MitoQ administration prevents endotoxin-induced cardiac dysfunction - PubMed (original) (raw)

MitoQ administration prevents endotoxin-induced cardiac dysfunction

G S Supinski et al. Am J Physiol Regul Integr Comp Physiol. 2009 Oct.

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.

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Figures

Fig. 1.

Fig. 1.

Cardiac OxyBlots. Top: OxyBlot determinations for cardiac samples from representative control, endotoxin, 10-(6′-ubiquinonyl)-decyltriphenylphosphonium (MitoQ), and endotoxin + MitoQ-treated animals. OxyBlot protein staining was more prominent for the endotoxin sample compared with the other groups. Bottom: a duplicate gel examining silver staining for all proteins contained in these samples; this serves as a loading control.

Fig. 2.

Fig. 2.

State 3 and state 4 respiration rates. State 3 respiration rate is a measure of maximum ADP-stimulated oxygen consumption, and state 4 respiration rate is a measure of basal oxygen consumption in the absence of ADP. Left: endotoxin administration elicited a large reduction in cardiac mitochondria state 3 rate (P < 0.001 for comparison of controls and to the endotoxin group), and administration of MitoQ prevented this endotoxin-induced reduction (P < 0.01 for comparison of the endotoxin group to the endotoxin + MitoQ group). Right: state 4 rates were similar for all experimental groups. *Statistically significant difference from the other groups.

Fig. 3.

Fig. 3.

Respiratory control and ADP-to-O ratios. The ADP-to-O ratio is an index of the coupling of oxygen consumption to oxidative phosphorylation. Endotoxin reduced the respiratory control ratio (RCR) (P < 0.001, for comparison of the control to the endotoxin group) but did not change the ADP-to-O ratio. Administration of MitoQ prevented this endotoxin-induced reduction in RCR (P < 0.01 for comparison of endotoxin to the endotoxin + MitoQ group). *Statistically significant difference from the other groups.

Fig. 4.

Fig. 4.

Cardiac caspase 3 (left) and caspase 9 (right) activity. Endotoxin induced a large increase in both cardiac caspase 3 and caspase 9 activities (P < 0.001 for comparison of control to endotoxin-treated groups). MitoQ administration blocked this endotoxin effect on caspase activities (P < 0.01 for comparison of caspase 3 between endotoxin and endotoxin + MitoQ groups; P < 0.01 for comparison of caspase 9 between these 2 groups). *Statistically significant difference from the other groups. AMC, amino-4-methylcoumarin.

Fig. 5.

Fig. 5.

Representative left ventricular pressure tracings. The heart from an animal given endotoxin administration developed a much lower left ventricular pressure (right top tracing) compared with the pressure generated by a heart from a control animal (left top tracing). Developed left ventricular pressure for a heart from an animal given both endotoxin and MitoQ (left bottom tracing) was similar to the pressure in a control heart. Pressures for animals given MitoQ alone (right bottom tracing) were similar to control.

Fig. 6.

Fig. 6.

Systolic pressure-to-diastolic pressure relationship. Endotoxin-induced a significant reduction in developed left ventricular pressure for cardiac Langendorf preparations over the entire range of diastolic pressures assessed [P < 0.01 for comparison of control (•) to endotoxin (○)]. Hearts from animals given both endotoxin and MitoQ (▴) developed systolic pressures higher than those for the endotoxin group (P < 0.02). Systolic pressures for the hearts from animals given MitoQ alone (▵) were similar to controls. *Statistically significant difference from the other groups.

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