Wawrzyniak Renata, Gaillard Tamara, Biesemans Margot, Zięba Bożena, Lewicka Ewa, Markuszewski Michał, Dąbrowska-Kugacka Alicja
Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdańsk, 80-416 Gdańsk, Poland.
First Department of Cardiology, Medical University of Gdansk, 80-214 Gdańsk, Poland.
Biomedicines. 2025 Jul 4;13(7):1637. doi: 10.3390/biomedicines13071637.
Pulmonary arterial hypertension (PAH) is a rare and severe condition characterized by increased pulmonary arterial pressure and vascular resistance. Women are more susceptible to PAH yet have higher survival rates than men, a phenomenon called the "estrogen paradox". This study aims to investigate the sex-based differences in PAH using plasma untargeted metabolomics. Plasma samples were collected from 43 PAH patients and 37 healthy controls. The samples were analyzed using two complementary analytical techniques: gas chromatography-mass spectrometry (GC-QqQ/MS) and liquid chromatography-mass spectrometry (LC-Q-ToF/MS). The metabolic differences between male and female PAH patients and controls were identified using multivariate statistical analyses. Our results show changes in the lipid, fatty acid, and amino acid metabolism in both sexes. Women presented additional changes in the carbohydrate, bile acid, and nucleotide metabolism. The metabolites affected by PAH in women included decreased threonine, tryptophan, and lipid intermediates and elevated bile acids. Men were found to have additional changes in the heme catabolism, cholesterol synthesis, and lipoxygenase pathways. The metabolites affected by PAH in men included decreased branched-chain amino acids and increased bilirubin, phospholipids, and oxidized fatty acids. The gender differences observed in the development of PAH are likely multifactorial. While estrogens and potentially other sex hormones have been implicated in modulating relevant biological pathways, their exact role in disease progression and pathogenesis remains to be fully elucidated. The specific metabolic changes in women and men point to distinct disease mechanisms, potentially explaining the differences in prevalence, prognosis, and treatment response of patients with PAH. The obtained results should be validated with the use of targeted quantitative analyses and larger numbers of patients.
肺动脉高压（PAH）是一种罕见且严重的疾病，其特征为肺动脉压力和血管阻力增加。女性更容易患PAH，但生存率却高于男性，这一现象被称为“雌激素悖论”。本研究旨在利用血浆非靶向代谢组学研究PAH的性别差异。从43例PAH患者和37名健康对照者中采集血浆样本。使用两种互补的分析技术对样本进行分析：气相色谱-三重四极杆质谱联用仪（GC-QqQ/MS）和液相色谱-四极杆飞行时间质谱联用仪（LC-Q-ToF/MS）。使用多变量统计分析确定男性和女性PAH患者及对照者之间的代谢差异。我们的结果显示，两性的脂质、脂肪酸和氨基酸代谢均发生了变化。女性在碳水化合物、胆汁酸和核苷酸代谢方面还出现了其他变化。PAH影响的女性代谢物包括苏氨酸、色氨酸和脂质中间体减少以及胆汁酸升高。发现男性在血红素分解代谢、胆固醇合成和脂氧合酶途径方面有其他变化。PAH影响的男性代谢物包括支链氨基酸减少以及胆红素、磷脂和氧化脂肪酸增加。在PAH发展过程中观察到的性别差异可能是多因素的。虽然雌激素和潜在的其他性激素被认为参与调节相关生物学途径，但其在疾病进展和发病机制中的确切作用仍有待充分阐明。男性和女性的特定代谢变化指向不同的疾病机制，这可能解释了PAH患者在患病率、预后和治疗反应方面的差异。所获得的结果应通过靶向定量分析和更多患者进行验证。
