| NADPH oxidase 2 mediates intermittent hypoxia-induced mitochondrial complex I inhibition: relevance to blood pressure changes in rats. | |
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MedLine Citation:
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PMID: 20618070 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Previous studies identified NADPH oxidases (Nox) and mitochondrial electron transport chain at complex I as major cellular sources of reactive oxygen species (ROS) mediating systemic and cellular responses to intermittent hypoxia (IH). In the present study, we investigated potential interactions between Nox and the mitochondrial complex I and assessed the contribution of mitochondrial ROS in IH-evoked elevation in blood pressure. IH treatment led to stimulus-dependent activation of Nox and inhibition of complex I activity in rat pheochromocytoma (PC)12 cells. After re-oxygenation, Nox activity returned to baseline values within 3 h, whereas the complex I activity remained downregulated even after 24 h. IH-induced complex I inhibition was prevented by Nox inhibitors, Nox2 but not Nox 4 siRNA, in cell cultures and was absent in gp91(phox-/Y) (Nox2 knock-out; KO) mice. Using pharmacological inhibitors, we show that ROS generated by Nox activation mobilizes Ca(2+) flux from the cytosol to mitochondria, leading to S-glutathionylation of 75- and 50-kDa proteins of the complex I and inhibition of complex I activity, which results in elevated mitochondrial ROS. Systemic administration of mito-tempol prevented the sustained but not the acute elevations of blood pressure in IH-treated rats, suggesting that mitochondrial-derived ROS contribute to sustained elevation of blood pressure. |
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Authors:
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Shakil A Khan; Jayasri Nanduri; Guoxiang Yuan; Brian Kinsman; Ganesh K Kumar; Joy Joseph; Balaraman Kalyanaraman; Nanduri R Prabhakar |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-10-19 |
Journal Detail:
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Title: Antioxidants & redox signaling Volume: 14 ISSN: 1557-7716 ISO Abbreviation: Antioxid. Redox Signal. Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2011-01-17 Completed Date: 2011-05-04 Revised Date: 2012-02-15 |
Medline Journal Info:
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Nlm Unique ID: 100888899 Medline TA: Antioxid Redox Signal Country: United States |
Other Details:
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Languages: eng Pagination: 533-42 Citation Subset: IM |
Affiliation:
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Department of Medicine, Center for Systems Biology of O2 Sensing, University of Chicago, Chicago, Illinois 60637, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anoxia / physiopathology* Blood Pressure / genetics, physiology* Electron Transport Complex I / metabolism* Glutathione / pharmacology Male Mice Mice, Knockout Mitochondria / metabolism* NADH, NADPH Oxidoreductases / genetics, metabolism* PC12 Cells Rats Rats, Sprague-Dawley Reactive Oxygen Species / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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HL-76537/HL/NHLBI NIH HHS; HL-86493/HL/NHLBI NIH HHS; HL-90554/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Reactive Oxygen Species; 70-18-8/Glutathione; EC 1.6.-/NADH, NADPH Oxidoreductases; EC 1.6.5.3/Electron Transport Complex I |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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