Abstract 203: Insulin Alleviates Cardiac Dysfunction After Mechanical Trauma by Inhibiting TNF-α--Mediated ROS Generation via the PI3K/Akt Pathway
Background: Intensive insulin treatment protects injured myocardium and reduces mortality in surgical critically ill patients but the mechanisms involved remain unclear. This study was designed to investigate whether insulin may alleviate cardiac dysfunction after mechanical trauma (MT) and the underlying mechanisms.
Methods and Results: Male adult rats were subjected to non-lethal MT (Noble-Collip drum trauma, 35 r/m, 200 r) and randomly received different treatments. Non-lethal MT increased cardiac TNF-α (13.8±2.4 vs. 5.7±2.7 pg/mg protein, P<0.01) and reactive oxygen species (ROS) production 0.5 h after trauma, resulted in immediate cardiac dysfunction 0.5 h post-trauma with subsequent myocardial injury as evidenced by increased serum troponin I (cTnI) and significant cardiomyocyte apoptosis 2 h post-trauma (n=6, all P<0.01). Administration of GIK (250 g/L glucose, 60 U/L insulin, 80 mmol/L potassium) markedly inhibited TNF-α and ROS overproduction together with reduced myocardial injury and alleviated cardiac dysfunction at 1 h, 2 h, 3 h and 4 h after trauma. However, MT had no effect on blood glucose level compared with the sham-operated group and there was no difference in blood glucose between the GIK-treated and vehicle-treated rats during the 4-h experiment (n=6, P>0.05). Blockade of TNF-α with etanercept (a fusion protein blocker of TNF-α, 16 mg/kg, i.p.) attenuated ROS generation and preserved cardiac function after MT (n=6, both P<0.01). Furthermore, combining GIK and etanercept treatment did not exert any additive effects on these two parameters. In addition, pretreatment with Tempol (30 mg/kg, i.v.), a ROS scavenger, enhanced cardiac functional recovery after MT. Interestingly, cotreatment with the PI3K inhibitor wortmannin completely abolished the anti-TNF-α, anti-oxidative and cardioprotective effects afforded by GIK.
Conclusions: These results demonstrated for the first time that insulin alleviates myocardial dysfunction after trauma by inhibiting TNF-α-mediated ROS generation via the PI3K/Akt pathway. The anti-inflammatory and anti-oxidative properties elicited by insulin may prevent cardiac dysfunction and improve outcomes in surgical critically ill patients.
- © 2011 by American Heart Association, Inc.