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Plecita-Hlavata 2015 Am J Respir Cell Mol Biol
Additional label 2016-03  +
Coupling states LEAK  + , ROUTINE  + , OXPHOS  + , ET  +
Diseases Other  +
Has abstract Remodeling of the distal pulmonary artery
Remodeling of the distal pulmonary artery wall is a characteristic feature of pulmonary hypertension (PH). In hypoxic pulmonary hypertension, the most substantial pathologic changes occur in the adventitia. Here, there is marked fibroblast proliferation and profound macrophage accumulation. These fibroblasts (PH-Fibs) maintain a hyperproliferative, apoptotic resistant and pro-inflammatory 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 downregulation of the accessory subunit NDUFS4. Due 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 NADPH oxidase 4. While 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 downregulation 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.
otentially occur independently of hypoxia.  +
Has info [http://www.ncbi.nlm.nih.gov/pubmed/26699943 PMID: 26699943]  +
Has publicationkeywords Complex I  + , Adventitial fibroblasts  + , Mitochondria  + , Oxidative metabolism  + , Pulmonary hypertension  +
Has title Plecitá-Hlavatá L, Tauber J, Li M, Zhang H
Plecitá-Hlavatá L, Tauber J, Li M, Zhang H, Flockton AR, Pullamsetti SS, Chelladurai P, D'alessandro A, El Kasmi KC, Ježek P, Stenmark KR (2015) Constitutive reprogramming of fibroblast mitochondrial metabolism in pulmonary hypertension. Am J Respir Cell Mol Biol 55:47-57.
nsion. Am J Respir Cell Mol Biol 55:47-57.  +
Instrument and method Oxygraph-2k  +
Mammal and model Human  + , Bovines  +
MiP area Respiration  + , mt-Biogenesis;mt-density  + , Comparative MiP;environmental MiP  +
Pathways N  + , CIV  + , Other combinations  +
Preparation Isolated mitochondria  + , Intact cells  +
Stress Oxidative stress;RONS  +
Tissue and cell Endothelial;epithelial;mesothelial cell  + , Fibroblast  +
Was published by MiPNetLab CZ Prague Jezek P +
Was published in journal Am J Respir Cell Mol Biol +
Was published in year 2015  +
Was written by Plecita-Hlavata L + , Tauber J + , Li M + , Zhang H + , Flockton AR + , Pullamsetti SS + , Chelladurai P + , D'alessandro A + , El Kasmi KC + , Jezek P + , Stenmark KR +
Categories Publications
Modification date
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13:40:26, 13 November 2017  +
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