The Oral Spleen Tyrosine Kinase Inhibitor Fostamatinib Attenuates Inflammation and Atherogenesis in Low-Density Lipoprotein Receptor-Deficient Mice

Ingo Hilgendorf, Sara Eisele, Imke Remer, Jochen Schmitz, Katharina Zeschky, Christian Colberg, Peter Stachon, Dennis Wolf, Florian Willecke, Maike Buchner, Katja Zirlik, Alexandra Ortiz-Rodriguez, Andrey Lozhkin, Natalie Hoppe, Constantin von zur Muhlen, Axel zur Hausen, Christoph Bode, Andreas Zirlik*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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. Conclusion-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. (Arterioscler Thromb Vasc Biol. 2011;31:1991-1999.)
Original languageEnglish
Pages (from-to)1991-U209
JournalArteriosclerosis Thrombosis and Vascular Biology
Issue number9
Publication statusPublished - Sept 2011


  • atherosclerosis
  • macrophages
  • signal transduction
  • vascular biology
  • SYK

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