Early Platelet Activation by Low Density Lipoprotein via p38MAP Kinase

Christian M. Hackeng; Ingrid A. M. Relou; Marc W. Pladet; Gertie Gorter; Herman J. M. van Rijn; Jan-Willem N. Akkerman

doi:10.1055/s-0037-1614909

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1999; 82(06): 1749-1756
DOI: 10.1055/s-0037-1614909

Rapid Communication

Schattauer GmbH

Early Platelet Activation by Low Density Lipoprotein via p38^MAP Kinase

Christian M. Hackeng

¹From the Departments of Clinical Chemistry and Utrecht University, The Netherlands

²Haematology, University Hospital Utrecht, and Institute for Biomembranes, Utrecht University, The Netherlands

,

Ingrid A. M. Relou

¹From the Departments of Clinical Chemistry and Utrecht University, The Netherlands

²Haematology, University Hospital Utrecht, and Institute for Biomembranes, Utrecht University, The Netherlands

,

Marc W. Pladet

¹From the Departments of Clinical Chemistry and Utrecht University, The Netherlands

,

Gertie Gorter

²Haematology, University Hospital Utrecht, and Institute for Biomembranes, Utrecht University, The Netherlands

,

Herman J. M. van Rijn

¹From the Departments of Clinical Chemistry and Utrecht University, The Netherlands

,

Jan-Willem N. Akkerman

²Haematology, University Hospital Utrecht, and Institute for Biomembranes, Utrecht University, The Netherlands

› Author Affiliations

Abstract

Summary

Low Density Lipoprotein (LDL) is known to sensitize platelets for physiological agonists. To clarify the basis of this sensitization, we investigated the involvement of p38^MAP Kinase (p38^MAPK). As dual phosphorylation on Thr¹⁸⁰ and Tyr¹⁸² of p38^MAPK is the trigger for activation of the kinase, p38^MAPK-activity was measured with an antibody that recognizes the dual-phosphorylated sequence. LDL induced a rapid and dose dependent activation of p38^MAPK. The activation was not inhibited by a wide variety of inhibitors of platelet signalling, including TxA₂-formation, Phospholipase C-activation, Ca²⁺-mobilization and ERK 1/2-activation. Only a slight reduction in p38^MAPK-activation was observed when protein kinase C was inhibited. Activation of p38^MAPK was strongly inhibited by a rise in cAMP. Thus, p38^MAPK-activation was upstream of most signalling pathways and close to the LDL-receptor. A number of platelet receptors was screened with the use of antibodies. Integrins α_IIbβ₃ and α₂β₁, as well as the FcγRII-receptor, CD36 (platelet glycoprotein IV), CD68 (gp110) and Low Density Lipoprotein-receptor related protein (LRP) were not implicated in LDL-induced p38^MAPK-activation. Inhibition of LDL binding by modification of apo B100 lysines reduced p38^MAPK-activation by 80 %. Activation of p38^MAPK resulted in an increase in release of arachidonic acid, the precursor for thromboxane A₂ synthesis. In conclusion, activation of p38^MAPK might be the first step in platelet sensitization by LDL, leading to formation of arachidonate metabolites and increased aggregation and secretion responses to physiological agonists.

Keywords

LDL - lipoproteins - mapkinase - platelet

Full Text

References

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