Arginine-glycine-aspartic acid- and fibrinogen gamma-chain carboxyterminal peptides inhibit platelet adherence to arterial subendothelium at high wall shear rates. An effect dissociable from interference with adhesive protein binding.
Arg-Gly-Asp (RGD)- and fibrinogen gamma-chain carboxyterminal (GQQHHLGGAKQAGDV) peptides inhibit fibrinogen, fibronectin (Fn), vitronectin, and von Willebrand factor (vWF) binding to the platelet glycoprotein IIb-IIIa complex (GP IIb-IIIa). GP IIb-IIIa, vWF, and Fn are essential for normal platelet adherence to subendothelium. We added peptides to normal citrated whole blood before perfusion over human umbilical artery subendothelium and evaluated platelet adherence morphometrically at high (2,600 s-1) and low (800 s-1) wall shear rates. We also examined the effects of the peptides on platelet adhesion to collagen in a static system. At the high wall shear rate, RGDS and GQQHHLGGAKQAGDV caused dose-dependent reduction in the surface coverage with spread and adherent platelets. Amino acid transposition and conservative substitutions of RGD peptides and the AGDV peptide significantly inhibited platelet adherence at 2,600 s-1. By contrast, the modified RGD peptides and AGDV do not affect adhesive protein binding to platelets. None of the native or modified RGD- or fibrinogen gamma-chain peptides significantly inhibited either platelet adherence to subendothelium at 800 s-1 or platelet adhesion to collagen. Our findings demonstrate that peptides that interfere with adhesive protein binding to GP IIb-IIIa inhibit platelet adherence to vascular subendothelium with flowing blood only at high wall shear rates. Platelet adherence to subendothelium at high wall shear rates appears to be mediated by different recognition specificities from those required for fluid-phase adhesive protein binding or static platelet adhesion.
Lawrence
J B
JB
Clinical Pathology Department, National Institutes of Health Clinical Center, Bethesda, Maryland 20892.
Kramer
W S
WS
McKeown
L P
LP
Williams
S B
SB
Gralnick
H R
HR
D000595:Amino Acid Sequence; D003094:Collagen / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000502:physiology; D005340:Fibrinogen / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology*; D010973:Platelet Adhesiveness / Q000187:drug effects*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000494:pharmacology; D014469:Umbilical Arteries; D014841:von Willebrand Factor / Q000378:metabolism
D009842:Oligopeptides; C027539:fibrinopeptides gamma; D014841:von Willebrand Factor; C047981:arginyl-glycyl-aspartic acid; D005340:Fibrinogen; D003094:Collagen; D013917:Thrombin