Carbon Monoxide Protects Pancreatic β-Cells From Apoptosis and Improves Islet Function/Survival After Transplantation

Abstract

Pancreatic islets transplanted to treat autoimmune type 1 diabetes often fail to function (primary nonfunction), likely because of islet ␤-cell apoptosis. We show that carbon monoxide (CO), a product of heme oxygenase activity, protects ␤-cells from apoptosis. Protection is mediated through guanylate cyclase activation, generation of cyclic GMP (cGMP), and activation of cGMPdependent protein kinases. This antiapoptotic effect is still observed when ␤-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. Diabetes 51:994 -999, 2002

Adeno-Associated Virus-Mediated IL-10 Gene Therapy Inhibits Diabetes Recurrence in Syngeneic Islet Cell Transplantation of NOD Mice

“…CO, a product of the HO-1-catalyzed enzymatic reaction, is thought to be the major mediator of these actions and can in return increase LPS-induced expression of IL-10 in macrophages (39). It has also recently been shown that HO-1 and CO protected pancreatic ␤-cells from apoptosis and improved islet function/survival after transplantation (22,40). A direct relationship between IL-10 and SOD has not been reported, but a number of studies have implicated the involvement of SOD in IL-10 -mediated protection.…”

Carbon Monoxide Protects Against Cardiac Ischemia—Reperfusion Injury In Vivo via MAPK and Akt—eNOS Pathways

“…According to other studies about the tissue protective role of CO, the most efficacious concentration of CO ranges from Ϸ250 ppm to 1000 ppm. [12][13][14]16,17 The most beneficial concentration of CO may be specific for each species and each tissue. We cannot extrapolate the most efficacious condition of CO administration for the treatment of myocardial infarction in human beings from our data alone.…”

“…HOderived CO reduces vasoconstriction, thus lowering blood pressure and increasing tissue blood flow. 10,11 Exogenous CO was reported to reduce ischemia-reperfusion injury of lung and apoptosis of pancreatic ␤ cells via activating soluble guanylate cyclase, 12,13 and to reduce hepatic ischemia-reperfusion injury, apoptosis of endothelial cells, and inflammation through p38 mitogen-activated protein kinase (p38MAPK) pathway. 14 -16 Motterlini et al reported that CO-releasing molecules could reduce the cardiac muscle damage induced by ischemia-reperfusion via activation of mitochondrial K ATP channel in an ex vivo model; 17 however, the precise mechanism of tissue protection by CO is still controversial.…”

Nuclear Factor-κB Regulates β-Cell Death

“…Assays were performed using a modified crystal violet method (23,24). Briefly, ␤-insulinoma (␤-TC 3 ) cells were pretreated (30 min) with 0.01 mol/l actinomycin D (Calbiochem, Kilsyth, Australia) before the addition of 100, 500, or 1000 units/ml of recombinant mouse tumor necrosis factor (TNF)-␣ (R&D Systems, Minneapolis, MN).…”