Hyperglycemia Induces Apoptosis of Human Pancreatic Islet Endothelial Cells : Effects of Pravastatin on the Akt Survival Pathway
| Autor: | Favaro, E, Miceli, I, Bussolati, Benedetta, Schimitt Ney, M, CAVALLO PERIN, Paolo, Camussi, Giovanni, Zanone, M. M. |
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| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Caspase 3
Cell Survival Microcirculation Diabetes Interleukin-1beta Endothelial Cells Membrane Proteins Nitric Oxide Synthase Type II Apoptosis Nitric Oxide Islets of Langerhans Phosphatidylinositol 3-Kinases Glucose Hyperglycemia Humans Endothelium Vascular Hydroxymethylglutaryl-CoA Reductase Inhibitors Phosphorylation Proto-Oncogene Proteins c-akt Cells Cultured Regular Articles Pravastatin Signal Transduction |
| Popis: | 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, P0.05). In parallel, apoptosis progressively increased from 7% after 2 days to 79% after 30 days in high glucose (P0.05) 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. |
| Databáze: | OpenAIRE |
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