Abstract 21: The Calcium-Binding Protein S100A1 Negatively Regulates Collagen-Dependent Platelet Activation and Thrombosis in Mice
Introduction: S100A1 is a member of the S100 family of calcium-binding proteins. S100A1 controls Ca2+ dynamics in cardiomyocytes and plays an important role in heart failure. S100A1 is also strongly expressed in mouse platelets, but its role in platelet biology has not been investigated.
Goal: To determine the role of S100A1 in platelet activation and thrombosis.
Methods and Results: Platelet activation in response to threshold levels of convulxin, a specific agonist for the collagen receptor GPVI, showed significantly increased activation of αIIbβ3 integrin and α-granule release in S100A1-deficient (SKO) platelets compared with wild-type (WT) platelets. Consistently, SKO platelets also showed a more robust aggregation response to convulxin and collagen. In contrast, SKO platelets responded normally to stimulation with PAR4 receptor-activating peptide or ADP. Adhesion of SKO platelets to collagen under flow conditions was not significantly different to that of WT platelets. However, we observed a ~3-fold increase in phosphatidylserine (PS)-positive SKO platelets bound to the collagen surface (p<0.001, n=9 mice/group), suggesting that S100A1 also regulates the procoagulant response in platelets. Consistent with this hypothesis, we observed increased coated platelet formation and more sustained calcium transients in SKO platelets compared to controls. The increased reactivity of SKO platelets to GPVI agonists is explained by a ~1.5-fold increase in GPVI receptors expressed on the surface of these cells (p<0.001, n=20 mice/group). A similar increase in GPVI expression was also found in bone marrow-derived megakaryocytes. When subjected to the FeCl3 carotid artery thrombosis model, the time to vessel occlusion was significantly shorter in SKO mice compared to WT controls (4.55 ± 0.27 min vs 7.00 ± 0.62 min, respectively; p<0.01; n=8 mice/group). Furthermore, by using a collagen-rich adventitial surface inserted intralumenally in the carotid artery, we observed that thrombus formation in SKO mice is significantly more stable compared to WT mice (p=0.01, n=7 WT, n=8 SKO)
Conclusions: We here identify S100A1 as a negative regulator of GPVI expression and collagen-dependent platelet activation and thrombosis in mice.
Author Disclosures: Y. Boulaftali: None. D.S. Paul: None. R. Piatt: None. D. Feng: None. B.C. Cooley: None. P. Most: None. W. Bergmeier: None.
- © 2014 by American Heart Association, Inc.