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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.

Original publication




Journal article


Arterioscler Thromb Vasc Biol

Publication Date





736 - 741


Animals, Cell Division, Cell Movement, Endothelium, Vascular, Gene Deletion, Humans, Kringles, Mice, Mice, Inbred C57BL, Neovascularization, Physiologic, Pancreatic Elastase, Peptide Fragments, Protein Structure, Tertiary, Recombinant Proteins, Serine Endopeptidases, Tissue Plasminogen Activator, Wound Healing