Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates GPIbalpha shedding from platelets in vitro and in vivo.
Interaction of the platelet receptor glycoprotein (GP) Ib-V-IX with von Willebrand factor exposed at a site of vascular injury is an essential step in the initiation of a hemostatic plug. Proteolytic cleavage (shedding) of the GPIbalpha subunit was first described >25 years ago, the protease mediating this event as well as its physiological function, however, have not been elucidated. We reported recently that shedding of GPIbalpha induced by platelet storage or mitochondrial injury involves a platelet-derived metalloproteinase(s). Here we show that GPIbalpha shedding in response to mitochondrial injury or physiological activation is inhibited in platelets obtained from chimeric mice, which express inactive tumor necrosis factor-alpha converting enzyme (TACE(DeltaZn/DeltaZn)) in blood cells only. Shedding was also inhibited in mouse and human platelets in the presence of 2 potent TACE inhibitors: TAP1 and TMI-1. Our data further suggest that TACE is important in the regulation of GPIbalpha expression in vivo because we observed an approximately 90% reduction in soluble GPIbalpha (glycocalicin) in plasma of TACE(DeltaZn/DeltaZn) chimeras as well as significantly increased levels of GPIbalpha on circulating platelets. In contrast, shedding of P-selectin from activated platelets was not affected by the mutation in TACE. Damaged TACE(DeltaZn/DeltaZn) platelets were further characterized by a markedly improved post-transfusion recovery and hemostatic function in mice. In conclusion, our data demonstrate that TACE is expressed in platelets and that it is the key enzyme mediating shedding of GPIbalpha.
Bergmeier
Wolfgang
W
CBR Institute for Biomedical Research, Harvard Medical School, Boston, Mass 02115-6399, USA.
Piffath
Crystal L
CL
Cheng
Guiying
G
Dole
Vandana S
VS
Zhang
Yuhua
Y
von Andrian
Ulrich H
UH
Wagner
Denisa D
DD
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D022781:Hepatocytes / Q000201:enzymology / Q000637:transplantation; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D019041:L-Selectin / Q000097:blood; D008297:Male; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism*; D017713:Platelet Transfusion; D011828:Radiation Chimera / Q000097:blood; D013917:Thrombin / Q000494:pharmacology; D013927:Thrombosis / Q000097:blood
D004151:Dipeptides; D006877:Hydroxamic Acids; D009025:Morpholines; C092152:N-((2-(hydroxyaminocarbonyl)methyl)-4-methylpentanoyl)-3-(2'-naphthyl)alanylalanine, 2-aminoethylamide; D019007:P-Selectin; D019038:Platelet Glycoprotein GPIb-IX Complex; C023592:glycocalicin; D019041:L-Selectin; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D000244:Adenosine Diphosphate; C484302:apratastat; D013917:Thrombin; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse