Document Detail

MitoQ administration prevents endotoxin-induced cardiac dysfunction.
MedLine Citation:
PMID:  19657095     Owner:  NLM     Status:  MEDLINE    
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.
G S Supinski; M P Murphy; L A Callahan
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-08-05
Journal Detail:
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:
Created Date:  2009-09-28     Completed Date:  2009-10-13     Revised Date:  2014-02-19    
Medline Journal Info:
Nlm Unique ID:  100901230     Medline TA:  Am J Physiol Regul Integr Comp Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  R1095-102     Citation Subset:  IM    
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MeSH Terms
Adenosine Triphosphate / metabolism
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*
Mitochondria, Heart / drug effects,  metabolism
Myocardial Contraction / drug effects
Myocardium / metabolism
Organophosphorus Compounds / administration & dosage*
Protein Carbonylation / drug effects
Tumor Necrosis Factor-alpha / metabolism
Ubiquinone / administration & dosage,  analogs & derivatives*
Ventricular Function, Left / drug effects*
Ventricular Pressure / drug effects
Grant Support
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; MC_U105663142//Medical Research Council
Reg. No./Substance:
0/10-(6'-ubiquinonyl)decyltriphenylphosphonium bromide; 0/Antioxidants; 0/Organophosphorus Compounds; 0/Tumor Necrosis Factor-alpha; 1339-63-5/Ubiquinone; 8L70Q75FXE/Adenosine Triphosphate; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 9

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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