title: Pathologic shear triggers shedding of vascular receptors: a novel mechanism for down-regulation of platelet glycoprotein VI in stenosed coronary vessels.
abstract: 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 α(IIb)β(3), GPIbα, 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 GPIbα 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.
authors.affiliation: Monash University, Australian Centre for Blood Diseases, Alfred Medical Research & Education Precinct, 89 Commercial Road,Melbourne, VIC 3004, Australia.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Al-Tamimi
authors.forename: Chee Wee
authors.initials: CW
authors.lastname: Tan
authors.forename: Jianlin
authors.initials: J
authors.lastname: Qiao
authors.forename: Gabrielle J
authors.initials: GJ
authors.lastname: Pennings
authors.forename: Ashkan
authors.initials: A
authors.lastname: Javadzadegan
authors.forename: Andy S C
authors.initials: AS
authors.lastname: Yong
authors.forename: Jane F
authors.initials: JF
authors.lastname: Arthur
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Davis
authors.forename: Jing
authors.initials: J
authors.lastname: Jing
authors.forename: Fi-Tjen
authors.initials: FT
authors.lastname: Mu
authors.forename: Justin R
authors.initials: JR
authors.lastname: Hamilton
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Jackson
authors.forename: Andreas
authors.initials: A
authors.lastname: Ludwig
authors.forename: Michael C
authors.initials: MC
authors.lastname: Berndt
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Ward
authors.forename: Leonard
authors.initials: L
authors.lastname: Kritharides
authors.forename: Robert K
authors.initials: RK
authors.lastname: Andrews
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Gardiner
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000502:physiology; D060050:Angina, Stable / Q000097:blood; D001792:Blood Platelets / Q000737:chemistry*; D001809:Blood Viscosity; D003094:Collagen / Q000502:physiology; D023921:Coronary Stenosis / Q000097:blood* / Q000235:genetics; D004151:Dipeptides / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D018056:Hemorheology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000502:physiology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D008875:Middle Aged; D010974:Platelet Aggregation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000502:physiology; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics; D053657:Platelet-Rich Plasma; D017434:Protein Structure, Tertiary; D013314:Stress, Mechanical; D056729:von Willebrand Disease, Type 3 / Q000097:blood
chemical_list: C555398:3-(formylhydroxyamino)-2-(3-phenyl-1-propyl)butanoic acid (2,2-dimethyl-1-methylcarbamoyl-1-propyl)amide; D004151:Dipeptides; D006877:Hydroxamic Acids; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; C094990:adhesion receptor; C098341:platelet membrane glycoprotein VI; D003094:Collagen; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human