{"doi":"10.1093/eurheartj/ehad044","title":"Purine synthesis suppression reduces the development and progression of pulmonary hypertension in rodent models","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.","journal":"European Heart Journal","year":2023,"id":326049,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":29,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9591,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":250309,"name":"Qiuhua Yang","orcid":"0000-0002-5582-3771","position":1,"is_corresponding":false},{"id":250306,"name":"Jiean Xu","orcid":"0000-0001-9176-5786","position":2,"is_corresponding":false},{"id":1002419,"name":"Hunter Sellers","orcid":"0000-0001-8994-9404","position":3,"is_corresponding":false},{"id":1044464,"name":"Zachary Brown","orcid":"0000-0002-1590-4534","position":4,"is_corresponding":false},{"id":250305,"name":"Zhiping Liu","orcid":"0000-0001-7272-6917","position":5,"is_corresponding":false},{"id":917536,"name":"Zsuzsanna Bordán","orcid":"0000-0002-8409-3712","position":6,"is_corresponding":false},{"id":1044465,"name":"Xiaofan Shi","orcid":"0009-0006-7073-7640","position":7,"is_corresponding":false},{"id":1044893,"name":"Dingwei Zhao","orcid":null,"position":8,"is_corresponding":false},{"id":730850,"name":"Yongfeng Cai","orcid":null,"position":9,"is_corresponding":false},{"id":234918,"name":"Vidhi Pareek","orcid":"0000-0003-1329-8021","position":10,"is_corresponding":false},{"id":1044466,"name":"Chunxiang Zhang","orcid":"0000-0002-2802-2645","position":11,"is_corresponding":false},{"id":386102,"name":"Guangyu Wu","orcid":"0000-0002-5660-1249","position":12,"is_corresponding":false},{"id":242441,"name":"Zheng Dong","orcid":"0000-0003-3538-8095","position":13,"is_corresponding":false},{"id":430450,"name":"Alexander D. Verin","orcid":"0000-0003-0627-7185","position":14,"is_corresponding":false},{"id":332592,"name":"Lin Gan","orcid":"0000-0001-5278-4554","position":15,"is_corresponding":false},{"id":658148,"name":"Quansheng Du","orcid":"0000-0003-4079-8662","position":16,"is_corresponding":false},{"id":234921,"name":"Stephen J. Benkovic","orcid":"0000-0003-3680-3481","position":17,"is_corresponding":false},{"id":849466,"name":"Suowen Xu","orcid":"0000-0002-5488-5217","position":18,"is_corresponding":false},{"id":3257,"name":"John M. Asara","orcid":"0000-0001-7450-2589","position":19,"is_corresponding":false},{"id":228954,"name":"Issam Ben‐Sahra","orcid":"0000-0001-9333-4162","position":20,"is_corresponding":false},{"id":330831,"name":"Scott A. Barman","orcid":"0000-0001-9085-5122","position":21,"is_corresponding":false},{"id":330830,"name":"Yunchao Su","orcid":"0009-0006-5062-4147","position":22,"is_corresponding":false},{"id":250316,"name":"David Fulton","orcid":"0000-0002-1528-1517","position":23,"is_corresponding":false},{"id":242440,"name":"Yuqing Huo","orcid":"0000-0002-0305-4122","position":24,"is_corresponding":false},{"id":250307,"name":"Qian Ma","orcid":"0000-0003-0622-987X","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-19T01:08:28.266998Z","pmid":"36721994","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}