title: Hyperglycemia induces apoptosis of human pancreatic islet endothelial cells: effects of pravastatin on the Akt survival pathway.
abstract: Pancreatic islet microendothelium and beta cells exhibit an interdependent physical and functional relationship. In this study, we analyzed the effect of chronic hyperglycemia on human pancreatic islet microendothelial cells as well as the involvement of the phosphatidylinositol 3-kinase/Akt and nephrin pathways, interleukin-1beta, and nitric oxide production. In addition, whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors can reverse the response to high-glucose conditions was investigated. Proliferation of purified islet microendothelial cells cultured under hyperglycemic conditions (28 mmol/L glucose) decreased compared to that of normoglycemic cells (from 12.7% after 2 days to 47.7% after 30 days, P < 0.05). In parallel, apoptosis progressively increased from 7% after 2 days to 79% after 30 days in high glucose (P < 0.05) concomitant with an early increase of caspase-3 activity. Intermittent hyperglycemia induced greater apoptosis than sustained hyperglycemia. Apoptosis was accompanied by a reduced p-Akt/Akt ratio and inhibition of nephrin tyrosine phosphorylation. Pravastatin (1 mumol/L) decreased apoptosis induced by high glucose or oxidized LDL and increased Akt phosphorylation. Hyperglycemia significantly increased the production of the proinflammatory cytokine interleukin-1beta and stimulated the expression of inducible nitric oxide synthase and the production of nitric oxide, possibly relevant to beta cell mass and function. Thus, chronic hyperglycemia reduces islet microendothelial cell survival by inhibiting the serine-threonine kinase Akt pathway, and the effect of pravastatin on this pathway represents a potential tool to improve islet vascularization and, indirectly, islet function.
authors.affiliation: Department of Internal Medicine, University of Torino, Torino, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Favaro
authors.forename: Ilaria
authors.initials: I
authors.lastname: Miceli
authors.forename: Benedetta
authors.initials: B
authors.lastname: Bussolati
authors.forename: Michel
authors.initials: M
authors.lastname: Schmitt-Ney
authors.forename: Michel
authors.initials: M
authors.lastname: Schimitt-Ney
authors.forename: Paolo
authors.initials: P
authors.lastname: Cavallo Perin
authors.forename: Giovanni
authors.initials: G
authors.lastname: Camussi
authors.forename: Maria M
authors.initials: MM
authors.lastname: Zanone
mesh_terms: D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D005947:Glucose / Q000502:physiology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006943:Hyperglycemia / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D007515:Islets of Langerhans / Q000098:blood supply*; D008565:Membrane Proteins / Q000378:metabolism; D008833:Microcirculation; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation; D017035:Pravastatin / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053583:Interleukin-1beta; D008565:Membrane Proteins; C113267:nephrin; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D005947:Glucose; D017035:Pravastatin