{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:14:02Z","timestamp":1791216842323,"version":"4.1.0"},"reference-count":51,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"25","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2017,12,19]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Pulmonary arterial hypertension (PAH) is characterized by abnormal growth and enhanced glycolysis of pulmonary artery endothelial cells. However, the mechanisms underlying alterations in energy production have not been identified.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      Here, we examined the miRNA and proteomic profiles of blood outgrowth endothelial cells (BOECs) from patients with heritable PAH caused by mutations in the bone morphogenetic protein receptor type 2 (\n                      <jats:italic>BMPR2<\/jats:italic>\n                      ) gene and patients with idiopathic PAH to determine mechanisms underlying abnormal endothelial glycolysis. We hypothesized that in BOECs from patients with PAH, the downregulation of microRNA-124 (miR-124), determined with a tiered systems biology approach, is responsible for increased expression of the splicing factor\n                      <jats:italic>PTBP1<\/jats:italic>\n                      (polypyrimidine tract binding protein), resulting in alternative splicing of pyruvate kinase muscle isoforms 1 and 2 (PKM1 and 2) and consequently increased PKM2 expression. We questioned whether this alternative regulation plays a critical role in the hyperglycolytic phenotype of PAH endothelial cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Heritable PAH and idiopathic PAH BOECs recapitulated the metabolic abnormalities observed in pulmonary artery endothelial cells from patients with idiopathic PAH, confirming a switch from oxidative phosphorylation to aerobic glycolysis. Overexpression of miR-124 or siRNA silencing of\n                      <jats:italic>PTPB1<\/jats:italic>\n                      restored normal proliferation and glycolysis in heritable PAH BOECs, corrected the dysregulation of glycolytic genes and lactate production, and partially restored mitochondrial respiration.\n                      <jats:italic>BMPR2<\/jats:italic>\n                      knockdown in control BOECs reduced the expression of miR-124, increased\n                      <jats:italic>PTPB1<\/jats:italic>\n                      , and enhanced glycolysis. Moreover, we observed reduced miR-124, increased\n                      <jats:italic>PTPB1<\/jats:italic>\n                      and\n                      <jats:italic>PKM2<\/jats:italic>\n                      expression, and significant dysregulation of glycolytic genes in the rat SUGEN-hypoxia model of severe PAH, characterized by reduced\n                      <jats:italic>BMPR2<\/jats:italic>\n                      expression and endothelial hyperproliferation, supporting the relevance of this mechanism in vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Pulmonary vascular and circulating progenitor endothelial cells isolated from patients with PAH demonstrate downregulation of miR-124, leading to the metabolic and proliferative abnormalities in PAH ECs via PTPB1 and PKM1\/PKM2. Therefore, the manipulation of this miRNA or its targets could represent a novel therapeutic approach for the treatment of PAH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.117.028034","type":"journal-article","created":{"date-parts":[[2017,10,2]],"date-time":"2017-10-02T20:40:22Z","timestamp":1506976822000},"page":"2451-2467","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":250,"title":["Identification of MicroRNA-124 as a Major Regulator of Enhanced Endothelial Cell Glycolysis in Pulmonary Arterial Hypertension via PTBP1 (Polypyrimidine Tract Binding Protein) and Pyruvate Kinase M2"],"prefix":"10.1161","volume":"136","author":[{"given":"Paola","family":"Caruso","sequence":"first","affiliation":[{"name":"Division of Respiratory Medicine, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke\u2019s Hospital, United Kingdom (P.C., B.J.D., L.L., P.D.U., C.H., F.N.K., L.A.H.., N.W.M.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin J.","family":"Dunmore","sequence":"additional","affiliation":[{"name":"Division of Respiratory Medicine, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke\u2019s Hospital, United Kingdom (P.C., B.J.D., L.L., P.D.U., C.H., F.N.K., L.A.H.., N.W.M.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenny","family":"Schlosser","sequence":"additional","affiliation":[{"name":"Ottawa Hospital Research Institute and University of Ottawa, Ontario, Canada (K.S., C.P.-I., J.R.L., M.T., D.J.S.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Schoors","sequence":"additional","affiliation":[{"name":"Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven, Belgium (S.S., P.C.)"},{"name":"Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, Department of Oncology, University of Leuven, Belgium (S.S., P.C.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Dos Santos","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Sciences, Queen\u2019s University, Kingston, Ontario, Canada (C.D.S., M.L.O.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Perez-Iratxeta","sequence":"additional","affiliation":[{"name":"Ottawa Hospital Research Institute and University of Ottawa, Ontario, Canada (K.S., C.P.-I., J.R.L., M.T., D.J.S.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessie R.","family":"Lavoie","sequence":"additional","affiliation":[{"name":"Ottawa Hospital Research Institute and University of Ottawa, Ontario, Canada (K.S., C.P.-I., J.R.L., M.T., D.J.S.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Cardiovascular Pulmonary Research 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