Abstract 11289: Suppression of De Novo Purine Synthesis Reduces Development and Progression of Pulmonary Hypertension in Rodent Models

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 catalyzed by the enzyme 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC). We 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 (LC-MS/MS). ATIC mRNA and protein expression was assessed in platelet-derived growth factor (PDGF)-treated PASMCs and in the lungs of PH rodents and patients with pulmonary artery hypertension (PAH). Mice with global and VSMC-specific knockout of Atic were utilized to investigate the role of ATIC in hypoxia-induced PH. ATIC-mediated DNPS at the mRNA, protein and enzymatic activity levels were increased in PDGF-treated PASMCs or PASMCs from PH rodents and patients with PAH. In cultured PASMCs, ATIC knockdown decreased DNPB, nucleic acid DNA/RNA synthesis and reduced cell proliferation. Global or VSMC-specific knockout of Atic attenuated vascular remodeling and inhibited the development and progression of 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 remodeling and ameliorating the development and progression of PH.