Insulin alleviates posttrauma cardiac dysfunction by inhibiting tumor necrosis factor-α-mediated reactive oxygen species production.

OBJECTIVE

Clinical evidence indicates that intensive insulin treatment prevents the incidence of multiple organ failures in surgical operation and severe trauma, but the mechanisms involved remain elusive. This study was designed to test the hypothesis that insulin may exert anti-inflammatory and antioxidative effects and thus alleviate cardiac dysfunction after trauma.

DESIGN

Prospective, randomized experimental study.

SETTING

Animal research laboratory.

SUBJECTS

Sprague Dawley rats.

INTERVENTIONS

Anesthetized rats were subjected to 200 revolutions at a rate of 35 rpm in Noble-Collip drum to induce a nonlethal mechanical trauma and were randomized to receive vehicle, insulin, and insulin + wortmannin treatments. An in vitro study was performed on cultured cardiomyocytes subjected to sham-traumatic serum (SS), traumatic serum (TS), SS + tumor necrosis factor (TNF)-α, SS + H2O2, TS + neutralizing anti-TNF-α antibody, or TS + tempol treatments.

MEASUREMENTS AND MAIN RESULTS

Immediate cardiac dysfunction occurred 0.5 hr after trauma without significant cardiomyocyte necrosis and apoptosis, while serum TNF-α and cardiac reactive oxygen species (ROS) production was increased. Importantly, incubation of cardiomyocytes with TS or SS + TNF-α significantly increased ROS generation together with dampened cardiomyocyte contractility and Ca transient, all of which were rescued by TNF-α antibody. Administration of insulin inhibited TNF-α and ROS overproduction and alleviated cardiac dysfunction 2 hours after trauma. Scavenging ROS with tempol also attenuated cardiac dysfunction after trauma, whereas insulin combined with tempol failed to further improve cardiac functional recovery compared with insulin treatment alone. Moreover, the aforementioned anti-TNF-α, antioxidative, and cardioprotective effects afforded by insulin were almost abolished by the phosphatidylinositol 3-kinase inhibitor wortmannin.

CONCLUSIONS

These results demonstrate for the first time that mechanical trauma induces a significant increase in TNF-α and ROS production, resulting in immediate cardiac dysfunction. Early posttrauma insulin treatment alleviates cardiac dysfunction by inhibiting TNF-α-mediated ROS production via a phosphatidylinositol 3-kinase/Akt-dependent mechanism.