Protein kinase C epsilon activation improves early survival in an acute porcine model of controlled hemorrhage.

Hemorrhage is the primary cause of preventable death in both military and civilian trauma cases, and the effective therapeutic options are limited. Activation of Protein Kinase C epsilon (PKC-ε) was shown to have a protective role in ischemia-reperfusion injury models. Thus, we evaluated the effects of a PKC-ε activator peptide in a swine model of controlled hemorrhagic shock. Controlled hemorrhage was induced in 25 Sus Domesticus female pigs by blood withdrawal. Fifteen animals were treated with PKC-ε activator peptide (3 mg/kg IM) five minutes following the initiation of hemorrhage, and 8 animals were bled without receiving the peptide. Two additional animals were treated with the peptide without having been bled for safety validation. Hemodynamic and biochemical parameters were monitored for 7 h, and mitochondrial function markers were analyzed and compared between groups. 73.3% of the pigs that received the peptide survived the hemorrhage until the end of the follow-up compared to only 25% of non-treated control animals. Kaplan-Meier survival analysis showed a significant difference between the groups (p = 0.044). This benefit was associated with a more favorable hemodynamic profile, including more stable blood pressure, heart rate and cardiac output, and a better acid-base balance. Mitochondrial analysis identified a significant increase in electron transport chain complex-I activity in the myocardium of treated animals compared with the controls (p = 0.033). In conclusion, Administration of PKC-ε activator is associated with improved survival, hemodynamic stability, and mitochondrial function in a porcine model of controlled hemorrhage.