College of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China; Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang 453003, China; Xinxiang Key Laboratory of Cascular Remodeling Intervention and Molecular Targeted Therapy Drug Development, 453003, China.
College of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China; Department of Pharmacy, The first Affiliated Hospital of Xinxiang Medical University, Xinxiang 453100, China; Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang 453003, China; Xinxiang Key Laboratory of Cascular Remodeling Intervention and Molecular Targeted Therapy Drug Development, 453003, China.
Int Immunopharmacol. 2024 May 10;132:111946. doi: 10.1016/j.intimp.2024.111946. Epub 2024 Mar 29.
Ensuring the homeostatic integrity of pulmonary artery endothelial cells (PAECs) is essential for combatting pulmonary arterial hypertension (PAH), as it equips the cells to withstand microenvironmental challenges. Spermidine (SPD), a potent facilitator of autophagy, has been identified as a significant contributor to PAECs function and survival. Despite SPD's observed benefits, a comprehensive understanding of its protective mechanisms has remained elusive. Through an integrated approach combining metabolomics and molecular biology, this study uncovers the molecular pathways employed by SPD in mitigating PAH induced by monocrotaline (MCT) in a Sprague-Dawley rat model. The study demonstrates that SPD administration (5 mg/kg/day) significantly corrects right ventricular impairment and pathological changes in pulmonary tissues following MCT exposure (60 mg/kg). Metabolomic profiling identified a purine metabolism disorder in MCT-treated rats, which SPD effectively normalized, conferring a protective effect against PAH progression. Subsequent in vitro analysis showed that SPD (0.8 mM) reduces oxidative stress and apoptosis in PAECs challenged with Dehydromonocrotaline (MCTP, 50 μM), likely by downregulating purine nucleoside phosphorylase (PNP) and modulating polyamine biosynthesis through alterations in S-adenosylmethionine decarboxylase (AMD1) expression and the subsequent production of decarboxylated S-adenosylmethionine (dcSAM). These findings advocate SPD's dual inhibitory effect on PNP and AMD1 as a novel strategy to conserve cellular ATP and alleviate oxidative injuries, thus providing a foundation for SPD's potential therapeutic application in PAH treatment.
确保肺血管内皮细胞（PAECs）的体内平衡完整性对于对抗肺动脉高压（PAH）至关重要，因为它使细胞能够承受微环境挑战。 spermidine（SPD）是自噬的有力促进剂，已被确定为 PAECs 功能和存活的重要贡献者。尽管 SPD 观察到了益处，但对其保护机制的全面了解仍然难以捉摸。通过结合代谢组学和分子生物学的综合方法，这项研究揭示了 SPD 在减轻 Sprague-Dawley 大鼠模型中单硝酸异山梨酯（MCT）诱导的 PAH 中所采用的分子途径。研究表明，SPD 给药（5mg/kg/天）可显著纠正 MCT 暴露后右心室损伤和肺组织的病理变化（60mg/kg）。代谢组学分析鉴定出 MCT 处理的大鼠嘌呤代谢紊乱，SPD 有效纠正了该紊乱，对 PAH 进展具有保护作用。随后的体外分析表明，SPD（0.8mM）可减少 50μM 脱水单硝酸异山梨酯（MCTP）对 PAECs 的氧化应激和细胞凋亡，可能通过下调嘌呤核苷磷酸化酶（PNP）并通过改变 S-腺苷甲硫氨酸脱羧酶（AMD1）表达和随后的脱羧 S-腺苷甲硫氨酸（dcSAM）的产生来调节多胺生物合成来发挥作用。这些发现主张 SPD 对 PNP 和 AMD1 的双重抑制作用是一种新的策略，可以保存细胞内的 ATP 并减轻氧化损伤，从而为 SPD 在 PAH 治疗中的潜在治疗应用提供了基础。
