title: Constitutive Reprogramming of Fibroblast Mitochondrial Metabolism in Pulmonary Hypertension.
abstract: Remodeling of the distal pulmonary artery wall is a characteristic feature of pulmonary hypertension (PH). In hypoxic PH, the most substantial pathologic changes occur in the adventitia. Here, there is marked fibroblast proliferation and profound macrophage accumulation. These PH fibroblasts (PH-Fibs) maintain a hyperproliferative, apoptotic-resistant, and proinflammatory phenotype in ex vivo culture. Considering that a similar phenotype is observed in cancer cells, where it has been associated, at least in part, with specific alterations in mitochondrial metabolism, we sought to define the state of mitochondrial metabolism in PH-Fibs. In PH-Fibs, pyruvate dehydrogenase was markedly inhibited, resulting in metabolism of pyruvate to lactate, thus consistent with a Warburg-like phenotype. In addition, mitochondrial bioenergetics were suppressed and mitochondrial fragmentation was increased in PH-Fibs. Most importantly, complex I activity was substantially decreased, which was associated with down-regulation of the accessory subunit nicotinamide adenine dinucleotide reduced dehydrogenase (ubiquinone) Fe-S protein 4 (NDUFS4). Owing to less-efficient ATP synthesis, mitochondria were hyperpolarized and mitochondrial superoxide production was increased. This pro-oxidative status was further augmented by simultaneous induction of cytosolic nicotinamide adenine dinucleotide phosphate reduced oxidase 4. Although acute and chronic exposure to hypoxia of adventitial fibroblasts from healthy control vessels induced increased glycolysis, it did not induce complex I deficiency as observed in PH-Fibs. This suggests that hypoxia alone is insufficient to induce NDUFS4 down-regulation and constitutive abnormalities in complex I. In conclusion, our study provides evidence that, in the pathogenesis of vascular remodeling in PH, alterations in fibroblast mitochondrial metabolism drive distinct changes in cellular behavior, which potentially occur independently of hypoxia.
authors.affiliation: 1 Department of Membrane Transport Biophysics, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Lydie
authors.initials: L
authors.lastname: Plecitá-Hlavatá
authors.affiliation: 1 Department of Membrane Transport Biophysics, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Tauber
authors.affiliation: 2 Developmental Lung Biology and Cardiovascular Pulmonary Research Laboratory, University of Colorado, Denver, Colorado.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: 2 Developmental Lung Biology and Cardiovascular Pulmonary Research Laboratory, University of Colorado, Denver, Colorado.|3 Department of Pediatrics, Shengjing Hospital of China Medical, University, Shenyang, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 2 Developmental Lung Biology and Cardiovascular Pulmonary Research Laboratory, University of Colorado, Denver, Colorado.
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Flockton
authors.affiliation: 4 Department of Lung Development and Remodeling, University of Giessen and Marburg Lung Center, Bad Nauheim, Germany; and.
authors.forename: Soni Savai
authors.initials: SS
authors.lastname: Pullamsetti
authors.affiliation: 4 Department of Lung Development and Remodeling, University of Giessen and Marburg Lung Center, Bad Nauheim, Germany; and.
authors.forename: Prakash
authors.initials: P
authors.lastname: Chelladurai
authors.affiliation: Department of 5 Biochemistry and Molecular Genetics, and.
authors.forename: Angelo
authors.initials: A
authors.lastname: D'Alessandro
authors.affiliation: 6 Pediatric Gastroenterology, University of Colorado, Denver, Colorado.
authors.forename: Karim C
authors.initials: KC
authors.lastname: El Kasmi
authors.affiliation: 1 Department of Membrane Transport Biophysics, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Ježek
authors.affiliation: 2 Developmental Lung Biology and Cardiovascular Pulmonary Research Laboratory, University of Colorado, Denver, Colorado.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Stenmark
mesh_terms: D000818:Animals; D002417:Cattle; D019069:Cell Respiration; D065150:Cellular Reprogramming; D002908:Chronic Disease; D002952:Citric Acid Cycle; D015536:Down-Regulation; D042967:Electron Transport Complex I / Q000378:metabolism; D004734:Energy Metabolism; D005347:Fibroblasts / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia / Q000150:complications / Q000473:pathology; D008168:Lung / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D019899:Paracrine Communication; D010641:Phenotype; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: D011768:Pyruvate Dehydrogenase Complex; D013481:Superoxides; D019289:Pyruvic Acid; D042967:Electron Transport Complex I
keywords: adventitial fibroblasts; complex I; mitochondria; oxidative metabolism; pulmonary hypertension