Prothrombinase acceleration by oxidatively damaged phospholipids |
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Authors: | Weinstein E A Li H Lawson J A Rokach J FitzGerald G A Axelsen P H |
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Affiliation: | Department of Pharmacology and Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. |
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Abstract: | The optimally efficient production of thrombin by the prothrombinase complex relies on suitable positioning of its component factors and substrate on phosphatidylserine-containing lipid membranes. The presence of oxidatively damaged phospholipids in a membrane disrupts the normal architecture of a lipid bilayer and might therefore be expected to interfere with prothrombinase activity. To investigate this possibility, we prepared phosphatidylserine-containing lipid vesicles containing oxidized arachidonoyl lipids, and we examined their ability to accelerate thrombin production by prothrombinase. Oxidized arachidonoyl chains caused dose-dependent increases in prothrombinase activity up to 6-fold greater than control values. These increases were completely attenuated by the presence of alpha-tocopherol, gamma-tocopherol, or ascorbate. Over the course of a 300-min oxidation, the ability of arachidonoyl lipids to accelerate prothrombinase peaked at 60 min and then declined to base-line levels. These results suggest that instead of being impeded by oxidative membrane damage, prothrombinase activity is enhanced by one or more products of nonenzymatic lipid oxidation. |
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