Inhibition of NF-κB improves left ventricular remodeling and cardiac dysfunction after myocardial infarction

Abstract

Several studies have demonstrated that NF-κB is substantially involved in the progression of cardiac remodeling; however, it remains uncertain whether the continuous inhibition of NF-κB is effective for the prevention of myocardial remodeling. Myocardial infarction (MI) was produced by ligation of the left anterior coronary artery of rats. IMD-0354 (10 mg/kg per day), a novel phosphorylation inhibitor of IκB that acts via inhibition of IKK-β, was injected intraperitoneally starting 24 h after induction of MI for 28 days. After 28 days, the IMD-0354-treated group showed significantly improved survival rate compared with that of the vehicle-treated group ( P < 0.05). Although infarct size was similar in both groups, improved left ventricular (LV) remodeling and diastolic dysfunction, as indicated by smaller LV cavity (LV end-diastolic area: vehicle, 74.13 ± 3.57 mm2; IMD-0354, 55.00 ± 3.73 mm2; P < 0.05), smaller peak velocity of early-to-late filling wave (E/A) ratio (vehicle, 3.87 ± 0.26; IMD-0354, 2.61 ± 0.24; P < 0.05), and lower plasma brain natriuretic peptide level (vehicle, 167.63 ± 14.87 pg/ml; IMD-0354, 110.75 ± 6.41 pg/ml; P < 0.05), were observed in the IMD-0354-treated group. Moreover, fibrosis, accumulation of macrophages, and expression of several factors (transforming growth factor-β1, monocyte chemoattractant protein-1, matrix metalloproteinase-9 and -2) in the noninfarcted myocardium was remarkably inhibited by IMD-0354. In conclusion, inhibition of NF-κB activation may reduce the proinflammatory reactions and modulate the extracellular matrix and provide an effective approach to prevent adverse cardiac remodeling after MI.