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(Circulation Research. 2004;94:1598.)
© 2004 American Heart Association, Inc.

Cellular Biology

Platelet 12-Lipoxygenase Activation via Glycoprotein VI

Involvement of Multiple Signaling Pathways in Agonist Control of H(P)ETE Synthesis

Marcus J. Coffey, Gavin E. Jarvis, Jonathan M. Gibbins, Barbara Coles, Natasha E. Barrett, Oliver R.E. Wylie, Valerie B. O’Donnell

From the Department of Medical Biochemistry and Immunology (M.J.C., B.C., O.R.E.W., V.B.O.), University of Wales College of Medicine, Heath Park, Cardiff, Wales; Department of Biochemistry (G.E.J.), University of Cambridge, Tennis Court Road, Cambridge; and the Cardiovascular Research Group (J.M.G., N.E.B.), University of Reading, Whiteknights, Reading, UK.

Correspondence to Dr Valerie B. O’Donnell or to Dr Marcus J. Coffey, PhD, Department of Medical Biochemistry & Immunology, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK. E-mail o-donnellvb{at}cardiff.ac.uk or coffeymj{at}cardiff.ac.uk

Lipoxygenases (LOX) contribute to vascular disease and inflammation through generation of bioactive lipids, including 12-hydro(pero)xyeicosatetraenoic acid (12-H(P)ETE). The physiological mechanisms that acutely control LOX product generation in mammalian cells are uncharacterized. Human platelets that contain a 12-LOX isoform (p12-LOX) were used to define pathways that activate H(P)ETE synthesis in the vasculature. Collagen and collagen-related peptide (CRP) (1 to 10 µg/mL) acutely induced platelet 12-H(P)ETE synthesis. This implicated the collagen receptor glycoprotein VI (GPVI), which signals via the immunoreceptor-based activatory motif (ITAM)-containing FcR chain. Conversely, thrombin only activated at high concentrations (> 0.2 U/mL), whereas U46619 and ADP alone were ineffective. Collagen or CRP-stimulated 12-H(P)ETE generation was inhibited by staurosporine, PP2, wortmannin, BAPTA/AM, EGTA, and L-655238, implicating src-tyrosine kinases, PI3-kinase, Ca²⁺ mobilization, and p12-LOX translocation. In contrast, protein kinase C (PKC) inhibition potentiated 12-H(P)ETE generation. Finally, activation of the immunoreceptor tyrosine-based inhibitory motif (ITIM)–containing platelet endothelial cell adhesion molecule (PECAM-1) inhibited p12-LOX product generation. This study characterizes a receptor-dependent pathway for 12-H(P)ETE synthesis via the collagen receptor GPVI, which is negatively regulated by PECAM-1 and PKC, and demonstrates a novel link between immune receptor signaling and lipid mediator generation in the vasculature.

Key Words: platelets • lipoxygenase • collagen • collagen receptor glycoprotein VI

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