This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 25/4/736    most recent 01.ATV.0000157980.15710.2bv1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Carroll, V. A. Articles by Harris, A. L. Search for Related Content PubMed PubMed Citation Articles by Carroll, V. A. Articles by Harris, A. L. Related Collections Angiogenesis Apoptosis Coagulation and fibronolysis

(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

This article has been cited by other articles:

				H.-K. Kim, D.-S. Oh, S.-B. Lee, J.-M. Ha, and Y. A. Joe Antimigratory effect of TK1-2 is mediated in part by interfering with integrin {alpha}2{beta}1 Mol. Cancer Ther., July 1, 2008; 7(7): 2133 - 2141. [Abstract] [Full Text] [PDF]

				L. Fredriksson, M. Ehnman, C. Fieber, and U. Eriksson Structural Requirements for Activation of Latent Platelet-derived Growth Factor CC by Tissue Plasminogen Activator J. Biol. Chem., July 22, 2005; 280(29): 26856 - 26862. [Abstract] [Full Text] [PDF]