Cytochrome c limits oxidative stress and decreases acidosis in a rat model of hemorrhagic shock and reperfusion injury.

Hemorrhagic shock and reperfusion (HSR) injury leads to a cascade of reactive oxygen species (ROS) production and mitochondrial dysfunction, which results in energy failure, cell death, and multiple organ dysfunction. Cytochrome c (cyt c) is the final electron carrier in the mitochondrial electron transport chain providing the electrochemical force for ATP production. We sought to determine whether exogenous cyt c administration would improve parameters of organ dysfunction and/or mitochondrial stability in a rat model of HSR.

Male rats were hemorrhaged to a mean arterial pressure (MAP) of 33 ± 2.0 mm Hg for 1 hour before resuscitation. Saline or cyt c (0.8 mg [HSR-LoCC] or 3.75 mg [HSR-HiCC]) was administered (i.v.) 30 minutes before resuscitation. Rats were euthanized by cardiac puncture 2 hours post-surgery and tissue collected and analyzed for lipid peroxidation, endogenous antioxidant activity (glutathione peroxidase (GPx) and catalase), TNF-α expression, mitochondrial function (complex-I activity), and circulating mitochondrial DNA (mtDNA).

Cyt c administration improved lactate clearance, decreased hepatic lipid peroxidation, increased hepatic GPx activity, restored pulmonary TNF-α to sham activity levels, and increased hepatic complex-I activity. Furthermore, addition of exogenous cyt c decreased circulating levels of mtDNA.

These studies demonstrate that cyt c reduces markers of physiologic stress, decreases oxidative stress, and lowers levels of circulating mtDNA. The impact of cytochrome c is organ specific. Further studies remain to determine the sum of the effects of cytochrome c on overall outcome.