Published online before print September 2, 2004, doi: 10.1161/01.RES.0000143899.73453.11
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Submitted on February 25, 2004
Revised on August 16, 2004
Accepted on August 19, 2004
Tumor Necrosis Factor-
-Converting Enzyme (ADAM17) Mediates GPIb Shedding From Platelets In Vitro and In Vivo
Wolfgang Bergmeier ;
From the CBR Institute for Biomedical Research (W.B., C.L.P., G.C., V.S.D., U.H.v.A., D.D.W.) and the Department of Pathology (W.B., V.S.D., U.H.v.A., D.D.W.), Harvard Medical School, Boston, Mass; and Wyeth Research (Y.Z.), Cambridge, Mass.
* To whom correspondence should be addressed. E-mail: wagner{at}cbr.med.harvard.edu.
Interaction of the platelet receptor GPIb-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 GPIb
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 GPIb induced by platelet storage or mitochondrial injury involves a platelet-derived metalloproteinase(s). Here we show that GPIb shedding in response to mitochondrial injury or physiological activation is inhibited in platelets obtained from chimeric mice, which express inactive tumor necrosis factor- converting enzyme (TACE
Zn/Zn) 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 GPIb expression in vivo because we observed an 
90% reduction in soluble GPIb (glycocalicin) in plasma of TACEZn/Zn chimeras as well as significantly increased levels of GPIb on circulating platelets. In contrast, shedding of P-selectin from activated platelets was not affected by the mutation in TACE. Damaged TACEZn/Zn 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 GPIb.
Key words: platelets • TACE • GPIb
, shedding
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