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

4 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
Early online dateJan 31 2023
DOIs
StatePublished - Apr 7 2023

Keywords

  • De novo purine synthesis
  • ATIC
  • Pulmonary hypertension
  • Vascular smooth muscle cells

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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