Kringle 5 of plasminogen is a novel inhibitor of endothelial cell growth.
Angiostatin is a potent angiogenesis inhibitor which has been identified as an internal fragment of plasminogen that includes its first four kringle modules. We have recently demonstrated that the anti-endothelial cell proliferative activity of angiostatin is also displayed by the first three kringle structures of plasminogen and marginally so by kringle 4 (Cao, Y., Ji, R.-W., Davidson, D., Schaller, J., Marti, D., Sohndel, S., McCance, S. G., O'Reilly, M. S. , Llinás, M., and Folkman, J. (1996) J. Biol. Chem. 271, 29461-29467). We now report that the kringle 5 fragment of human plasminogen is a specific inhibitor for endothelial cell proliferation. Kringle 5 obtained as a proteolytic fragment of human plasminogen displays potent inhibitory effect on bovine capillary endothelial cells with a half-maximal concentration (ED50) of approximately 50 nM. Thus, kringle 5 would appear to be more potent than angiostatin on inhibition of basic fibroblast growth factor-stimulated capillary endothelial cell proliferation. Appropriately folded recombinant mouse kringle 5 protein, expressed in Escherichia coli, exhibits a comparable inhibitory effect as the proteolytic kringle 5 fragment. Thus, kringle 5 domain of human plasminogen is a novel endothelial inhibitor that is sufficiently potent to block the growth factor-stimulated endothelial cell growth.
Cao
Y
Y
Laboratory of Angiogenesis Research, Department of Cell and Molecular Biology, Karolinska Institute, S-171 77 Stockholm, Sweden. yihai.cao@cmb.ki.se
Chen
A
A
An
S S
SS
Ji
R W
RW
Davidson
D
D
Llinás
M
M
D000595:Amino Acid Sequence; D043168:Angiostatins; D000818:Animals; D002417:Cattle; D002455:Cell Division; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D006131:Growth Inhibitors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006868:Hydrolysis; D018082:Kringles; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology; D010958:Plasminogen / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D017386:Sequence Homology, Amino Acid
D006131:Growth Inhibitors; D010446:Peptide Fragments; D011994:Recombinant Proteins; D043168:Angiostatins; D010958:Plasminogen