Ding Jingjing, Chu Chunyan, Mao Zhengsheng, Yang Jiawen, Wang Jie, Hu Li, Chen Peng, Cao Yue, Li Yan, Wan Hua, Wei Dong, Chen Jingyu, Chen Feng, Yu Youjia
Department of Forensic Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
Wuxi Lung Transplantation Center, Wuxi People's Hospital Affiliated with Nanjing Medical University, Wuxi, China.
Hypertens Res. 2022 Jun;45(6):990-1000. doi: 10.1038/s41440-022-00898-0. Epub 2022 Mar 30.
Pulmonary arterial hypertension has led to global health and social problems, but the pathogenic mechanism has not been fully elucidated. Dysregulated metabolism is closely associated with the pathogenesis of pulmonary arterial hypertension. Here, we investigated metabolic profile shifts to reveal the molecular mechanisms underlying pulmonary hypertension. Explanted lung tissues from 13 idiopathic pulmonary arterial hypertension patients, 5 pulmonary arterial hypertension associated with congenital heart disease patients, and 16 controls were collected for untargeted metabolomics analysis with liquid chromatography coupled with tandem mass spectrometry. The KEGG database and MetaboAnalyst 5.0 were used for pathway analysis. A Cox survival analysis model was applied to evaluate the predictive value of metabolites on prognosis. Protein expression levels in human and rat pulmonary arterial hypertension lungs and hypoxia-exposed human pulmonary artery smooth muscle cells were detected by Western blotting to study the molecular mechanisms. Significant differences in metabolites and metabolic pathways were identified among the pulmonary arterial hypertension subgroups and control tissues. The levels of spermine were positively correlated with the patients' cardiac output, and (2e)-2,5-dichloro-4-oxo-2-hexenedioic acid was positively correlated with the patients' serum creatinine levels. Patients with higher thymine levels had a better prognosis. Moreover, seven differential metabolites were associated with the AKT pathway. AKT pathway inactivation was confirmed in human and rat pulmonary hypertensive lungs and pulmonary artery smooth muscle cells exposed to hypoxia. Our findings provide the first metabolomics evidence for pulmonary arterial hypertension pathogenesis in human lungs and may contribute to the improvement in therapeutic strategies.
肺动脉高压已引发全球健康和社会问题，但其发病机制尚未完全阐明。代谢失调与肺动脉高压的发病机制密切相关。在此，我们研究了代谢谱变化以揭示肺动脉高压潜在的分子机制。收集了13例特发性肺动脉高压患者、5例先天性心脏病相关肺动脉高压患者的离体肺组织以及16例对照者的肺组织，采用液相色谱-串联质谱法进行非靶向代谢组学分析。使用KEGG数据库和MetaboAnalyst 5.0进行通路分析。应用Cox生存分析模型评估代谢物对预后的预测价值。通过蛋白质印迹法检测人和大鼠肺动脉高压肺组织以及缺氧暴露的人肺动脉平滑肌细胞中的蛋白质表达水平，以研究分子机制。在肺动脉高压亚组和对照组织之间鉴定出代谢物和代谢途径的显著差异。精胺水平与患者的心输出量呈正相关，(2E)-2,5-二氯-4-氧代-2-己烯二酸与患者的血清肌酐水平呈正相关。胸腺嘧啶水平较高的患者预后较好。此外，七种差异代谢物与AKT通路相关。在人和大鼠肺动脉高压肺组织以及缺氧暴露的肺动脉平滑肌细胞中证实了AKT通路失活。我们的研究结果为人类肺部肺动脉高压发病机制提供了首个代谢组学证据，并可能有助于改善治疗策略。
