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Do SRC family kinases (SFKs) regulate platelet mediated leukocyte recruitment in atherosclerosis?

      The role of platelets in the formation of arterial thrombus on atherosclerotic plaque are well established. In early disease, platelets also appear to play a role in enabling the recruitment of inflammatory leukocytes. We have previously described a paradigm where the recruitment of monocytes to TGF-β1 stimulated endothelial cells (EC) is mediated by platelet bridges. TGF-β1 promotes the expression of a matrix of Von Willebrand factor (VWF) on the EC surface which recruits platelets from flowing blood. Upon platelet activation at the EC surface by ADP, monocytes are in turn recruited by platelet P-selectin. The SFKs play an important role in platelet signalling during haemostasis and we propose that these molecules could represent therapeutic targets for intervention in platelet mediated monocyte recruitment during atherogenesis. The broad spectrum SFK inhibitor Dasatinib ablated ADP dependent aggregation of both human and murine platelets, inhibited the activation of platelets and the secondary recruitment of monocytes on substrates of immobilised VWF or on TGF-β1 stimulated EC. In addition, platelets from the Lyn-/- and Fgr-/- mice, showed deficiencies in aggregation in response to ADP, reduced adhesion to VWF and inhibited monocyte recruitment under flow conditions. These data strongly imply that targeting specific SFK members could inhibit platelet dependent recruitment of monocytes, and may represent drugable targets for intervening in the inflammatory processes that support atheroma formation.
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