title: CXC chemokine ligand 12 protects pancreatic β-cells from necrosis through Akt kinase-mediated modulation of poly(ADP-ribose) polymerase-1 activity.
abstract: The diabetes prevention paradigm envisages the application of strategies that support the maintenance of appropriate β-cell numbers. Herein we show that overexpression of CXC chemokine ligand12 (CXCL12) considerably improves the viability of isolated rat Langerhans islet cells and Rin-5F pancreatic β-cells after hydrogen peroxide treatment. In rat islets and wt cells hydrogen peroxide treatment induced necrotic cell death that was mediated by the rapid and extensive activation of poly(ADP-ribose) polymerase-1 (PARP-1). In contrast, CXCL12-overexpressing cells were protected from necrotic cell death as a result of significantly reduced PARP-1 activity. CXCL12 downstream signalling through Akt kinase was responsible for the reduction of PARP-1 activity which switched cell death from necrosis to apoptosis, providing increased protection to cells from oxidative stress. Our results offer a novel aspect of the CXCL12-mediated improvement of β-cell viability which is based on its antinecrotic action through modulation of PARP-1 activity.
authors.affiliation: Department of Molecular Biology, Institute for Biological Research, University of Belgrade, Belgrade, Serbia.
authors.forename: Nevena
authors.initials: N
authors.lastname: Grdović
authors.affiliation: Department of Molecular Biology, Institute for Biological Research, University of Belgrade, Belgrade, Serbia.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Dinić
authors.affiliation: Department of Molecular Biology, Institute for Biological Research, University of Belgrade, Belgrade, Serbia.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Mihailović
authors.affiliation: Department of Molecular Biology, Institute for Biological Research, University of Belgrade, Belgrade, Serbia.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Uskoković
authors.affiliation: Department of Molecular Biology, Institute for Biological Research, University of Belgrade, Belgrade, Serbia.
authors.forename: Jelena Arambašić
authors.initials: JA
authors.lastname: Jovanović
authors.affiliation: Department of Molecular Biology, Institute for Biological Research, University of Belgrade, Belgrade, Serbia.
authors.forename: Goran
authors.initials: G
authors.lastname: Poznanović
authors.affiliation: Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Wagner
authors.affiliation: Department of Molecular Biology, Institute for Biological Research, University of Belgrade, Belgrade, Serbia.
authors.forename: Melita
authors.initials: M
authors.lastname: Vidaković
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000009:adverse effects / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009336:Necrosis; D016877:Oxidants / Q000009:adverse effects / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: C575935:CXCL12 protein, rat; D054377:Chemokine CXCL12; D016877:Oxidants; D006861:Hydrogen Peroxide; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt