Endothelin-1 Induces a Glycolytic Switch in Pulmonary Arterial Endothelial Cells via the Mitochondrial Translocation of Endothelial Nitric Oxide Synthase
| Autor: | Yunchao Su, Yali Hou, Sanjiv Kumar, Shruti Sharma, Saurabh Aggarwal, Stephen M. Black, Jeffrey R. Fineman, Christine Gross, Sung Gon Lee, Sridevi Dasarathy, Weihong Han, Xutong Sun, Qing Lu, Mary L Meadows, Olga Rafikova |
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| Rok vydání: | 2014 |
| Předmět: |
Pulmonary and Respiratory Medicine
Nitric Oxide Synthase Type III Cells Respiratory System Clinical Biochemistry Oxidative phosphorylation Pulmonary Artery Cardiorespiratory Medicine and Haematology Mitochondrion Cardiovascular medicine.disease_cause peroxynitrite mitochondrial bioenergetics chemistry.chemical_compound Adenosine Triphosphate Enos Carnitine medicine Animals Phosphorylation Lung Molecular Biology Cells Cultured Original Research Cultured Endothelin-1 biology Cell Membrane Endothelial Cells endothelial nitric oxide synthase uncoupling Cell Biology protein kinase C delta biology.organism_classification Endothelin 1 Mitochondria Rats Cell biology Protein Kinase C-delta chemistry superoxide Reactive Oxygen Species Glycolysis Adenosine triphosphate Oxidative stress Signal Transduction |
| Zdroj: | American journal of respiratory cell and molecular biology, vol 50, iss 6 |
| ISSN: | 1535-4989 1044-1549 |
| DOI: | 10.1165/rcmb.2013-0187oc |
| Popis: | Recent studies have indicated that, during the development of pulmonary hypertension (PH), there is a switch from oxidative phosphorylation to glycolysis in the pulmonary endothelium. However, the mechanisms underlying this phenomenon have not been elucidated. Endothelin (ET)-1, an endothelial-derived vasoconstrictor peptide, is increased in PH, and has been shown to play an important role in the oxidative stress associated with PH. Thus, in this study, we investigated whether there was a potential link between increases in ET-1 and mitochondrial remodeling. Our data indicate that ET-1 induces the redistribution of endothelial nitric oxide synthase (eNOS) from the plasma membrane to the mitochondria in pulmonary arterial endothelial cells, and that this was dependent on eNOS uncoupling. We also found that ET-1 disturbed carnitine metabolism, resulting in the attenuation of mitochondrial bioenergetics. However, ATP levels were unchanged due to a compensatory increase in glycolysis. Further mechanistic investigations demonstrated that ET-1 mediated the redistribution of eNOS via the phosphorylation of eNOS at Thr495 by protein kinase C δ. In addition, the glycolytic switch appeared to be dependent on mitochondrial-derived reactive oxygen species that led to the activation of hypoxia-inducible factor signaling. Finally, the cell culture data were confirmed in vivo using the monocrotaline rat model of PH. Thus, we conclude that ET-1 induces a glycolytic switch in pulmonary arterial endothelial cells via the redistribution of uncoupled eNOS to the mitochondria, and that preventing this event may be an approach for the treatment of PH. |
| Databáze: | OpenAIRE |
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