MitoQ administration prevents endotoxin-induced cardiac dysfunction.

TitleMitoQ administration prevents endotoxin-induced cardiac dysfunction.
Publication TypeJournal Article
Year of Publication2009
AuthorsSupinski, GS, Murphy, MP, Callahan, LA
JournalAm J Physiol Regul Integr Comp Physiol
Date Published2009 Oct
KeywordsAdenosine Triphosphate, Animals, Antioxidants, Caspase 3, Caspase 9, Cell Respiration, Disease Models, Animal, Drug Administration Schedule, Endotoxemia, Enzyme Activation, Heart Diseases, Mice, Mitochondria, Heart, Myocardial Contraction, Myocardium, Organophosphorus Compounds, Protein Carbonylation, Rats, Tumor Necrosis Factor-alpha, Ubiquinone, Ventricular Function, Left, Ventricular Pressure

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.

Alternate JournalAm. J. Physiol. Regul. Integr. Comp. Physiol.
Citation Key10.1152/ajpregu.90902.2008
PubMed ID19657095
PubMed Central IDPMC2763820
Grant ListHL-80429 / HL / NHLBI NIH HHS / United States
MC_U105663142 / / Medical Research Council / United Kingdom
HL-80609 / HL / NHLBI NIH HHS / United States
HL-63698 / HL / NHLBI NIH HHS / United States
HL-81525 / HL / NHLBI NIH HHS / United States
HL-69821 / HL / NHLBI NIH HHS / United States