The pathogenesis of atherosclerosis involves the activation of platelets by oxidized low density lipoprotein (LDL). Maschberger et al. examined the signaling pathways activated in platelets by mildly oxidized LDL (mox-LDL). Mox-LDL stimulated shape changes and transient increases in [Ca2+]i. These responses were inhibited by a lysophosphatidic (LPA) receptor antagonist and showed heterologous desensitization with LPA, indicating that both responses were mediated by activation of the LPA receptors by mox-LDL. The shape change induced by mox-LDL appeared not to be dependent on the increase in [Ca2+]i, because calcium chelators did not inhibit the shape change and because the low concentration of LPA required to stimulate shape changes did not increase [Ca2+]i. Shape changes did correlate with mox-LDL-stimulated increases in tyrosine phosphorylation of several proteins including the nonreceptor tyrosine kinases Fyn, Src, and Syk, and shape changes were inhibited if the cells were treated with general tyrosine kinase inhibitors. Finally, mox-LDL increased the association of the tyrosine-phosphorylated proteins with the cytoskeleton, suggesting a mechanism by which mox-LDL could alter the cytoskeleton to induce shape changes.
Maschberger, P., Bauer, M., Baumann-Siemons, J., Zangl, K.J., Negrescu, E.V., Reininger, A.J., and Siess, W. (2000) 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. J. Biol. Chem. 275: 19159-19166. [Abstract] [Full Text]