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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:372.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Downregulation of Platelet Responsiveness Upon Contact With LDL by the Protein-Tyrosine Phosphatases SHP-1 and SHP-2

Suzanne J.A. Korporaal; C. Arnold Koekman; Sandra Verhoef; Dianne E. van der Wal; Martineke Bezemer; Miranda Van Eck; Jan-Willem N. Akkerman

From the Department of Clinical Chemistry and Haematology (S.J.A.K., C.A.K., S.V., D.E.v.d.W., M.B., J.-W.N.A.), University Medical Center, Utrecht, and the Division of Biopharmaceutics (S.J.A.K., M.V.E.), 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 (G.03.550), University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands. E-mail j.w.n.akkerman{at}umcutrecht.nl

Objective— The sensitivity of platelets to aggregating agents increases when low-density lipoprotein (LDL) binds to apolipoprotein E receptor 2' (apoER2'), triggering activation of p38^MAPK and formation of thromboxane A₂. LDL signaling is terminated by PECAM-1 through recruitment and activation of the Ser/Thr protein phosphatase PP2A, but platelets remain unresponsive to LDL when PECAM-1 activation disappears. We report a second mechanism that halts LDL signaling and in addition lowers platelet responsiveness to aggregating agents.

Methods and Results— After a first stimulation with LDL, platelets remain unresponsive to LDL for 60 minutes, despite normal apoER2' activation by a second dose of LDL. A possible cause is persistent activation of the tyrosine phosphatases SHP-1 and SHP-2, which may not only block a second activation of p38^MAPK, PECAM-1, and PP2A by LDL but also seem to reduce aggregation by TRAP, collagen, and ADP.

Conclusion— These findings reveal that p38^MAPK phosphorylation and platelet activation by LDL are suppressed by two mechanisms: (1) short activation of PECAM-1/PP2A, and (2) prolonged activation of SHP-1 and SHP-2. Activation of SHP-1 and SHP-2 is accompanied by reduced responsiveness to aggregating agents, which—if present in vivo—would make LDL an aggregation inhibitor during prolonged contact with platelets.

Key Words: platelets • lipoproteins • phosphatases • signal transduction • PECAM-1

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