C-terminal ADAMTS-18 fragment induces oxidative platelet fragmentation, dissolves platelet aggregates, and protects against carotid artery occlusion and cerebral stroke.
Anti-platelet integrin GPIIIa49-66 antibody (Ab) induces complement-independent platelet oxidative fragmentation and death by generation of platelet peroxide following NADPH oxidase activation. A C-terminal 385-amino acid fragment of ADAMTS-18 (a disintegrin metalloproteinase with thrombospondin motifs produced in endothelial cells) induces oxidative platelet fragmentation in an identical kinetic fashion as anti-GPIIIa49-66 Ab. Endothelial cell ADAMTS-18 secretion is enhanced by thrombin and activated by thrombin cleavage to fragment platelets. Platelet aggregates produced ex vivo with ADP or collagen and fibrinogen are destroyed by the C-terminal ADAMTS-18 fragment. Anti-ADAMTS-18 Ab shortens the tail vein bleeding time. The C-terminal fragment protects against FeCI3-induced carotid artery thrombosis as well as cerebral infarction in a postischemic stroke model. Thus, a new mechanism is proposed for platelet thrombus clearance, via platelet oxidative fragmentation induced by thrombin cleavage of ADAMTS-18.
Li
Zongdong
Z
Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
Nardi
Michael A
MA
Li
Yong-Sheng
YS
Zhang
Wei
W
Pan
Ruimin
R
Dang
Suying
S
Yee
Herman
H
Quartermain
David
D
Jonas
Saran
S
Karpatkin
Simon
S
D051722:ADAM Proteins / Q000378:metabolism / Q000494:pharmacology*; D000071096:ADAMTS Proteins; D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D016893:Carotid Stenosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000242:Cyclic AMP / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000494:pharmacology*; D019151:Peptide Library; D010974:Platelet Aggregation / Q000187:drug effects*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D020521:Stroke / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013917:Thrombin / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology
D010446:Peptide Fragments; D019151:Peptide Library; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C106958:platelet glycoprotein (GP)IIIa 49-66; D000242:Cyclic AMP; D013917:Thrombin; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C510099:ADAMTS18 protein, human