RRC ID 63378
Author Delgado Lagos F, Elgheznawy A, Kyselova A, Meyer Zu Heringdorf D, Ratiu C, Randriamboavonjy V, Mann AW, Fisslthaler B, Siragusa M, Fleming I.
Title Secreted modular calcium-binding protein 1 binds and activates thrombin to account for platelet hyperreactivity in diabetes.
Journal Blood
Abstract Secreted modular calcium binding protein 1 (SMOC1) is an osteonectin/SPARC related matricellular protein, whose expression is regulated by miR-223. Given that platelets are rich in miR-223, this study investigated the expression of SMOC1 and its contribution to platelet function. Both human and murine platelets expressed SMOC1, whereas platelets from SMOC1+/- mice presented no detectable mature SMOC1 protein. Platelets from SMOC1+/- mice demonstrated attenuated responsiveness to thrombin (platelet neutrophil aggregate formation, aggregation, clot formation, Ca2+ increase and β3 integrin phosphorylation), while responses to other platelet agonists were unaffected. SMOC1 has been implicated in TGFb singling but no link to this pathway was detected in platelets. Rather, the SMOC1 kazal domain directly bound thrombin to potentiate its activity in vitro as well as its actions on isolated platelets. The latter effects were prevented by monoclonal antibodies against SMOC1. Platelets from miR-223-deficient mice expressed high levels of SMOC1 and exhibited hyper-reactivity to thrombin that was also reversed by pre-incubation with monoclonal antibodies against SMOC1. Similarly, SMOC1 levels were markedly upregulated in platelets from individuals with type 2 diabetes and the SMOC1 antibody abrogated platelet hyper-responsiveness to thrombin. Taken together, we have identified SMOC1 as a novel thrombin-activating protein that makes a significant contribution to the pathophysiological changes in platelet function associated with type 2 diabetes. Thus, strategies that target SMOC1 or its interaction with thrombin may be attractive therapeutic approaches to normalize platelet function in diabetes.
Volume 137(12)
Pages 1641-1651
Published 2021-3-25
DOI 10.1182/blood.2020009405
PII S0006-4971(21)00232-9
PMID 33529332
MeSH Adult Animals Blood Platelets / cytology Blood Platelets / metabolism* Diabetes Mellitus, Type 2 / metabolism* Female Humans Male Mice Mice, Inbred C57BL Middle Aged Osteonectin / metabolism* Platelet Activation Platelet Aggregation Thrombin / metabolism*
IF 17.794
Mice RBRC01680