OBJECTIVE: Spleen tyrosine kinase (SYK) has come into focus as a potential 
therapeutic target in chronic inflammatory diseases, such as rheumatoid 
arthritis and asthma, as well as in B-cell lymphomas. SYK has also been involved 
in the signaling of immunoreceptors, cytokine receptors, and integrins. We 
therefore hypothesized that inhibition of SYK attenuates the inflammatory 
process underlying atherosclerosis and reduces plaque development.
METHODS AND RESULTS: Low-density lipoprotein receptor-deficient mice consuming a 
high-cholesterol diet supplemented with 2 doses of the orally available SYK 
inhibitor fostamatinib for 16 weeks showed a dose-dependent reduction in 
atherosclerotic lesion size by up to 59±6% compared with the respective 
controls. Lesions of fostamatinib-treated animals contained fewer macrophages 
but more smooth muscle cells and collagen-characteristics associated with more 
stable plaques in humans. Mechanistically, fostamatinib attenuated adhesion and 
migration of inflammatory cells and limited macrophage survival. Furthermore, 
fostamatinib normalized high-cholesterol diet -induced monocytosis and 
inflammatory gene expression.
CONCLUSIONS: We present the novel finding that the SYK inhibitor fostamatinib 
attenuates atherogenesis in mice. Our data identify SYK inhibition as a 
potentially fruitful antiinflammatory therapeutic strategy in atherosclerosis.