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Originally published In Press as doi:10.1074/jbc.M005931200 on October 27, 2000

J. Biol. Chem., Vol. 276, Issue 3, 1829-1836, January 19, 2001
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Lipid Oxidation Enhances the Function of Activated Protein C*

Omid SafaDagger , Kenneth Hensley§, Mikhail D. SmirnovDagger , Charles T. EsmonDagger ||**Dagger Dagger , and Naomi L. EsmonDagger §§

From the Departments of Dagger  Cardiovascular Biology and § Free Radical Biology and Aging, Oklahoma Medical Research Foundation, the Departments of  Pathology and || Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, and the ** Howard Hughes Medical Institute, Oklahoma City 73104

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.

* This work was supported by a Specialized Center on Thrombosis NHLBI Grant P50 HL54502 from the National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Dagger Investigator of the Howard Hughes Medical Institute and holds the Lloyd Noble Chair in Cardiovascular Research at the Oklahoma Medical Research Foundation.

§§ To whom correspondence should be addressed: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, 825 N.E. 13th St., Oklahoma City, OK 73104. Tel.: 405-271-7399; Fax: 405-271-3137; E-mail: Naomi-esmon@omrf.ouhsc.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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Copyright © 2001 by the American Society for Biochemistry and Molecular Biology.