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dc.contributor.authorRafikova, Olga
dc.contributor.authorSrivastava, Anup
dc.contributor.authorDesai, Ankit A.
dc.contributor.authorRafikov, Ruslan
dc.contributor.authorTofovic, Stevan P.
dc.date.accessioned2018-05-24T18:44:14Z
dc.date.available2018-05-24T18:44:14Z
dc.date.issued2018-04-23
dc.identifier.citationRafikova, O., Srivastava, A., Desai, A. A., Rafikov, R., & Tofovic, S. P. (2018). Recurrent inhibition of mitochondrial complex III induces chronic pulmonary vasoconstriction and glycolytic switch in the rat lung. Respiratory research, 19(1), 69.en_US
dc.identifier.issn1465-993X
dc.identifier.pmid29685148
dc.identifier.doi10.1186/s12931-018-0776-1
dc.identifier.urihttp://hdl.handle.net/10150/627794
dc.description.abstractBackground: Pulmonary arterial hypertension (PAH) is a fatal disease; however, the mechanisms directly involved in triggering and the progression of PAH are not clear. Based on previous studies that demonstrated a possible role of mitochondrial dysfunction in the pathogenesis of PAH, we investigated the effects of chronic inhibition of mitochondrial function in vivo in healthy rodents. Methods: Right ventricle systolic pressure (RVSP) was measured in female rats at baseline and up to 24 days after inhibition of mitochondrial respiratory Complex III, induced by Antimycin A (AA, 035 mg/kg, given three times starting at baseline and then days 3 and 6 as a bolus injection into the right atrial chamber). Results: Rodents exposed to AA demonstrated sustained increases in RVSP from days 6 through 24. AA-exposed rodents also possessed a progressive increase in RV end-diastolic pressure but not RV hypertrophy, which may be attributed to either early stages of PAH development or to reduced RV contractility due to inhibition of myocardial respiration. Protein nitration levels in plasma were positively correlated with PAH development in AA-treated rats. This finding was strongly supported by results obtained from PAH humans where plasma protein nitration levels were correlated with markers of PAH severity in female but not male PAH patients. Based on previously reported associations between increased nitric oxide production levels with female gender, we speculate that in females with PAH mitochondrial dysfunction may represent a more deleterious form, in part, due to an increased nitrosative stress development. Indeed, the histological analysis of AA treated rats revealed a strong perivascular edema, a marker of pulmonary endothelial damage. Finally, AA treatment was accompanied by a severe metabolic shift toward glycolysis, a hallmark of PAH pathology. Conclusions: Chronic mitochondrial dysfunction induces the combination of vascular damage and metabolic reprogramming that may be responsible for PAH development. This mechanism may be especially important in females, perhaps due to an increased NO production and nitrosative stress development.en_US
dc.description.sponsorshipNIH [1R01HL133085, R01HL136603, 1R01HL132918, 14SDG20480354]en_US
dc.language.isoenen_US
dc.publisherBIOMED CENTRAL LTDen_US
dc.relation.urlhttps://respiratory-research.biomedcentral.com/articles/10.1186/s12931-018-0776-1en_US
dc.rights© The Author(s). 2018. Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License.en_US
dc.subjectPulmonary hypertensionen_US
dc.subjectGlycolytic switchen_US
dc.subjectMitochondrial complexesen_US
dc.subjectProtein nitrationen_US
dc.subjectMetabolomicsen_US
dc.titleRecurrent inhibition of mitochondrial complex III induces chronic pulmonary vasoconstriction and glycolytic switch in the rat lungen_US
dc.typeArticleen_US
dc.contributor.departmentUniv Arizona, Dept Med, Div Endocrinolen_US
dc.contributor.departmentUniv Arizona, Dept Meden_US
dc.identifier.journalRESPIRATORY RESEARCHen_US
dc.description.noteOpen Access Journal.en_US
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en_US
dc.eprint.versionFinal published versionen_US
dc.source.journaltitleRespiratory Research
dc.source.volume19
dc.source.issue1
refterms.dateFOA2018-05-24T18:44:14Z


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