title: IGF-I-induced VEGF expression in HUVEC involves phosphorylation and inhibition of poly(ADP-ribose)polymerase.
abstract: Insulin-like growth factor-I (IGF-I) has been shown to promote angiogenesis by enhancing vascular endothelial growth factor (VEGF) expression. However, how IGF-I-induces VEGF expression is not yet fully understood. With this investigation, we propose a new possible mechanism involving downregulation of poly(ADP-ribosyl)ation (pADPR). We first demonstrated that IGF-I increased VEGF protein expression in endothelial cells. Inhibitors of mitogen activated kinase (PD 98059), phosphatidyl-3-inositol-kinase (LY 294002), and protein kinase C (staurosporine) diminished the IGF-I effect suggesting the involvement of signal transduction. Since there is an established link between pADPR and transcriptional activity, we focused on a possible role of poly(ADP-ribose)polymerase (PARP). The inhibition of PARP by 3-aminobenzamide or nicotinamide enhanced VEGF expression. Additionally, IGF-I markedly decreased PARP activity. Furthermore, the IGF-I-mediated inhibition of PARP could be demonstrated as a result of protein phosphorylation since phosphorylation of PARP decreased its activity in vitro and IGF-I treatment of endothelial cells induced PARP phosphorylation. The IGF-I-mediated phosphorylation and inhibition of PARP represent a novel mechanism of VEGF protein expression.
authors.affiliation: Department of Surgery, School of Medicine, University of California, San Francisco, 94123, USA. stefan.beckert@med.uni-tuebingen.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Beckert
authors.forename: Farshid
authors.initials: F
authors.lastname: Farrahi
authors.forename: Q
authors.initials: Q
authors.lastname: Perveen Ghani
authors.forename: Rummana
authors.initials: R
authors.lastname: Aslam
authors.forename: Heinz
authors.initials: H
authors.lastname: Scheuenstuhl
authors.forename: Stephan
authors.initials: S
authors.lastname: Coerper
authors.forename: Alfred
authors.initials: A
authors.lastname: Königsrainer
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Hunt
authors.forename: M Zamirul
authors.initials: MZ
authors.lastname: Hussain
mesh_terms: D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage*; D010766:Phosphorylation / Q000187:drug effects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D007334:Insulin-Like Growth Factor I; D011065:Poly(ADP-ribose) Polymerases