Reconstitution of CD39 in liposomes amplifies nucleoside triphosphate diphosphohydrolase activity and restores thromboregulatory properties.

Journal of Vascular Surgery
Carolyn A HallerElliot L Chaikof

Abstract

CD39 (nucleoside triphosphate diphosphohydrolase [NTPDase-1]) expressed on the luminal surface of endothelial cells rapidly metabolizes extracellular adenosine triphosphate (ATP) and adenosine diphosphate (ADP) to adenosine monophosphate (AMP), and abrogates platelet reactivity. Optimization of CD39 enzymatic activity appears dependent upon the expression of both transmembrane domains within plasma membranes. Thus, motivation exists to examine therapeutic antiplatelet formulations that consist of liposomal CD39. Full-length human CD39 was produced by using a yeast expression system, purified, and reconstituted within lipid vesicles. The catalytic efficiency (kcat/Km) of CD39-mediated phosphohydrolysis of ADP and ATP was determined both for detergent-solubilized and protein-reconstituted CD39 within lipid membranes. The capacity of CD39-containing lipid vesicles to inhibit platelet activation induced by ADP, collagen, or thrombin was determined in vitro by platelet aggregometry. A murine model of thromboplastin-induced thromboembolism was used to determine the effectiveness of intravenous liposomal CD39 in limiting platelet consumption and mortality. Reconstitution of human CD39 in lipid vesicles was associated with a decrease i...Continue Reading

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