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Blood, 1 June 2004, Vol. 103, No. 11, pp. 4180-4187.
Prepublished online as a Blood First Edition Paper on February 24, 2004; DOI 10.1182/blood-2003-06-2144.
Submitted June 27, 2003
Accepted February 9, 2004
RGDS peptide induces caspase 8 and caspase 9 activation in human endothelial cells
Maria Simona Aguzzi, Claudia Giampietri, Francesco De Marchis, Fabrizio Padula, Roberto Gaeta, Gianluca Ragone, Maurizio C Capogrossi, and Antonio Facchiano*
Lab. Patologia Vascolare, Istituto Dermopatico della Immacolata, IDI, Rome, Italy
Dip. Istologia ed Embriologia Medica, University La Sapienza, Rome, Italy
Divisione di Cardiochirurgia, IRCCS San Matteo, Pavia, Italy; Cattedra di Cardiochirurgia, University of Messina, Messina, Italy
Laboratorio Oncogenesi Molecolare, Istituto Dermopatico della Immacolata, IDI, Rome, Italy
* Corresponding author; email: a.facchiano{at}idi.it.
Peptides containing the RGD-motif inhibit cell adhesion and exhibit a variety of other biological effects including anti-coagulant and anti-metastatic activities. The aim of the present study was to examine the anchorage-independent effects of an RGD-containing peptide (RGDS) on human umbilical vein endothelial cells (HUVEC). Assays were performed on HUVEC seeded onto collagen IV; under these experimental conditions RGDS did not exert anti-adhesive effects but significantly reduced FGF-2-dependent chemotaxis after 4 h treatment and reduced proliferation after 24 h treatment. Experiments carried out with caspase-specific inhibitors indicated that the observed anti-chemotactic effects required caspase 8 and caspase 9 activation. RGDS activated both caspase 8 and caspase 9 after 4 h treatment and caspase 3 after 24 h treatment, and markedly enhanced HUVEC apoptosis by TUNEL/Hoechst staining and FACS analysis. Finally, confocal microscopy showed that RGDS localizes in the cytoplasm of live HUVEC within 4 h and in vitro experiments showed that RGDS directly interacts with recombinant caspases 8 and 9 in a specific way. In summary, these results indicate that RGDS directly binds and activates caspases 8 and 9, inhibits chemotaxis and induces apoptosis of HUVEC with a mechanism independent from its anti-adhesive effect.
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