title: The oral spleen tyrosine kinase inhibitor fostamatinib attenuates inflammation and atherogenesis in low-density lipoprotein receptor-deficient mice.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Cardiology, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Hilgendorf
authors.forename: Sara
authors.initials: S
authors.lastname: Eisele
authors.forename: Imke
authors.initials: I
authors.lastname: Remer
authors.forename: Jochen
authors.initials: J
authors.lastname: Schmitz
authors.forename: Katharina
authors.initials: K
authors.lastname: Zeschky
authors.forename: Christian
authors.initials: C
authors.lastname: Colberg
authors.forename: Peter
authors.initials: P
authors.lastname: Stachon
authors.forename: Dennis
authors.initials: D
authors.lastname: Wolf
authors.forename: Florian
authors.initials: F
authors.lastname: Willecke
authors.forename: Maike
authors.initials: M
authors.lastname: Buchner
authors.forename: Katja
authors.initials: K
authors.lastname: Zirlik
authors.forename: Alexandra
authors.initials: A
authors.lastname: Ortiz-Rodriguez
authors.forename: Andrey
authors.initials: A
authors.lastname: Lozhkin
authors.forename: Natalie
authors.initials: N
authors.lastname: Hoppe
authors.forename: Constantin
authors.initials: C
authors.lastname: von zur Muhlen
authors.forename: Axel
authors.initials: A
authors.lastname: zur Hausen
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.forename: Andreas
authors.initials: A
authors.lastname: Zirlik
mesh_terms: D000284:Administration, Oral; D000631:Aminopyridines; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy*; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D007249:Inflammation / Q000188:drug therapy*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009025:Morpholines; D010078:Oxazines / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000627:therapeutic use*; D011743:Pyrimidines; D011973:Receptors, LDL / Q000172:deficiency*; D000072377:Syk Kinase
chemical_list: D000631:Aminopyridines; D002791:Cholesterol, Dietary; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D010078:Oxazines; D011725:Pyridines; D011743:Pyrimidines; D011973:Receptors, LDL; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C523665:fostamatinib