Critical role for Syk in responses to vascular injury

Abstract

Although current antiplatelet therapies provide potent antithrombotic effects, their efficacy is limited by a heightened risk of bleeding and failure to affect vascular remodeling after injury. New lines of research suggest that thrombosis and hemorrhage may be uncoupled at the interface of pathways controlling thrombosis and inflammation. Here, as one remarkable example, studies using a novel and highly selective pharmacologic inhibitor of the spleen tyrosine kinase Syk [PRT060318; 2-((1R,2S)-2-aminocyclohexylamino)-4-(m-tolylamino)pyrimidine-5-carboxamide] coupled with genetic experiments, demonstrate that Syk inhibition ameliorates both the acute and chronic responses to vascular injury without affecting hemostasis. Specifically, lack of Syk (murine radiation chimeras) attenuated shear-induced thrombus formation ex vivo, and PRT060318 strongly inhibited arterial thrombosis in vivo in multiple animal species while having minimal impact on bleeding. Furthermore, leukocyte-platelet–dependent responses to vascular injury, including inflammatory cell recruitment and neointima formation, were markedly inhibited by PRT060318. Thus, Syk controls acute and long-term responses to arterial vascular injury. The therapeutic potential of Syk may be exemplary of a new class of antiatherothrombotic agents that target the interface between thrombosis and inflammation.

The Novel Oral Syk Inhibitor, Bl1002494, Protects Mice From Arterial Thrombosis and Thromboinflammatory Brain Infarction

“…The unaltered bleeding times in Bl1002494-treated mice are in line with observations made with other Syk inhibitors, such as fostamatinib 21 or PRT060318, 15,22 and strongly suggest that Syk inhibition might be a safe antithrombotic regimen. However, as with all preclinical studies, differences between animal studies and the human situation need to be considered.…”

Anti–miR-148a regulates platelet FcγRIIA signaling and decreases thrombosis in vivo in mice

“…Syk plays a critical role in vascular injury response and thrombosis, as demonstrated by strong antithrombotic effects in vivo by Syk inhibitors. 6,61 Upregulation of TULA-2 by anti-miR-148a acts as a Syk inhibitor. We speculate that with multiple phosphate groups to be removed on active Syk, the amount of Syk phosphatase, TULA-2, is rate limiting.…”

The N-terminal SH2 domain of Syk is required for (hem)ITAM, but not integrin, signaling in mouse platelets

“…These results are similar to those for Syk-and GPVI-deficient platelets. 50,51 A ferric chloride injury to the mesenteric arteriolar wall was used to investigate the functional consequence of the Syk-R41A mutation ( Figure 4B). Syk R41Afl/fl;PF4-Cre mice had a significant delay in the initiation of thrombus formation in response to injury, with the median increased to 8.50 6 0.71 minutes relative to 5.13 6 0.98 minutes in the control.…”