Inhibition of angiogenesis by two-chain high molecular weight kininogen (HKa) and kininogen-derived polypeptides.
We recently reported that the two-chain form of human high molecular weight kininogen (HKa) inhibits angiogenesis by inducing endothelial cell apoptosis (Zhang et al. 2000). This property appears to be primarily conferred by HKa domain 5 (HKa D5). In this manuscript, we further characterize the activity of these polypeptides toward proliferating endothelial cells, as well as their in vivo anti-angiogenic activity in the chick chorioallantoic membrane (CAM). We also demonstrate that short peptides derived from endothelial cell binding regions in HKa domains 3 and 5 inhibit endothelial cell proliferation and induce endothelial cell apoptosis. Like HKa and HKa D5, peptides derived from the latter domain induce endothelial cell apoptosis in a Zn(2+)-dependent manner, while those derived from domain 3 function independently of Zn2+. The implications of these findings to the regulation of angiogenesis and development of anti-angiogenic therapeutics are discussed.
Zhang
Jing-Chuan
JC
Department of Medicine, Case Western Reserve University, School of Medicine, University Hospitals of Cleveland, OH 44106-4937, USA.
Qi
Xiaoping
X
Juarez
Jose
J
Plunkett
Marian
M
Donaté
Fernando
F
Sakthivel
Ramasamy
R
Mazar
Andrew P
AP
McCrae
Keith R
KR
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002642:Chick Embryo; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D019679:Kininogen, High-Molecular-Weight / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D015032:Zinc / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; C419369:HKa protein, human; D019679:Kininogen, High-Molecular-Weight; D010446:Peptide Fragments; D015032:Zinc