Abstract
Pathological mechanisms of pulmonary arterial hypertension (PAH) remain largely unexplored. Effective treatment of PAH remains a challenge. The aim of this study was to discover the underlying mechanism of PAH through functional metabolomics and to help develop new strategies for prevention and treatment of PAH.
Metabolomic profiling of plasma in patients with idiopathic PAH was evaluated through high-performance liquid chromatography mass spectrometry, with spermine identified to be the most significant and validated in another independent cohort. The roles of spermine and spermine synthase were examined in pulmonary arterial smooth muscle cells (PASMCs) and rodent models of pulmonary hypertension.
Using targeted metabolomics, plasma spermine levels were found to be higher in patients with idiopathic PAH compared to healthy controls. Spermine administration promoted proliferation and migration of PASMCs and exacerbated vascular remodelling in rodent models of pulmonary hypertension. The spermine-mediated deteriorative effect can be attributed to a corresponding upregulation of its synthase in the pathological process. Inhibition of spermine synthase in vitro suppressed platelet-derived growth factor-BB-mediated proliferation of PASMCs, and in vivo attenuated monocrotaline-mediated pulmonary hypertension in rats.
Plasma spermine promotes pulmonary vascular remodelling. Inhibiting spermine synthesis could be a therapeutic strategy for PAH.
Abstract
Elevated plasma spermine promotes pulmonary vascular remodelling and spermine synthase is identified as a potential therapeutic target for the pathogenesis of pulmonary arterial hypertension https://bit.ly/3038QDX
Footnotes
This article has an editorial commentary: https://doi.org/10.1183/13993003.02350-2020
This article has supplementary material available from erj.ersjournals.com
Conflict of interest: Y-Y. He has nothing to disclose.
Conflict of interest: Y. Yan has nothing to disclose.
Conflict of interest: X. Jiang has nothing to disclose.
Conflict of interest: J-H. Zhao has nothing to disclose.
Conflict of interest: Z. Wang has nothing to disclose.
Conflict of interest: T. Wu has nothing to disclose.
Conflict of interest: Y. Wang has nothing to disclose.
Conflict of interest: S-S. Guo has nothing to disclose.
Conflict of interest: J. Ye has nothing to disclose.
Conflict of interest: T-Y Lian has nothing to disclose.
Conflict of interest: X-Q. Xu has nothing to disclose.
Conflict of interest: J-L. Zhang has nothing to disclose.
Conflict of interest: K. Sun has nothing to disclose.
Conflict of interest: F-H. Peng has nothing to disclose.
Conflict of interest: Y-P. Zhou has nothing to disclose.
Conflict of interest: Y-M. Mao has nothing to disclose.
Conflict of interest: X. Zhang has nothing to disclose.
Conflict of interest: J.W. Chen has nothing to disclose.
Conflict of interest: S-Y. Zhang has nothing to disclose.
Conflict of interest: Z-C. Jing has nothing to disclose.
Support statement: This work was supported by grants from the National Natural Science Foundation of China (81630003, 81700059), 13th Five-Year Plan – Precision Medicine – Key Research and Development Program – Clinical Cohort of Rare Disease (2016YFC0901500), Beijing Natural Science Foundation (7181009, 7182139), CAMS Innovation Fund for Medical Sciences (2016-I2M-1-002, 2017-I2M-BR-02, 2017PT32016, 2017-I2M-1-004, 2017-I2M-1-011, 2017-I2M-2-001). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received March 2, 2020.
- Accepted May 29, 2020.
- Copyright ©ERS 2020