It is well established that expression of heme oxygenase-1 (HO-1) acts in a cytoprotective manner in a variety of cell types, including in endothelial cells (EC). We have recently shown that HO-1 expression protects EC from undergoing apoptosis. We have also shown that the antiapoptotic effect of HO-1 is mediated through heme catabolism into the gas carbon monoxide (CO). In this review, we discuss the possible molecular mechanisms by which HO-1-derived CO suppresses EC apoptosis. We will review data suggesting that the antiapoptotic effect of CO acts through the activation of the p38 mitogen-activated protein kinase signal transduction pathway and requires the activation of the transcription factor nuclear factor-kappa B (NF-kappa B), as well as the expression of a subset of NF-kappa B-dependent antiapoptotic genes.

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

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