Abstract 9434: A Specific IKK Inhibitor Suppresses Experimental Autoimmune Myocarditis in Rats

Abstract

Introduction: Nuclear factor-kappa B (NF-κB), which is regulated by the inhibitor NF-κB kinase (IKK), plays a critical role in the development of myocarditis. However, little is known about the role of IKK in its pathophysiology. Hypothesis: We assessed the hypothesis that IKK inhibition could attenuate cardiac inflammation in the progression of myocarditis. Methods: Lewis rats were immunized with porcine cardiac myosin to induce experimental autoimmune myocarditis (EAM). We administered the IKK inhibitor (IMD-0354, 15mg/kg/day, n=6) to EAM rats daily; the drug-free vehicle was used as untreated EAM control (n=7). We analyzed the therapeutic effects of IKK inhibition against EAM using echocardiography and pathological examination. Cytokine expression in the hearts and cell proliferation by myosin restimulation were also analyzed. Results: Echocardiogram revealed that the IKK inhibitor improved left ventricular fractional shortening (52.7±4.5%) in comparison to the untreated group (37.3±3.1%, p<0.05). Pathologically, severe myocardial cell infiltration was observed in the untreated EAM group (affected area per whole heart, 55.8±6.1%), while the IKK inhibitor treated group showed to suppress these changes (26.3±4.2%, p<0.05). In the IKK inhibitor treated group, mRNA expression of IFN-gamma (3.9 ±0.7 fold vs. untreated group, p<0.05) and MCP-1 (17.1±0.8 fold vs. untreated group, p<0.05) was significantly suppressed in comparison to the untreated EAM group (IFN-gamma: 14.5±2.7 fold, MCP-1: 51.4±3.9 fold). Moreover, the IKK inhibitor suppressed production of IL-2 and T cell proliferation in a dose dependent manner in vitro. Conclusion: In conclusion, the IKK inhibitor ameliorated EAM by suppressing cytokine production and attenuating inflammatory cell infiltration. IKK regulation is a promising treatment of clinical myocarditis.