A novel IKK inhibitor suppresses heart failure and chronic remodeling after myocardial ischemia via MMP alteration

Objective: 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-kappa B) is involved in this amplification through a positive feedback loop of pro-inflammatory cytokines. We investigated the efficacy of IKK blockade with IMD-0560, a novel inhibitor of IKK, in a rat myocardial ischemia model. Methods/results: Left coronary artery occlusion (28 days) was carried out in Sprague-Dawley rats. Daily intraperitoneal injections of IMD-0560 (5 mg/kg) were done after the operation. Treatment with IMD-0560 significantly improved cardiac function as indicated by the preservation of fractional shortening and lower serum brain natriuretic peptide level. Histological analysis showed that IMD-0560 treatment suppressed thinning in the infarcted area compared with vehicle-treated hearts. Moreover, in situ zymography showed matrix metalloprotease-9 activity was inhibited in the infarct area. Conclusion: We revealed that the IKK blockade is potent for the suppression of chronic ventricular remodeling after myocardial ischemia.