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Accumulated evidence confirmed that microRNA\u201026 family play critical roles in cardiovascular disease; however, their function in PAH remains largely unknown. Here, we investigated the expression of miR\u201026 family in plasma from PAH patients using quantitative RT\u2010PCR, and identified miR\u201026a\u20105p as the most downregulated member, which was also decreased in hypoxia\u2010induced pulmonary arterial smooth muscle cell (PASMC) autophagy models and lung tissues of PAH patients. Furthermore, chromatin immunoprecipitation (ChIP) analysis and luciferase reporter assays revealed that hypoxia\u2010inducible factor 1\u03b1 (HIF\u20101\u03b1) specifically interacted with the promoter of miR\u201026a\u20105p and inhibited its expression in PASMCs. Tandem mRFP\u2010GFP\u2010LC3B fluorescence microscopy demonstrated that miR\u201026a\u20105p inhibited hypoxia\u2010induced PAMSC autophagy, characterized by reduced formation of autophagosomes and autolysosomes. In addition, results showed that miR\u201026a\u20105p overexpression potently inhibited PASMC proliferation and migration, as determined by cell counting kit\u20108, EdU staining, wound\u2010healing, and transwell assays. Mechanistically, PFKFB3, ULK1, and ULK2 were direct targets of miR\u201026a\u20105p, as determined by dual\u2010luciferase reporter gene assays and western blots. Meanwhile, PFKFB3 could further enhance the phosphorylation level of ULK1 and promote autophagy in PASMCs. Moreover, intratracheal administration of adeno\u2010miR\u201026a\u20105p markedly alleviated right ventricular hypertrophy and pulmonary vascular remodeling in hypoxia\u2010induced PAH rat models in vivo. Taken together, the HIF\u20101\u03b1\/miR\u201026a\u20105p\/PFKFB3\/ULK1\/2 axis plays critical roles in the regulation of hypoxia\u2010induced PASMC autophagy and proliferation. MiR\u201026a\u20105p may represent as an attractive biomarker for the diagnosis and treatment of PAH.<\/jats:p>","DOI":"10.1096\/fj.202200699rr","type":"journal-article","created":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T11:27:30Z","timestamp":1681385250000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["The HIF\u20101\u03b1\/miR\u201026a\u20105p\/PFKFB3\/ULK1\/2 axis regulates vascular remodeling in hypoxia\u2010induced pulmonary hypertension by modulation of autophagy"],"prefix":"10.1096","volume":"37","author":[{"given":"Chaoqun","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Cardiology, Changhai Hospital Naval Medical University  Shanghai China"},{"name":"Cardiovascular Research Institute and Department of Cardiology General Hospital of Northern Theater Command  Shenyang Liaoning 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