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- Title
Purine synthesis suppression reduces the development and progression of pulmonary hypertension in rodent models.
- Authors
Ma, Qian; Yang, Qiuhua; Xu, Jiean; Sellers, Hunter G; Brown, Zach L; Liu, Zhiping; Bordan, Zsuzsanna; Shi, Xiaofan; Zhao, Dingwei; Cai, Yongfeng; Pareek, Vidhi; Zhang, Chunxiang; Wu, Guangyu; Dong, Zheng; Verin, Alexander D; Gan, Lin; Du, Quansheng; Benkovic, Stephen J; Xu, Suowen; Asara, John M
- 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.
- Subjects
PULMONARY hypertension; PULMONARY arterial hypertension; LIQUID chromatography-mass spectrometry; VASCULAR smooth muscle; PURINE nucleotides; DNA polymerases
- Publication
European Heart Journal, 2023, Vol 44, Issue 14, p1265
- ISSN
0195-668X
- Publication type
Article
- DOI
10.1093/eurheartj/ehad044