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J. Biol. Chem. 275 (25): 19159-19166

© 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

Mildly Oxidized Low Density Lipoprotein Rapidly Stimulates via Activation of the Lysophosphatidic Acid Receptor Src Family and Syk Tyrosine Kinases and Ca2+ Influx in Human Platelets*

Petra MaschbergerDagger , Markus BauerDagger , Jutta Baumann-SiemonsDagger , Konrad J. ZanglDagger , Emil V. NegrescuDagger §, Armin J. Reininger||, and Wolfgang SiessDagger **

From the Dagger  Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Universität München, Pettenkoferstrasse P, D-80336 München, Germany and  Institut für Anatomie, Technische Universität München, Biedersteiner Strasse 29, D-80802 München, Germany

In contrast to native low density lipoprotein (LDL), mildly oxidized LDL (mox-LDL) induced platelet shape change and stimulated during shape change the tyrosine phosphorylation of specific proteins including Syk; the translocation of Src, Fyn, and Syk to the cytoskeleton; and the increase of cytosolic Ca2+ due to mainly Ca2+ entry. The stimulation of these early signal pathways by mox-LDL was inhibited by desensitization of the lysophosphatidic acid (LPA) receptor and specific LPA receptor antagonists, was independent of the alpha IIbbeta 3-integrin, and was mimicked by LPA. Stimulation of tyrosine phosphorylation and Syk activation were independent of the increase of cytosolic Ca2+ and were suppressed by genistein and two specific inhibitors of the Src family tyrosine kinases, PP1 and PD173956. In contrast to PP1 and PD 173956, genistein prevented shape change by mox-LDL. The results indicate that mox-LDL, through activation of the LPA receptor, stimulates two separate early signal pathways, (a) Src family and Syk tyrosine kinases, and (b) Ca2+ entry. The activation of these early signaling pathways by mox-LDL probably plays a role in platelet responses subsequent to shape change. The inhibition of mox-LDL-induced platelet activation by LPA receptor antagonists or dietary isoflavonoids such as genistein could have implications in the prevention and therapy of cardiovascular diseases.

* This work was supported by the Ernst und Berta Grimmke-Stiftung, Deutsche Forschungsgemeinschaft Grants Si 274 6-1 and GRK 438, and the August-Lenz-Stiftung. This work is submitted in partial fulfillment of thesis requirements for P. M., M. B., J. B.-S., and K. J. Z. at the University of Munich.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.

§ Present address: Dept. of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, The Cleveland Clinic Foundation, Cleveland, OH 44195.

|| Present address: The Scripps Research Institute, Department of Molecular and Experimental Medicine, La Jolla, CA 92037.

** To whom correspondence should be addressed: Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Klinikum Innenstadt, Universität München, Pettenkoferstr. 9, D-80336 München, Germany. Tel.: 49-89-5160-4380; Fax: 49-89-5160-4382; E-mail:

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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