MitoQ administration prevents endotoxin-induced cardiac dysfunction

Abstract

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.

The Mitochondria-Targeted Antioxidant Mitoquinone Protects against Cold Storage Injury of Renal Tubular Cells and Rat Kidneys

“…Protecting complex I and II activity is important because these complexes initiate oxidative phosphorylation and can generate additional oxidants once inactivated. MitoQ has been shown to restore mitochondrial function in a rodent model of cardiac dysfunction induced by sepsis (Supinski et al, 2009). Those authors previously determined that cardiac mitochondrial dysfunction in this model was associated with a significant increase in ROS generation.…”

Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics

“…Indeed, the development of antioxidant molecules that achieve concentrations in mitochondria 100-to 1,000-fold higher than in the cytosol, such as Szeto-Schiller (SS) synthetic antioxidant peptides (26,178,179,230), MitoQ (176,205), and Euk-8 (a SOD/catalase mimetic and antioxidant) (94,202), have demonstrated some efficacy in models of cardiovascular stress. A recent study in spontaneous hypertensive rats showed that MitoQ treatment for 8 weeks significantly reduced systolic blood pressure, improved endothelial function, and attenuated cardiac hypertrophy (64).…”

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“…Although it is unclear whether mitochondria play a causative role in the pathology of neurodegenerative diseases, aging, and carcinogenesis, mitochondria-targeted antioxidants have been shown to be potent at sequestering reactive oxygen intermediates 80,81,93 . The use of mitochondrialtargeted antioxidants is a step toward understanding whether antioxidants can be efficient preventive or therapeutic tools against age-related diseases.…”