C1qTNF-related protein-1 (CTRP-1): a vascular wall protein that inhibits collagen-induced platelet aggregation by blocking VWF binding to collagen.
CTRP-1 is a novel member of the C1qTNF-related protein family containing family characteristic collagen and TNF-like domains and shows marked expression in vascular wall tissue. We observed that recombinant human CTRP-1 specifically bound to fibrillar collagen and blocked collagen-induced platelet aggregation. CTRP-1 completely or partially prevented VWF and GPVI-Fc4 binding to collagen, respectively. However, GPVI-Fc4 failed to compete for the binding of CTRP-1 to collagen. CTRP-1 had no effects on alpha(2)beta(1) integrin I-domain binding to collagen. Using whole human blood under flow at low and high shear rates, CTRP-1 prevented platelets from accumulating on a collagen-coated surface but had no effects on "platelet-rolling" on a surface coated with VWF. These data suggest that CTRP-1 prevents collagen-induced platelet aggregation by specific blockade of VWF binding to collagen. By using the Folts vascular injury model in nonhuman primates (Macaca fascicularis), we were able to demonstrate that CTRP-1 can prevent platelet thrombosis in vivo. This effect was achieved in the absence of changes in activated-clotting time (ACT) and template cut bleeding times, suggesting that CTRP-1 has promising antiplatelet thrombotic activity and most likely acts by pacifying the thrombogenic site of vascular injury.
Lasser
Gerald
G
ZymoGenetics, Cardiovascular Biology, Seattle, WA 98102, USA.
Guchhait
Prasenjit
P
Ellsworth
Jeff L
JL
Sheppard
Paul
P
Lewis
Ken
K
Bishop
Paul
P
Cruz
Miguel A
MA
Lopez
Jose A
JA
Fruebis
Joachim
J
D000818:Animals; D024042:Collagen Type I / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000293:injuries / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism; D008252:Macaca fascicularis; D010973:Platelet Adhesiveness; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000494:pharmacology; D013927:Thrombosis / Q000503:physiopathology* / Q000517:prevention & control; D014841:von Willebrand Factor / Q000378:metabolism* / Q000494:pharmacology
D024042:Collagen Type I; D038982:Integrin alpha2beta1; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011994:Recombinant Proteins; C098341:platelet membrane glycoprotein VI; D014841:von Willebrand Factor