危险因素，尤其是在女性中。
