C1qTNF–related protein-1 (CTRP-1): a vascular wall protein that inhibits collagen-induced platelet aggregation by blocking VWF binding to collagen

Abstract

CTRP-1 is a novel member of the C1q-TNF-related protein family containing family characteristic collagen and TNFlike 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, GPVIFc4 failed to compete for the binding of CTRP-1 to collagen. CTRP-1 had no effects on ␣ 2 ␤ 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. IntroductionC1qTNF-related protein-1 (CTRP-1) belongs to a family of proteins characterized by a common TNF alpha-like globular domain. 1-3 A second, less conserved structural element in this family is the N-terminal collagen-like region with typical glycine-X-Y repeats. The basic structure of proteins in the CTRP family appears to be a trimer that, in turn, can form higher order structures. 4 While structurally related, members of this protein family are functionally diverse and include the plasma protein C1q, which is involved in immune functions and possibly platelet hemostasis, 5 and adiponectin 6-8 and the hibernation proteins 20, 25, and 27, which are thought to be regulators of metabolism 9 ; other CTRP family members appear to have more structural or extracellular matrix-related functions (eg, collagen types VIII and X,. 10 Since C1q may play a role in collagen-induced platelet activation, 11 we investigated whether CTRP-1 might exhibit similar properties. Initial studies indicated that CTRP-1 had affinity for collagen and blocked collagen-induced platelet activation. This raises the potential significance of CTRP-1 for human disease because of the central role collagen-induced platelet activation and thrombus formation play in acute cardiovascular and cerebrovascular events. Spontaneous rupture of atherosclerotic plaque or medical interventions can cause an injury to the arterial endothelial lining, thus exposing the subendothelial extracellular matrix to circulating blood. Collagens are a major component of the extracellular matrix and can directly and indirectly activate platelets. [12][13][14][15][16] Three platelet receptors are thought to mediate these interactions. Integrin ␣ 2 ␤ 1 is thought to have a ma...

Aegyptin, a Novel Mosquito Salivary Gland Protein, Specifically Binds to Collagen and Prevents Its Interaction with Platelet Glycoprotein VI, Integrin α2β1, and von Willebrand Factor

“…Our results indicate that aegyptin displays antihemostatic properties through inhibition of collagen interaction with its three major ligands and therefore mechanistically and functionally distinguishes it from other collagen-binding proteins described previously (13)(14)(15)57). These findings are particularly relevant because the adhesive potential of platelets results from the sum of distinct pathways supported by coordinated receptor-ligand interactions specially adapted to respond to different environmental conditions (26).…”

“…On the other hand, saratin effectively inhibits vWf binding but only partially affects platelet aggregation at very high concentrations (100 g/ml) (15). Furthermore, CTRP-1 prevents platelet aggregation primarily because it blocks vWf binding to collagen (57). Therefore, each molecule distinctly recognizes binding sites in the collagen molecule, ultimately resulting in a certain degree of inhibition of platelet function as demonstrated for saratin (59), rLAPP (60), and CTRP-1 (57) when tested in vivo.…”

Adipose tissue-derived cytokines, CTRPs as biomarkers and therapeutic targets in metabolism and the cardiovascular system

“…In contrast to suppression of CTRP6 expression by cytokines, cytokines IL-1β and TNF-α elevate the expression of CTRP1 adaptively in the adipose tissue by which CTRP1 suppresses inflammation [30] . Meanwhile, CTRP1 impedes collagen-induced platelet coagulation, indicating its potent therapeutic value for treating vascular disorders during the inflammatory process [31] . CTRP3 has been shown to be capable of decreasing the secretion of pro-inflammatory mediators by primary human leukocytes, suggesting strongly an anti-inflammatory function, comparable to adiponectin [32][33][34] .…”

C1q/TNF-related Protein-12 (CTRP12), a Novel Adipokine That Improves Insulin Sensitivity and Glycemic Control in Mouse Models of Obesity and Diabetes

“…The defining feature of CTRPs is the presence of the signature "C1q/TNF-like" globular domain located at the C terminus, which is homologous to the immune complement C1q and structurally resembles that of TNF-␣ (9). Functional studies thus far have indicated significant roles for CTRPs in the endocrine (4 -8, 10, 11), immune (12), vascular (13,14), skeletal (15), and sensory systems (16 -18).…”