Abstract 12079: The Oral Spleen Tyrosin Kinase Inhibitor Fostamatinib Disodium (R788) Attenuates Inflammation and Atherogenesis in Low Density Lipoprotein Receptor-Deficient Mice
Background: Recently spleen tyrosine kinase (SYK), originally shown to mediate immunoreceptor downstream signaling, came into focus as a potential therapeutic target in chronic inflammatory diseases such as rheumatoid arthritis, asthma, and in B cell lymphomas. Beyond that, SYK was shown to be involved in the signaling of cytokine receptors and integrins. We therefore hypothesized that inhibition of SYK suppresses the inflammatory process underlying atherosclerosis and reduces plaque development in vivo.
Methods and Results: Low density lipoprotein receptor-deficient mice consuming a high cholesterol diet (HCD) supplemented with two doses of the orally available SYK inhibitor fostamatinib disodium (R788 0.5g/kg and 2.0g/kg) for 16 weeks showed a dose-dependent reduction in atherosclerotic lesion size by up to 58.1±5.9% compared with control animals (N>18 per group). Lesions of R788-treated animals contained significantly less macrophages and more smooth muscle cells and collagen, characteristics associated with more stable plaques in humans. Lipid and CD4 content remained unchanged. Mechanistically, R788 treatment normalized HCD-induced leukocytosis and inhibited thioglycollate-induced accumulation of inflammatory cells in the peritoneal cavity. Furthermore, R788 attenuated the expression of inflammatory cytokines and chemokines both in vivo and in vitro in bone marrow-derived macrophages and endothelial cells, cells typically resident in atherosclerotic plaques.
Conclusions: We present the novel finding that SYK inhibition by fostamatinib disodium (R788), an agent that recently generated promising results in clinical phase II trials for rheumatoid arthritis and lymphoma, significantly attenuates atherogenesis in LDLR−/− mice. This effect is most likely mediated by impairment of inflammatory cell recruitment and reduction in inflammatory gene expression. Our data identify SYK inhibition by fostamatinib disodium as a potential therapeutic strategy for atherosclerosis.
- © 2010 by American Heart Association, Inc.