Pathologic shear triggers shedding of vascular receptors: A novel mechanism for down-regulation of platelet glycoprotein VI in stenosed coronary vessels

Mohammad Al-Tamimi, Chee Wee Tan, Jian Lin Qiao, Gabrielle Pennings, Ashkan Javadzadegan, Andy Yong, Jane Frances Arthur, Amanda Davis, Jing Jing, Fi-Tjen Mu, Justin Raymond Hamilton, Shaun Jackson, Andreas Ludwig, Michael Claude Berndt, Christopher Ward, Leonard Kritharides, Robert Keith Andrews, Elizabeth Ellen Gardiner

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75 Citations (Scopus)


Ligand-induced ectodomain shedding of glycoprotein VI (GPVI) is a metalloproteinase-dependent event. We examined whether shear force, in the absence of GPVI ligand, was sufficient to induce shedding of GPVI. Human-citrated platelet-rich plasma or washed platelets were subjected to increasing shear rates in a cone-plate viscometer, and levels of intact and cleaved GPVI were examined by Western blot and ELISA. Pathophysiologic shear rates (3000-10 000 seconds -1) induced platelet aggregation and metalloproteinase-dependent appearance of soluble GPVI ectodomain, and GPVI platelet remnant. Shedding of GPVI continued after transient exposure to shear. Blockade of I? IIbI? 3, GPIbI?, or intracellular signaling inhibited shear-induced platelet aggregation but minimally affected shear-induced shedding of GPVI. Shear-induced GPVI shedding also occurred in platelet-rich plasma or washed platelets isolated from a von Willebrand disease type 3 patient with no detectable VWF, implying that shear-induced activation of platelet metalloproteinases can occur in the absence of GPVI and GPIbI? ligands. Significantly elevated levels of sGPVI were observed in 10 patients with stable angina pectoris, with well-defined single vessel coronary artery disease and mean intracoronary shear estimates at 2935 seconds -1 (peak shear, 19 224 seconds -1). Loss of GPVI in platelets exposed to shear has potential implications for the stability of a forming thrombus at arterial shear rates. A? 2012 by The American Society of Hematology.
Original languageEnglish
Pages (from-to)4311 - 4320
Number of pages10
Issue number18
Publication statusPublished - 2012

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