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

作者：Korporaal Suzanne J A; Koekman C Arnold; Verhoef Sandra; van der Wal Dianne E; Bezemer Martineke; van Eck Miranda; Akkerman Jan Willem N^*

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2009, 29(3): 372-379.

DOI：10.1161/ATVBAHA.108.173278

• platelets
• lipoproteins
• phosphatases
• signal transduction
• PECAM-1

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 A(2). 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. (Arterioscler Thromb Vasc Biol. 2009;29:372-379.)

• 出版日期2009-3