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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:736.)
© 2005 American Heart Association, Inc.

Vascular Biology

Antiangiogenic Activity of a Domain Deletion Mutant of Tissue Plasminogen Activator Containing Kringle 2

Veronica A. Carroll; Leonid L. Nikitenko; Roy Bicknell; Adrian L. Harris

From the Molecular Oncology Laboratory (V.A.C., A.L.H.) and Molecular Angiogenesis Laboratory (L.L.N., R.B.), Cancer Research UK, the Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.

Correspondence to Adrian L. Harris, John Radcliffe Hospital, Headington, Oxfordshire, OX3 9DS United Kingdom. E-mail aharris.lab{at}cancer.org.uk

Objective— The thrombolytic therapy drug, Reteplase, is a domain deletion mutant of tissue plasminogen activator (tPA), comprising the kringle 2 and protease (K2P) domains. Some kringle domains of hemostatic proteins are antiangiogenic and promote apoptosis. The objective of this study was to investigate whether K2P is an angiogenesis inhibitor because of the presence of kringle 2.

Methods and Results— K2P inhibited basic fibroblast growth factor-induced human endothelial cell proliferation and migration. Inhibition was not dependent on the protease activity of K2P because similar results were obtained with catalytically inactivated K2P. Purification of the kringle 2 domain derived from elastase cleavage of K2P at the Arg²⁷⁵–Ile²⁷⁶ bond revealed that inhibition was mediated by this domain. In addition, K2P inhibited angiogenesis in vivo and increased endothelial cell apoptosis.

Conclusions— Wound healing and angiogenesis are severely compromised by K2P. These data provide new mechanistic insights into the bleeding complications observed in some patients while undergoing thrombolytic therapy with this drug. In addition, we identify the kringle 2 domain of tPA as a novel target for antiangiogenic therapy.

In this study, we report that wound healing and angiogenesis are compromised with the fibrinolytic drug, Reteplase, and show that these effects are critically dependent on the kringle 2 domain. These data provide new mechanistic insights into the bleeding complications that can occur in some patients with this drug.

Key Words: antiangiogenesis • reteplase • kringle 2 • endothelial cells • wound healing

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