Journal article
Domain 5 of high molecular weight kininogen (kininostatin) down-regulates endothelial cell proliferation and migration and inhibits angiogenesis
Blood, Vol.95(2), pp.543-550
15 Jan 2000
PMID: 10627460
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
We have demonstrated that high molecular weight kininogen (HK) binds specifically on endothelial cells to domain 2/3 of the urokinase receptor (uPAR). Inhibition by vitronectin suggests that kallikrein-cleaved HK (HKa) is antiadhesive. Plasma kallikrein bound to HK cleaves prourokinase to urokinase, initiating cell-associated fibrinolysis. We postulated that HK cell binding domains would inhibit angiogenesis. We found that recombinant domain 5 (D5) inhibited endothelial cell migration toward vitronectin 85% at 0.27 μM with an IC50 (concentration to yield 50% inhibition) = 0.12 μM. A D5 peptide, G486-K502, showed an IC50 = 0.2 μM, but a 25-mer peptide from a D3 cell binding domain only inhibited migration 10% at 139 μM (IC50 > 50 μM). D6 exhibited weaker inhibitory activity (IC50 = 0.50 μM). D5 also potently inhibited endothelial cell proliferation with an IC50 = 30 nM, while D3 and D6 were inactive. Using deletion mutants of D5, we localized the smallest region for full activity to H441-D474. To further map the active region, we created a molecular homology model of D5 and designed a series of peptides displaying surface loops. Peptide 440-455 was the most potent (IC50 = 100 nM) in inhibiting proliferation but did not inhibit migration. D5 inhibited angiogenesis stimulated by fibroblast growth factor FGF2 (97%) in a chicken chorioallantoic membrane assay at 270 nM, and peptide 400-455 was also inhibitory (79%). HK D5 (for which we suggest the designation, “kininostatin”) is a potent inhibitor of endothelial cell migration and proliferation in vitro and of angiogenesis in vivo.
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Details
- Title
- Domain 5 of high molecular weight kininogen (kininostatin) down-regulates endothelial cell proliferation and migration and inhibits angiogenesis
- Creators
- Robert W. Colman - Temple UniversityBradford A. Jameson - Wilmington UniversityYingzhang Lin - Wilmington UniversityDonald Johnson - Wilmington UniversityShaker A. Mousa - Wilmington University
- Publication Details
- Blood, Vol.95(2), pp.543-550
- Publisher
- American Society of Hematology (ASH)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- [Retired Faculty]
- Identifiers
- 991019168027204721
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- Web of Science research areas
- Hematology