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Metabolomics-based mechanism exploration of pulmonary arterial hypertension pathogenesis: novel lessons from explanted human lungs

Hypertension Research volume 45, pages 990–1000 (2022)Cite this article

Abstract

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.

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Data availability

Due to protection of patient data privacy, sharing of data on a publicly available repository is not possible, but data are available from the corresponding authors upon request.

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Acknowledgements

This research was supported by the National Natural Science Foundation of China (81570378, 81922041, 81772020, and 82002028) and the Medical and Technology Development Program of Nanjing (YKK17115).

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Author notes

  1. These authors contributed equally: Jingjing Ding, Chunyan Chu, Zhengsheng Mao

Authors and Affiliations

  1. Department of Forensic Medicine, Nanjing Medical University, Nanjing, Jiangsu, China

    Jingjing Ding, Chunyan Chu, Zhengsheng Mao, Jiawen Yang, Jie Wang, Li Hu, Peng Chen, Yue Cao, Yan Li, Hua Wan, Feng Chen & Youjia Yu

  2. Wuxi Lung Transplantation Center, Wuxi People’s Hospital Affiliated with Nanjing Medical University, Wuxi, China

    Dong Wei & Jingyu Chen

  3. Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China

    Feng Chen

  4. The Institute of Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China

    Feng Chen

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  1. Jingjing Ding
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  2. Chunyan Chu
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Contributions

All authors contributed to the study. Conception, design and experiment: JD, CC, FC, and ZM. Analysis and interpretation: JY, JW, LH, PC, YC, YL, HW, FC, and DW. Drafting the paper for important intellectual content: JC, FC, and YY.

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Correspondence to Jingyu Chen, Feng Chen or Youjia Yu.

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Ding, J., Chu, C., Mao, Z. et al. Metabolomics-based mechanism exploration of pulmonary arterial hypertension pathogenesis: novel lessons from explanted human lungs. Hypertens Res 45, 990–1000 (2022). https://doi.org/10.1038/s41440-022-00898-0

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