Abstract
AimsGlycoprotein VI (GPVI) is a key platelet receptor which mediates plaque-induced platelet activation and consecutive atherothrombosis, but GPVI is also involved in platelet-mediated atheroprogression. Therefore, interference in GPVI-mediated platelet activation has the potential to combine short-term and long-term beneficial effects, specificity and safety especially regarding bleeding complications.Methods and ResultsWe investigated the effects of the soluble dimeric GPVI receptor fusion protein, Revacept, an antagonist of collagen-mediated platelet activation, in an animal model of atherosclerosis: twenty week old rabbits, which had been fed on a cholesterol-rich diet for 8 weeks, received Revacept (8 mg/kg) or control twice weekly for 4 weeks. Pharmacokinetics indicated a slight accumulation of the drug in the serum after repeated dosing of Revacept for 3 weeks. A significant improvement of endothelial dysfunction after 0.06 and 0.6 µg/min acetylcholine and a significant decrease of vessel wall thickening were found after Revacept treatment. Accordingly, aortic vessel weight was reduced, and plaque sizes, macrophage and T-cell invasion tended to be reduced in histological evaluations. Bleeding time was determined after tail clipping in mice. Revacept alone or in combination with widely used anti-platelet drugs revealed a high safety margin with no prolongation of bleeding times.ConclusionRepeated doses of Revacept led to a significant improvement of endothelial dysfunction and vascular morphology in atherosclerotic rabbits. Furthermore, no influence of Revacept on bleeding time alone or in combinations with various anti-platelet drugs was found in mice. Thus, the inhibition of collagen-mediated platelet interaction with the atherosclerotic endothelium by Revacept exerts beneficial effects on morphology and vascular function in vivo and seems to have a wide therapeutic window without influencing the bleeding time.
Highlights
Rupture of atherosclerotic plaques leads to adhesion of circulating platelets to exposed sub-endothelial matrix proteins which trigger subsequent platelet activation and aggregation
Repeated doses of Revacept led to a significant improvement of endothelial dysfunction and vascular morphology in atherosclerotic rabbits
No influence of Revacept on bleeding time alone or in combinations with various anti-platelet drugs was found in mice
Summary
Rupture of atherosclerotic plaques leads to adhesion of circulating platelets to exposed sub-endothelial matrix proteins which trigger subsequent platelet activation and aggregation. Revacept is a dimeric recombinant fusion protein consisting of the Fc part of a human immunoglobulin G (IgG) together with the hinge region and the functional GPVI domain at the N-terminus (GPVI-Fc) [1] This novel antiplatelet tool has been proven beneficial in various animal models of acute vascular injury [1,9]. Human GPVI-Fc/Revacept is thought to act by blocking the binding sites of platelets at collagen, fibronectin [8,11] and possibly other vascular ligands, such as von Willebrand factor, and might interfere with platelets in acute plaque rupture and during chronic interaction with the activated but intact atherosclerotic endothelium
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