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Here, we describe a metabolic theory that proposes that many apparently unrelated molecular abnormalities in PAH do have a common denominator; they either cause or promote a mitochondrial suppression (inhibition of glucose oxidation) in pulmonary vascular cells; in turn, the signaling downstream from this mitochondrial suppression can also explain numerous molecular events previously not connected. This integration of signals upstream and downstream of mitochondria has similarities to cancer and can explain many features of the PAH vascular phenotype, including proliferation and apoptosis resistance. This suppression of glucose oxidation (with secondary upregulation of glycolysis) also underlies the abnormalities in extrapulmonary tissues, suggesting a global metabolic disturbance. The metabolic theory places mitochondria at the center stage for our understanding of PAH pathogenesis and for the development of novel diagnostic and therapeutic tools. Current PAH therapies are each addressing 1 abnormality (eg, upregulation of endothelin-1) and were not developed specifically for PAH but for systemic vascular diseases. Compared with the available therapies, mitochondria-targeting therapies have the advantage of addressing multiple molecular abnormalities simultaneously (thus being potentially more effective) and achieving higher specificity because they address PAH-specific biology.<\/jats:p>","DOI":"10.1161\/circresaha.115.301130","type":"journal-article","created":{"date-parts":[[2014,6,20]],"date-time":"2014-06-20T14:52:25Z","timestamp":1403275945000},"page":"148-164","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":290,"title":["The Metabolic Theory of Pulmonary Arterial Hypertension"],"prefix":"10.1161","volume":"115","author":[{"given":"Roxane","family":"Paulin","sequence":"first","affiliation":[{"name":"From the Department of Medicine, University of Alberta, Edmonton, Alberta, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelos D.","family":"Michelakis","sequence":"additional","affiliation":[{"name":"From 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