Aprotinin stimulates angiogenesis and human endothelial cell migration through the growth factor pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta.
Pleiotrophin is an 18 kDa secreted polypeptide growth factor with direct pro-angiogenic and tumorigenic properties. Pleiotrophin is a substrate for proteolytic enzymes, such as plasmin, leading to proteolytic fragments with distinct activities on endothelial cell activation in vitro or angiogenesis in vivo. Aprotinin is a naturally occurring broad spectrum protease inhibitor, used widely in cardiac surgery due to its ability to inhibit plasmin and reduce perioperative bleeding. Since we have seen that aprotinin inhibits proteolysis of pleiotrophin by plasmin, the aim of the present study was to evaluate the possible role of pleiotrophin in the effects of aprotinin on angiogenesis and human endothelial cell migration. Our data demonstrate that aprotinin, in a concentration-dependent manner, is angiogenic in the chicken embryo chorioallantoic membrane assay in vivo and induces human endothelial cell migration in vitro. Aprotinin inhibits pleiotrophin proteolysis and induces expression and secretion of pleiotrophin through an AP-1-dependent transcriptional activation of the pleiotrophin gene, and pleiotrophin seems to mediate the stimulatory effects of aprotinin on cell migration through its receptor protein tyrosine phosphatase beta/zeta. The stimulatory effect of aprotinin on pleiotrophin expression and cell migration may explain, at least partly, the problems observed with the clinical use of aprotinin.
Koutsioumpa
Marina
M
Department of Pharmacy, Laboratory of Molecular Pharmacology, University of Patras, Patras, Greece.
Hatziapostolou
Maria
M
Mikelis
Constantinos
C
Koolwijk
Pieter
P
Papadimitriou
Evangelia
E
D000818:Animals; D007611:Aprotinin / Q000494:pharmacology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011480:Protease Inhibitors / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
D002352:Carrier Proteins; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D011480:Protease Inhibitors; D018808:Transcription Factor AP-1; C066845:pleiotrophin; D007611:Aprotinin; D017027:Protein Tyrosine Phosphatases