Abstract 1408: Simvastatin Suppresses Dendritic Cell-induced Autoimmune Myocarditis via Inhibition of Dendritic Cell Activation
Background: Immune mediators such as leukocytes and cytokines play a critical role in the pathogenesis of autoimmune myocarditis which is one of causes of dilated cardiomyopathy. Dendritic cells (DCs) are the most potent antigen-presenting cells and play a central role in the initiation and activation of immune response. It has been shown that statins have a broad range of cholesterol-independent protective effects including immune suppression. In the present study, we hypothesized that statins would suppress autoimmune myocarditis by inhibiting the activation of DCs.
Methods and Results: Immature bone marrow-derived DCs were generated by incubating with GM-CSF. Immature DCs were pulsed with alpha-myosin heavy chain (αMHC) peptide, and stimulated with LPS for 4 hours. Autoimmune myocarditis was induced in Balb/c mice by administration of LPS-stimulated DCs pulsed with αMHC peptide. Massive myocarditis was induced 7 days after αMHC-loaded DCs administration. Left ventricular dilatation and increase of heart to body weight ratio were observed 28 days after αMHC-loaded DCs administration. Next, we examined the effect of simvastatin (20mg/kg i.p.) on the DCs-induced myocarditis. The inflammatory cell infiltration score of myocarditis was smaller in simvastatin-treated group than that in PBS-treated group (n=5, 2.5±0.32 vs 1.2±0.25; p<0.05). The heart to body weight ratio was significantly smaller in simvastatin-treated group than in PBS-treated group (n=5, 7.0±0.9 vs 5.7±0.6%; p<0.05). We also examined the effects of simvastatin on the activation and cytokines production of bone marrow-derived DCs in vitro. Simvastatin significantly inhibited the LPS-induced expressions of MHC classII and co-stimulatory molecules including CD40, CD80 and CD86. In addition, simvastatin significantly inhibited the LPS-induced productions of proinflammatory cytokines and chemokine including TNF-alpha, IL-6 and MCP1 (n=4, 222.5±33.4 vs 138.4±26.2pg/ml; p<0.05, 180.1±19.4 vs 122.4±10.4pg/ml; p<0.05, 1819.5±99.3 vs 512.3±67.9pg/ml; p<0.05).
Conclusion: These results suggest that simvastatin may suppress dendritic cell-induced autoimmune myocarditis, possibly by inhibiting the activation and inflammatory cytokines production of DCs.