Impact of antioxidative treatment on nuclear factor kappa-B regulation during myocardial ischemia-reperfusion

Abstract

Nuclear factor kappa-B (NFkappaB), a transcription factor, plays a role in numerous pathological states such as myocardial ischemia-reperfusion (I/R), apoptosis, and ischemic preconditioning. As both myocardial ischemia and reperfusion (by reactive oxygen intermediates) can activate NFkappaB, we investigated the impact of the antioxidant N-acetylcysteine (NAC) on NFkappaB-regulation in patients subjected to cardioplegic arrest (CA) on cardiopulmonary bypass (CPB). Seventeen coronary artery surgery patients (66+/-9[S.D.] years) subjected to cardiopulmonary bypass (CPB) and cardioplegic arrest were randomized in a double-blind fashion to receive either NAC (100 mg/kg into CPB prime followed by infusion at 20 mg/kg/h; n=9) or placebo (n=8). Transmural LV biopsies were collected prior to CPB (baseline) and at CPB-end and immuno-cytochemically stained against active NFkappaB and phosphorylated IkappaB alpha (activates NFkappaB). At the end of CPB both NFkappaB and IkappaB alpha were unchanged in endothelial cells of controls compared to baseline (45.6+/-7.6 vs. 49.9+/-7.1 and 36.8+/-6.1 vs. 47.5+/-8.6 counts per viewfield (cpv), P>0.05, respectively). In NAC, NFkappaB and IkappaB alpha in endothelial cells were significantly decreased at CPB-end (19.8+/-1.7 vs. 39.1+/-4.1 cpv, P<0.001, and 22.1+/-1.9 vs. 38.3+/-4.4 cpv, P=0.006). In cardiomyocytes, however, there were no changes observed in either group. Antioxidative treatment with NAC decreases NFkappaB-activity following I/R in endothelial cells. We conclude that NFkappaB-activity post I/R is mediated by free radicals rather than ischemia alone.