Spermidine attenuates monocrotaline-induced pulmonary arterial hypertension in rats by inhibiting purine metabolism and polyamine synthesis-associated vascular remodeling

• Published in: International immunopharmacology 2024-05, Vol.132, p.111946-111946, Article 111946
• Main Authors: Chen, Yu-jing, Li, Han-fei, Zhao, Fan-rong, Yu, Miao, Pan, Si-yu, Sun, Wen-ze, Yin, Yan-yan, Zhu, Tian-tian
• Format: Article
• Language: English
• Subjects: Adenosylmethionine Decarboxylase - metabolism; Animals; Apoptosis - drug effects; Cells, Cultured; Disease Models, Animal; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Humans; Hypertension, Pulmonary - chemically induced; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - metabolism; Male; Monocrotaline; Oxidative Stress - drug effects; Polyamine synthesis; Polyamines - metabolism; Pulmonary arterial hypertension; Pulmonary Arterial Hypertension - chemically induced; Pulmonary Arterial Hypertension - drug therapy; Pulmonary Arterial Hypertension - metabolism; Pulmonary Artery - drug effects; Pulmonary Artery - metabolism; Pulmonary Artery - pathology; Pulmonary artery endothelial cells; Purine metabolism; Purine-Nucleoside Phosphorylase - metabolism; Purines - pharmacology; Rats; Rats, Sprague-Dawley; Spermidine; Spermidine - pharmacology; Spermidine - therapeutic use; Vascular Remodeling - drug effects
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2024.111946

•Spermidine (SPD) can attenuate pulmonary arterial hypertension and pulmonary vascular remodeling.•SPD attenuates pulmonary arterial hypertension and pulmonary vascular remodeling by inhibiting purine metabolism and polyamine synthesis.•SPD's protective role in counteracting MCT-induced PAH via a dual mechanism: the inhibition of PNP and AMD1 expression. This modulation reduces ATP consumption, subsequently mitigating oxidative stress and apoptotic processes. 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.