Lipid Oxidation Enhances the Function of Activated Protein C

Omid Safa,Kenneth Hensley,Mikhail D Smirnov,Charles T Esmon,Naomi L Esmon

doi:10.1074/jbc.m005931200

Omid Safa, Kenneth Hensley + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m005931200

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Abstract

Although lipid oxidation products are usually associated with tissue injury, it is now recognized that they can also contribute to cell activation and elicit anti-inflammatory lipid mediators. In this study, we report that membrane phospholipid oxidation can modulate the hemostatic balance. Oxidation of natural phospholipids results in an increased ability of the membrane surface to support the function of the natural anticoagulant, activated protein C (APC), without significantly altering the ability to support thrombin generation. Lipid oxidation also potentiated the ability of protein S to enhance APC-mediated factor Va inactivation. Phosphatidylethanolamine, phosphatidylserine, and polyunsaturation of the fatty acids were all required for the oxidation-dependent enhancement of APC function. A subgroup of thrombotic patients with anti-phospholipid antibodies specifically blocked the oxidation-dependent enhancement of APC function. Since leukocytes are recruited and activated at the thrombus or sites of vessel injury, our findings suggest that after the initial thrombus formation, lipid oxidation can remodel the membrane surface resulting in increased anticoagulant function, thereby reducing the thrombogenicity of the thrombus or injured vessel surface. Anti-phospholipid antibodies that block this process would therefore be expected to contribute to thrombus growth and disease.

Highlights

The central role of the membrane surface in the reactions of the coagulation cascade has been well known for many years [1, 2]
Since leukocytes are recruited and activated at the thrombus or sites of vessel injury, our findings suggest that after the initial thrombus formation, lipid oxidation can remodel the membrane surface resulting in increased anticoagulant function, thereby reducing the thrombogenicity of the thrombus or injured vessel surface
The ability of phospholipid oxidation, a time-dependent process, to enhance activated protein C (APC) anticoagulant function would be expected to contribute to this process

Summary

Introduction

The central role of the membrane surface in the reactions of the coagulation cascade has been well known for many years [1, 2]. The nature of the phospholipid head group was known to play a role, and phosphatidylserine (PS) has been considered the most important [4, 5] For many years, it was believed the reactions of the coagulation cascade shared similar requirements for the membrane surface. Apoptotic cells with negatively charged surfaces can be immunogenic and lead to the development of anti-phospholipid antibodies (APAs) with procoagulant activity [28]. These observations led Horrko et al [29, 30] to determine that many APAs are directed toward epitopes of oxidized phospholipids

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