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(Circulation Research. 2004;95:677.)
© 2004 American Heart Association, Inc.

Molecular Medicine

Tumor Necrosis Factor-–Converting Enzyme (ADAM17) Mediates GPIb Shedding From Platelets In Vitro and In Vivo

Wolfgang Bergmeier, Crystal L. Piffath, Guiying Cheng, Vandana S. Dole, Yuhua Zhang, Ulrich H. von Andrian, Denisa D. Wagner

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.

Correspondence to Dr Denisa D. Wagner, Harvard Medical School, CBR Institute for Biomedical Research, 800 Huntington Ave, Boston, MA 02115-6399. E-mail wagner{at}cbr.med.harvard.edu

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 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 TACE^Zn/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 TACE^Zn/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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