Abstract 22: Direct Interaction of Kindlin-3 with Integrins in Platelets and Neutrophils is Essential for Supporting Arterial and Venous Thrombosis in Mice
Kindlin-3 is a critical supporter of integrin activation in hematopoietic cells. Lack of expression of kindlin-3 protein in patients can cause impaired platelet aggregation and leukocyte adhesion, leading to severe bleeding and recurrent infections. Although kindlin-3 has been categorized as one of the integrin binding partners, the functional significance of the direct interaction of kindlin-3 with integrins in platelets and leukocytes has not been established. In this study, we generated a strain of Kindlin-3 knock-in (K3KI) mice that carry a specific mutation in the Kindlin-3 gene, therefore introducing an integrin interaction defective substitution (Q597W598/AA) in kindlin-3 protein. Functional analysis revealed that K3KI mice exhibited defective platelet function, including impaired integrin αIIbβ3 activation, suppressed platelet spreading and aggregation, prolonged tail bleeding time, absence of platelet-mediated clot retraction and resistance to in vitro thrombus formation and in vivo arterial thrombosis. In addition, β2-integrin mediated adhesion of neutrophils from K3KI mice was dramatically inhibited and, as a consequence, deep vein thrombus formation in a flow-restricted inferior vena cava was significantly suppressed in K3KI mice. Taken together, these observations demonstrate that the direct binding of kindlin-3 to integrin in hematopoietic cells is required for supporting integrin function in platelets and leukocytes, and significantly contributes to both arterial and venous thrombus formation. Our data also suggests that the direct crosstalk between kindlin-3 and integrin represents a potential therapeutic target for developing novel anti-thrombotic strategies.
Author Disclosures: Z. Xu: None. J. Gao: None. X. Chen: None. H. Zhi: None. J. Liu: None. G.C. White: None. E.F. Plow: None. Y. Ma: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.