Abstract
Pancreatic islets transplanted to treat autoimmune type 1 diabetes often fail to function (primary nonfunction), likely because of islet beta-cell apoptosis. We show that carbon monoxide (CO), a product of heme oxygenase activity, protects beta-cells from apoptosis. Protection is mediated through guanylate cyclase activation, generation of cyclic GMP (cGMP), and activation of cGMP-dependent protein kinases. This antiapoptotic effect is still observed when beta-cells are exposed to CO for 1 h before the apoptotic stimulus. In a similar manner, mouse islets exposed to CO for just 2 h function significantly better after transplantation than islets not exposed to CO. These findings suggest a potential therapeutic application for CO in improving islet function/survival after transplantation in humans.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects*
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Carbon Monoxide / pharmacology*
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Cell Survival / drug effects
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Cycloheximide / pharmacology
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Cysteine Proteinase Inhibitors / pharmacology
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DNA Fragmentation
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Enzyme Activation / drug effects
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Etoposide / pharmacology
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Graft Survival / drug effects*
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Guanylate Cyclase / metabolism
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Insulinoma
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Islets of Langerhans / cytology*
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Islets of Langerhans / drug effects
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Islets of Langerhans / metabolism
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Islets of Langerhans Transplantation / pathology
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Islets of Langerhans Transplantation / physiology*
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Kinetics
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Male
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Mice
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Mice, Inbred C57BL
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Oligopeptides / pharmacology
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Pancreatic Neoplasms
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Recombinant Proteins / pharmacology
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Transfection
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Cysteine Proteinase Inhibitors
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Oligopeptides
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Recombinant Proteins
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Tumor Necrosis Factor-alpha
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benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone
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Etoposide
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Carbon Monoxide
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Cycloheximide
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Guanylate Cyclase