Abstract 3893: A Novel IKK Inhibitor IMD-0560: Suppresses Chronic Remodeling after Myocardial Ischemia
Amplification of inflammatory response in the non-infarct area plays an important role in the pathogenesis of ventricular remodeling after myocardial ischemia. Activation of nuclear factor-kappa B (NF-kB) is involved in this amplification through a positive feedback loop of proinflammatory cytokines. We investigated the efficiency of IKK blockade with IMD-0560, a novel inhibitor of IKK, in a rat myocardial ischemia model. Left coronary artery occlusion (28 days) was carried out in Sprague-Dawley rats. The rats were assigned randomly to the two groups:
IMD-0560 injection (5mg/kg i.p.) daily for 28 days (MI + IMD group, n=10);
vehicle injection (i.p.) daily for 28 days (MI + vehicle group, n=10); and
thoracotomy with LAD isolation without ligation (Sham group, n=5).
Treatment with IMD-0560 significantly improved cardiac function, as indicated by the preservation of % fractional shortening (vehicle-treated, 20.2±1.5; IMD-0560-treated, 26.7±2.4; P < 0.05), and lower serum brain natriuretic peptide level (vehicle, 0.079±0.040; IMD-0560, 0.033±0.016; P < 0.05). Histological analysis showed that hypertrophy of myocardium was suppressed in the peri-infarct area (vehicle, 756.71±48.57mm2; IMD-0560, 633.35±29.83mm2; P < 0.05), and the thickness of infarct area was maintained (vehicle, 0.890±0.027mm; IMD-0560, 1.136±0.087mm; P < 0.05). The sham group showed no effect. Moreover, in situ zymography showed that matrix metalloproteinase-9 activity was inhibited in the infarct area. We revealed that IMD-0560 is potent in the suppression of chronic ventricular remodeling after myocardial ischemia.