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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2476.)
© 2007 American Heart Association, Inc.

Thrombosis

Platelet Activation by Oxidized Low Density Lipoprotein Is Mediated by Cd36 and Scavenger Receptor-A

Suzanne J.A. Korporaal; Miranda Van Eck; Jelle Adelmeijer; Martin Ijsseldijk; Ruud Out; Ton Lisman; Peter J. Lenting; Theo J.C. Van Berkel; Jan-Willem N. Akkerman

From the Department of Clinical Chemistry and Haematology (S.J.A.K., J.A., M.I., T.L., P.J.L., J.-W.N.A.), University Medical Center Utrecht, and Institute of Biomembranes, Utrecht University, the Netherlands; and the Division of Biopharmaceutics (S.J.A.K., M.V.E., R.O., T.J.C.V.B.), Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, the Netherlands.

Correspondence to Prof Dr J.W.N. Akkerman, Department of Clinical Chemistry and Haematology (G03.550), University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, the Netherlands. E-mail j.w.n.akkerman{at}umcutrecht.nl

Objective— The interaction of platelets with low density lipoprotein (LDL) contributes to the development of cardiovascular disease. Platelets are activated by native LDL (nLDL) through apoE Receptor 2' (apoER2')-mediated signaling to p38^MAPK and by oxidized LDL (oxLDL) through lysophosphatidic acid (LPA) signaling to Rho A and Ca²⁺. Here we report a new mechanism for platelet activation by oxLDL.

Methods and Results— Oxidation of nLDL increases p38^MAPK activation through a mechanism that is (1) independent of LPA, and (2) unlike nLDL-signaling not desensitized by prolonged platelet-LDL contact or inhibited by receptor-associated protein or chondroitinase ABC. Antibodies against scavenger receptors CD36 and SR-A alone fail to block p38^MAPK activation by oxLDL but combined blockade inhibits p38^MAPK by >40% and platelet adhesion to fibrinogen under flow by >60%. Mouse platelets deficient in either CD36 or SR-A show normal p38^MAPK activation by oxLDL but combined deficiency of CD36 and SR-A disrupts oxLDL-induced activation of p38^MAPK by >70%.

Conclusion— These findings reveal a novel platelet-activating pathway stimulated by oxLDL that is initiated by the combined action of CD36 and SR-A.

Platelets are activated by nLDL through binding to apoER2', which signals to p38^MAPK. Oxidation induces more p38^MAPK activation through loss of apoER2' binding thereby initiating the combined activity of CD36 and SR-A.

Key Words: platelets • LDL • oxidized LDL • CD36 • scavenger receptor-A

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