| MitoQ administration prevents endotoxin-induced cardiac dysfunction. | |
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MedLine Citation:
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PMID: 19657095 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Sepsis elicits severe alterations in cardiac function, impairing cardiac mitochondrial and pressure-generating capacity. Currently, there are no therapies to prevent sepsis-induced cardiac dysfunction. We tested the hypothesis that administration of a mitochondrially targeted antioxidant, 10-(6'-ubiquinonyl)-decyltriphenylphosphonium (MitoQ), would prevent endotoxin-induced reductions in cardiac mitochondrial and contractile function. Studies were performed on adult rodents (n = 52) given either saline, endotoxin (8 mg x kg(-1) x day(-1)), saline + MitoQ (500 microM), or both endotoxin and MitoQ. At 48 h animals were killed and hearts were removed for determination of either cardiac mitochondrial function (using polarography) or cardiac pressure generation (using the Langendorf technique). We found that endotoxin induced reductions in mitochondrial state 3 respiration rates, the respiratory control ratio, and ATP generation. Moreover, MitoQ administration prevented each of these endotoxin-induced abnormalities, P < 0.001. We also found that endotoxin produced reductions in cardiac pressure-generating capacity, reducing the systolic pressure-diastolic relationship. MitoQ also prevented endotoxin-induced reductions in cardiac pressure generation, P < 0.01. One potential link between mitochondrial and contractile dysfunction is caspase activation; we found that endotoxin increased cardiac levels of active caspases 9 and 3 (P < 0.001), while MitoQ prevented this increase (P < 0.01). These data demonstrate that MitoQ is a potent inhibitor of endotoxin-induced mitochondrial and cardiac abnormalities. We speculate that this agent may prove a novel therapy for sepsis-induced cardiac dysfunction. |
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Authors:
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G S Supinski; M P Murphy; L A Callahan |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2009-08-05 |
Journal Detail:
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Title: American journal of physiology. Regulatory, integrative and comparative physiology Volume: 297 ISSN: 1522-1490 ISO Abbreviation: Am. J. Physiol. Regul. Integr. Comp. Physiol. Publication Date: 2009 Oct |
Date Detail:
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Created Date: 2009-09-28 Completed Date: 2009-10-13 Revised Date: 2013-06-02 |
Medline Journal Info:
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Nlm Unique ID: 100901230 Medline TA: Am J Physiol Regul Integr Comp Physiol Country: United States |
Other Details:
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Languages: eng Pagination: R1095-102 Citation Subset: IM |
Affiliation:
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Division of Pulmonary, Critical Care, and Sleep Medicine, University of Kentucky, Lexington, Kentucky 40536-0284, USA. gsupi2@email.uky.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Triphosphate
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metabolism Animals Antioxidants / administration & dosage* Caspase 3 / metabolism Caspase 9 / metabolism Cell Respiration / drug effects Disease Models, Animal Drug Administration Schedule Endotoxemia / complications, drug therapy*, metabolism, physiopathology Enzyme Activation Heart Diseases / etiology, metabolism, physiopathology, prevention & control* Mice Mitochondria, Heart / drug effects, metabolism Myocardial Contraction / drug effects Myocardium / metabolism Organophosphorus Compounds / administration & dosage* Protein Carbonylation / drug effects Rats Tumor Necrosis Factor-alpha / metabolism Ubiquinone / administration & dosage, analogs & derivatives* Ventricular Function, Left / drug effects* Ventricular Pressure / drug effects |
| Grant Support | |
ID/Acronym/Agency:
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HL-63698/HL/NHLBI NIH HHS; HL-69821/HL/NHLBI NIH HHS; HL-80429/HL/NHLBI NIH HHS; HL-80609/HL/NHLBI NIH HHS; HL-81525/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/10-(6'-ubiquinonyl)decyltriphenylphosphonium bromide; 0/Antioxidants; 0/Organophosphorus Compounds; 0/Tumor Necrosis Factor-alpha; 1339-63-5/Ubiquinone; 56-65-5/Adenosine Triphosphate; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 9 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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