title: Tirofiban induces VEGF production and stimulates migration and proliferation of endothelial cells.
abstract: Tirofiban is a fibrinogen receptor antagonist, generated using the tripeptide Arg-Gly-Asp (RGD) as a template. RGD activates integrin receptors and integrin-mediated signals are necessary for normal cells to promote survival and stimulate cell cycle progression. We investigated whether tirofiban activated growth-stimulatory signals in endothelium. For this study human umbilical vein endothelial cells (HUVEC) and human aortic endothelial cells (HAEC) were used. Analysis of cell proliferation, by cell counts, showed that the number of endothelial cells doubled after 72 h of culture in the absence of tirofiban, while they were tripled and even quadrupled, in the presence of increasing doses of the drug. Moreover, tirofiban-stimulated cells had a greater ability to migrate through the transwell filters of Boyden chamber, compared to unstimulated cells. The scratch assay, which mimics cell migration during wound healing, showed that tirofiban stimulated HUVECs to migrate into the leading hedge of the scratch. Western blot showed that tirofiban increased the expression levels of VEGF and the downstream effectors Erk and cyclin D. An inhibitor of VEGFR2 counteracted tirofiban-induced-proliferation, suggesting a role for VEGF in such effect. Our study shows that tirofiban stimulates the migration and proliferation of endothelial cells suggesting that it can promote endothelial repair. Ex vivo cultures of arterial rings confirmed the growth stimulatory effect of tirofiban on endothelium. Thus, the benefits of tirofiban in those with acute coronary syndromes undergoing PTCA may be due to rapid endothelization of damaged vessel, besides antiplatelet effects.
authors.affiliation: Invasive Cardiology Unit, Pineta Grande Hospital, Castelvolturno, Italy.
authors.forename: Arturo
authors.initials: A
authors.lastname: Giordano
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: D'Angelillo
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Romano
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: D'Arrigo
authors.affiliation: Invasive Cardiology Unit, Pineta Grande Hospital, Castelvolturno, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Corcione
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Bisogni
authors.affiliation: Invasive Cardiology Unit, Pineta Grande Hospital, Castelvolturno, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Messina
authors.affiliation: Invasive Cardiology Unit, Pineta Grande Hospital, Castelvolturno, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Polimeno
authors.affiliation: Cardiovascular Surgery, Pineta Grande Hospital, Castelvolturno, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pepino
authors.affiliation: Invasive Cardiology Unit, Pineta Grande Hospital, Castelvolturno, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ferraro
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy. Electronic address: mariafiammetta.romano@unina.it.
authors.forename: Maria Fiammetta
authors.initials: MF
authors.lastname: Romano
mesh_terms: D001011:Aorta / Q000166:cytology / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D005343:Fibrinolytic Agents; D042461:Vascular Endothelial Growth Factor A; D014443:Tyrosine; D000077466:Tirofiban
keywords: Endothelial; GPIIb/IIIa; Migration; Proliferation