Carbon Monoxide Protects Pancreatic β-Cells From Apoptosis and Improves Islet Function/Survival After Transplantation
- Lukas Günther1,
- Pascal O. Berberat1,
- Manabu Haga1,
- Sophie Brouard3,
- R. Neal Smith2,
- Miguel P. Soares1,
- Fritz H. Bach1 and
- Edda Tobiasch1
- 1Immunobiology Research Center, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
- 2Immunopathology Unit, Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
- 3INSERM U437, ITERT, Nantes, France
Abstract
Pancreatic islets transplanted to treat autoimmune type 1 diabetes often fail to function (primary nonfunction), likely because of islet β-cell apoptosis. We show that carbon monoxide (CO), a product of heme oxygenase activity, protects β-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 β-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.
Footnotes
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Address correspondence and reprint requests to Fritz H. Bach, Immunobiology Research Center, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115. E-mail: fritzhbach{at}aol.com.
Received for publication 18 December 2001 and accepted in revised form 8 January 2002.
F.H.B. is the Lewis Thomas Professor of Surgery at Harvard Medical School and is a paid consultant for Novartis Pharma.
8-Br–cGMP, 5′-cyclic-monophosphate–cyclic GMP; cGK, cyclic GMP–dependent protein kinase; CHX, cycloheximide; cGMP, cyclic guanine monophosphate; HO-1, heme oxygenase-1; IL, interleukin; ODQ, 1H[1,2,4]oxadiazolo[4,3-α]quinoxalin-1; SnPPIX, tin protoporphyrin IX; TNF-α, tumor necrosis factor-α.
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