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Prothrombinase acceleration by oxidatively damaged phospholipids
E A Weinstein1, H Li, J A Lawson
1Department of Pharmacology and Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
The Journal of Biological Chemistry
|May 10, 2000
Summary
Oxidative damage to membrane lipids surprisingly enhances prothrombinase activity, increasing thrombin production. Antioxidants like alpha-tocopherol and ascorbate can reverse this effect, suggesting specific oxidation products are responsible.
Area of Science:
- Biochemistry
- Membrane Biophysics
- Hemostasis
Background:
- Prothrombinase complex activity is crucial for efficient thrombin generation.
- Phosphatidylserine-rich membranes are essential for optimal prothrombinase complex assembly and function.
- Oxidative damage to membrane lipids is generally expected to disrupt membrane structure and impair protein function.
Purpose of the Study:
- To investigate the effect of oxidized phospholipids on prothrombinase complex activity.
- To determine if oxidative membrane damage inhibits or enhances thrombin production.
- To identify potential protective agents against observed effects.
Main Methods:
- Preparation of phosphatidylserine-containing lipid vesicles with oxidized arachidonoyl lipids.
- Assay of thrombin production by the prothrombinase complex using these vesicles.
- Evaluation of the impact of antioxidants (alpha-tocopherol, gamma-tocopherol, ascorbate) on prothrombinase activity.
- Kinetic analysis of prothrombinase activity over a 300-minute oxidation period.
Main Results:
- Oxidized arachidonoyl lipids dose-dependently increased prothrombinase activity up to 6-fold compared to controls.
- The enhancing effect of oxidized lipids on prothrombinase activity was fully reversed by alpha-tocopherol, gamma-tocopherol, or ascorbate.
- Prothrombinase activity enhancement peaked at 60 minutes of oxidation and subsequently declined.
Conclusions:
- Contrary to expectations, products of nonenzymatic lipid oxidation enhance, rather than impede, prothrombinase activity.
- Specific oxidized lipid species appear to modulate the prothrombinase complex, leading to increased thrombin generation.
- Antioxidants can mitigate the procoagulant effects of oxidized membrane lipids.
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