Carbon monoxide protects pancreatic beta-cells from apoptosis and improves islet function/survival after transplantation.
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.
Günther
Lukas
L
Immunobiology Research Center, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
Berberat
Pascal O
PO
Haga
Manabu
M
Brouard
Sophie
S
Smith
R Neal
RN
Soares
Miguel P
MP
Bach
Fritz H
FH
Tobiasch
Edda
E
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002248:Carbon Monoxide / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation; D004789:Enzyme Activation / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects*; D006162:Guanylate Cyclase / Q000378:metabolism; D007340:Insulinoma; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000473:pathology / Q000502:physiology*; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000494:pharmacology; D010190:Pancreatic Neoplasms; D011994:Recombinant Proteins / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; D005047:Etoposide; D002248:Carbon Monoxide; D003513:Cycloheximide; D006162:Guanylate Cyclase