The ghrelin gene products and exendin-4 promote survival of human pancreatic islet endothelial cells in hyperglycaemic conditions, through phosphoinositide 3-kinase/Akt, extracellular signal-related kinase (ERK)1/2 and cAMP/protein kinase A (PKA) signalling pathways

• DOI: 10.1007/s00125-011-2423-y
• Publication Date: 2012-01-09T15:49:01Z
• Authors: E. Favaro; R. Granata; I. Miceli; A. Baragli; F. Settanni; P. Cavallo Perin; E. Ghigo; G. Camussi; M. M. Zanone
• Keywords: 0301 basic medicine; Cell Survival; Endocrinology, Diabetes and Metabolism; Apoptosis; Article; Islets of Langerhans; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Internal Medicine; Cyclic AMP; Humans; Phosphorylation; Akt; cAMP; Endothelial cells; ERK1/2; Exendin-4; Ghrelin; Hyperglycaemia; Obestatin; Pancreatic islets of Langerhans; VEGF; Extracellular Signal-Regulated MAP Kinases; Receptors, Ghrelin; Cells, Cultured; Cell Proliferation; Caspase 3; Endothelial Cells; Cyclic AMP-Dependent Protein Kinases; Ghrelin; Glucose; Exenatide; Peptides; Proto-Oncogene Proteins c-akt; Signal Transduction

Pancreatic islet microendothelium exhibits unique features in interdependent relationship with beta cells. Gastrointestinal products of the ghrelin gene, acylated (AG), unacylated (UAG) and obestatin (Ob), incretin, glucagon-like peptide-1 (GLP-1), prevent apoptosis pancreatic We investigated whether gene GLP-1 receptor agonist exendin-4 (Ex-4) display survival effects human microendothelial cells (MECs) exposed to chronic hyperglycaemia. Islet MECs were cultured high glucose concentration treated AG, UAG, Ob or Ex-4. Apoptosis was assessed by DNA fragmentation, Hoechst staining nuclei caspase-3 activity. Western blot analyses pharmacological inhibition protein kinase B (Akt) extracellular signal-related (ERK)1/2 pathways, detection intracellular cAMP levels blockade adenylyl cyclase (AC)/cAMP/protein A (PKA) signalling performed. Levels NO, IL-1β vascular endothelial growth factor (VEGF)-A cell culture supernatant fractions measured. express GHS-R1A as well GLP-1R. Treatment Ex-4 promoted significantly inhibited glucose-induced apoptosis, through activation PI3K/Akt, ERK1/2 phosphorylation increase. Moreover, peptides upregulated lymphoma 2 (BCL-2) downregulated BCL-2-associated X (BAX) CD40 ligand (CD40L) production, reduced secretion VEGF-A. The gene-derived exert cytoprotective MECs. anti-apoptotic involve phosphoinositide 3-kinase (PI3K)/Akt, cAMP/PKA pathways. These could therefore represent a potential tool improve vascularisation and, indirectly, function.