Kringle 5 of plasminogen is a novel inhibitor of endothelial cell growth

J Biol Chem. 1997 Sep 5;272(36):22924-8. doi: 10.1074/jbc.272.36.22924.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Angiostatins
  • Animals
  • Cattle
  • Cell Division
  • Cells, Cultured
  • Endothelium, Vascular / cytology*
  • Endothelium, Vascular / drug effects
  • Growth Inhibitors / chemistry
  • Growth Inhibitors / genetics
  • Growth Inhibitors / physiology*
  • Humans
  • Hydrolysis
  • Kringles*
  • Mice
  • Molecular Sequence Data
  • Peptide Fragments / pharmacology
  • Plasminogen / chemistry
  • Plasminogen / genetics
  • Plasminogen / pharmacology
  • Plasminogen / physiology*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Sequence Homology, Amino Acid


  • Growth Inhibitors
  • Peptide Fragments
  • Recombinant Proteins
  • Angiostatins
  • Plasminogen