Purine synthesis suppression reduces the development and progression of pulmonary hypertension in rodent models

Qian Ma, Qiuhua Yang, Jiean Xu, Hunter G. Sellers, Zach L. Brown, Zhiping Liu, Zsuzsanna Bordan, Xiaofan Shi, Dingwei Zhao, Yongfeng Cai, Vidhi Pareek, Chunxiang Zhang, Guangyu Wu, Zheng Dong, Alexander D. Verin, Lin Gan, Quansheng Du, Stephen J. Benkovic, Suowen Xu, John M. AsaraIssam Ben-Sahra, Scott Barman, Yunchao Su, David J.R. Fulton, Yuqing Huo

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Aims: Proliferation of vascular smooth muscle cells (VSMCs) is a hallmark of pulmonary hypertension (PH). Proliferative cells utilize purine bases from the de novo purine synthesis (DNPS) pathways for nucleotide synthesis; however, it is unclear whether DNPS plays a critical role in VSMC proliferation during development of PH. The last two steps of DNPS are catalysed by the enzyme 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC). This study investigated whether ATIC-driven DNPS affects the proliferation of pulmonary artery smooth muscle cells (PASMCs) and the development of PH. Methods and results: Metabolites of DNPS in proliferative PASMCs were measured by liquid chromatography-tandem mass spectrometry. ATIC expression was assessed in platelet-derived growth factor-treated PASMCs and in the lungs of PH rodents and patients with pulmonary arterial hypertension. Mice with global and VSMC-specific knockout of Atic were utilized to investigate the role of ATIC in both hypoxia- and lung interleukin-6/hypoxia-induced murine PH. ATIC-mediated DNPS at the mRNA, protein, and enzymatic activity levels were increased in platelet-derived growth factor-treated PASMCs or PASMCs from PH rodents and patients with pulmonary arterial hypertension. In cultured PASMCs, ATIC knockdown decreased DNPS and nucleic acid DNA/RNA synthesis, and reduced cell proliferation. Global or VSMC-specific knockout of Atic attenuated vascular remodelling and inhibited the development and progression of both hypoxia- and lung IL-6/hypoxia-induced PH in mice. Conclusion: Targeting ATIC-mediated DNPS compromises the availability of purine nucleotides for incorporation into DNA/RNA, reducing PASMC proliferation and pulmonary vascular remodelling and ameliorating the development and progression of PH.

Original languageEnglish (US)
Pages (from-to)1265-1279
Number of pages15
JournalEuropean Heart Journal
Volume44
Issue number14
DOIs
StatePublished - Apr 7 2023

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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