Secreted modular calcium-binding protein 1 binds and activates thrombin to account for platelet hyperreactivity in diabetes

Abstract Secreted modular calcium-binding protein 1 (SMOC1) is an osteonectin/SPARC-related matricellular protein, whose expression regulated by microRNA-223 (miR-223). Given that platelets are rich in miR-223, this study investigated the of SMOC1 and its contribution to platelet function. Human murine expressed SMOC1, whereas from SMOC1+/? mice did not present detectable mature protein. Platelets demonstrated attenuated responsiveness thrombin (platelet neutrophil aggregate formation, aggregation, clot Ca2+ increase, ?3 integrin phosphorylation), responses other agonists were unaffected. has been implicated transforming growth factor-? signaling, but no link pathway was detected platelets. Rather, Kazal domain directly bound potentiate activity vitro, as well actions on isolated The latter effects prevented monoclonal antibodies against SMOC1. miR-223–deficient high levels exhibited hyperreactivity also reversed preincubation with Similarly, markedly upregulated individuals type 2 diabetes, antibody abrogated hyperresponsiveness thrombin. Taken together, we have identified a novel thrombin-activating makes significant pathophysiological changes function associated diabetes. Thus, strategies target or interaction may be attractive therapeutic approaches normalize