1: Ann Biomed Eng. 2004 Sep;32(9):1193-201. 

Role of the Pyk2-MAP kinase-cPLA2 signaling pathway in shear-dependent platelet
aggregation.

Sun L, Feng S, Resendiz JC, Lu X, Durante W, Kroll MH.

Michael E. DeBakey VA Medical Center, Baylor College of Medicine and Rice
University, Houston, TX 77030, USA.

Mechanisms of shear-induced platelet aggregation are not established. Data that
ristocetin-induced von Willebrand factor (VWF) binding to glycoprotein (Gp)
Ibalpha activates proline-rich tyrosine kinase 2 (Pyk2) and
extracellular-regulated kinase (ERK) has led to speculation that these events
are coupled and that a MAP kinase may activate cytosolic phospholipase A2
(cPLA2)-mediated arachidonic acid (AA) release. To test this hypothesis and
clarify the role of AA metabolism in shear-induced VWF-dependent platelet
aggregation, we examined Pyk2, ERK1/2, and p38 phosphorylation, and arachidonic
acid release and metabolism in platelets subjected to pathological shear stress
in vitro. We observe tyrosine phosphorylation of Pyk2, p38, and ERK1/2 but no
measurable increase in free AA, 12-hydroxyeicosatetraenoic acid, or thromboxane
A2. Inhibitors of ERK, p38, or cyclooxygenase activation fail to affect
shear-induced platelet aggregation. When washed platelets are
aspirin-pretreated, arachidonic acid release becomes measurable and aggregation
at 60 and 120 s is attenuated. These data indicate that shear-induced VWF
binding to platelet GpIb-IX-V activates Pyk2, ERK1/2, p38, and cPLA2, but that
the magnitude of these responses is below the threshold needed to enhance
shear-induced VWF-dependent platelet aggregation in the presence of plasma.
These results provide a mechanistic basis for the long-standing observation that
shear-dependent platelet aggregation is unaffected by the antiplatelet drug
aspirin.

PMID: 15493507 [PubMed - indexed for MEDLINE]