title: Pharmacological inhibition of poly(ADP-ribose) polymerase activity down-regulates the expression of syndecan-4 and Id-1 in endothelial cells.
abstract: Poly(ADP-ribose) polymerase (PARP) is a family of nuclear proteins which regulate a number of cell functions, such as DNA repair, transcription, remodelling of chromatin structure, cell division and cell death. We and others have recently demonstrated that down-regulation of cellular PARP activity, using pharmacological inhibitors, impairs a number of endothelial functions and angiogenesis. In the present study, we investigated the potential mechanisms underlying the anti-angiogenic effect exerted by the potent PARP inhibitor GPI 15427, analyzing gene expression in human endothelial cells shortly after treatment with this compound. Analysis of gene and protein expression indicated that a 2-h exposure of human endothelial cells to GPI 15427 induced a rapid decrease of syndecan-4 (SDC-4), a transmembrane protein involved in modulation of cell signalling during angiogenesis that plays a role in endothelial cell migration and adhesion. Moreover, treatment with the PARP inhibitor induced a reduction of a helix-loop-helix transcription factor, the inhibitor of DNA binding-1 (Id-1), also implicated in the control of endothelial functions. We suggest that the inhibitory effect exerted by GPI 15427 on the angiogenic process is likely due to the reduced activity of specific transcription factors, such as Oct-1 and CREB that contribute to the regulation of SDC-4 and Id-1 expression, respectively. In conclusion, these results strongly suggest that PARP activity is capable of modulating molecules required for endothelial cell migration, adhesion, proliferation or differentiation during the angiogenic process.
authors.affiliation: Laboratory of Molecular Oncology, Istituto Dermopatico dell'Immacolata, 00167 Rome, Italy.
authors.forename: Pedro Miguel
authors.initials: PM
authors.lastname: Lacal
authors.forename: Lucio
authors.initials: L
authors.lastname: Tentori
authors.forename: Alessia
authors.initials: A
authors.lastname: Muzi
authors.forename: Federica
authors.initials: F
authors.lastname: Ruffini
authors.forename: Annalisa Susanna
authors.initials: AS
authors.lastname: Dorio
authors.forename: Weizheng
authors.initials: W
authors.lastname: Xu
authors.forename: Diego
authors.initials: D
authors.lastname: Arcelli
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Grazia
authors.initials: G
authors.lastname: Graziani
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000096:biosynthesis* / Q000235:genetics; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D053671:Syndecan-4 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D053671:Syndecan-4; D011065:Poly(ADP-ribose) Polymerases