Abstract
Hyperglycemia significantly stimulates pancreatic islet endothelial cell apoptosis; however, the precise mechanisms are not fully understood. In the present study, treating pancreatic islet endothelial (MS-1) cells with high glucose (30mmol/l) but not mannitol significantly increased the number of apoptotic cells as compared with a physiological glucose concentration (5.5mmol/l). Hyperglycemia significantly stimulated the expression of inducible nitric oxide synthase (iNOS) and production of NO and peroxynitrite (ONOO(-)), relevant to MS-1 cell apoptosis. Moreover, induced reactive nitrogen species (RNS) significantly increased the expression of bax, cleaved caspase-3 and poly adenosine diphosphate (ADP)-ribose polymerase (PARP) via JNK activation, but the expression of bcl-2 was not altered. Furthermore, SP600125 (a specific inhibitor of JNK) and 1400W (a specific inhibitor of iNOS) significantly attenuated cell apoptosis induced by high glucose. Therefore, hyperglycemia triggers MS-1 cell apoptosis by activating an intrinsic-dependent apoptotic pathway via RNS-mediated JNK activation.
Copyright © 2011 Elsevier B.V. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amidines / pharmacology
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Animals
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Anthracenes / pharmacology
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Apoptosis / drug effects*
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Benzylamines / pharmacology
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Blotting, Western
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Caspase 3 / metabolism
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Cell Line
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Dose-Response Relationship, Drug
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Endothelial Cells / drug effects*
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Endothelial Cells / metabolism
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Glucose / pharmacology*
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Immunohistochemistry
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Islets of Langerhans / cytology
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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JNK Mitogen-Activated Protein Kinases / metabolism*
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Mice
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Mice, Inbred C57BL
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Models, Biological
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Nitric Oxide / metabolism
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Nitric Oxide Synthase Type II / antagonists & inhibitors
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Nitric Oxide Synthase Type II / metabolism
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Peroxynitrous Acid / metabolism
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Poly(ADP-ribose) Polymerases / metabolism
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Reactive Nitrogen Species / metabolism*
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bcl-2-Associated X Protein / metabolism
Substances
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Amidines
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Anthracenes
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Bax protein, mouse
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Benzylamines
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Enzyme Inhibitors
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N-(3-(aminomethyl)benzyl)acetamidine
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Reactive Nitrogen Species
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bcl-2-Associated X Protein
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Peroxynitrous Acid
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pyrazolanthrone
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Nitric Oxide
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Nitric Oxide Synthase Type II
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Poly(ADP-ribose) Polymerases
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JNK Mitogen-Activated Protein Kinases
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Caspase 3
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Glucose