Abstract 9400: Inhibition of IκB Phosphorylation by a Novel IKK Inhibitor IMD-1041 Attenuates Myocardial Dysfunction After Infarction
Background: Ischemia after myocardial infarction (MI) frequently causes left ventricular (LV) dysfunction. This condition is due to inflammatory reactions and fibrosis of myocardium. LV remodeling after MI is the pathological process which includes expansion of the infarcted area, ventricular dilatation and distortion of the ventricular shape. Recently, several studies have demonstrated that nuclear factor-kappa B (NF-κB) is related to inflammation and LV remodeling and that NF-κB is activated in infarcted hearts. However, the effects of the continuous inhibition of NF-κB for the prevention of LV dysfunction after MI are still controversial. A novel IKK inhibitor IMD-1041, which inhibits phosphorylation of I-κB via inhibition of IKK-β, is under clinical trial for chronic obstructive pulmonary disease. In spite of these progressive studies on pulmonary disease, the effects of IMD-1041 on cardiovascular disease are not yet well examined. The aim of this study was to investigate the effects of IMD-1041 on myocardial remodeling after infarction.
Methods and Results: To analyze the effects of IMD-1041 on myocardial dysfunction after MI, we continuously administered IMD-1041 (low dose; 30mg/kg/day, high dose; 100mg/kg/day) or vehicle (0.5% CMC) orally to mice with ligation of the left anterior descending coronary artery (LAD). After 28 days of ligation, MI mice exhibited LV dilatation and contractile dysfunction. However, IMD-1041 treatment significantly improved cardiac function, as indicated by the preservation of fractional shortening (30mg/kg/day of IMD-1041, 25.8±0.8%, n=12; 100mg/kg/day of IMD-1041, 29.3±0.6%, n=12; vehicle-treated, 21.6±1.6%, n=11; P<0.05). Histological analysis also showed that IMD-1041 treatment effectively inhibited LV remodeling through reduction of the ratios of fibrosis per whole area compared with vehicle control group (30mg/kg/day of IMD-1041, 21.5±2.0%, n=12; 100mg/kg/day of IMD-1041, 24.0±1.7%, n=12; vehicle-treated, 33.2±3.6%, n=11; P<0.05).
Conclusion: These results suggest that IMD-1041 treatment effectively improves LV remodeling after MI through attenuation of myocardial fibrosis. It may provide an effective approach to prevent myocardial dysfunction.
- © 2011 by American Heart Association, Inc.