A Protective Role for Heme Oxygenase Expression in Pancreatic Islets Exposed to Interleukin-1 

Abstract

Heme oxygenase (HO)-1 expression was investigated in rat isolated pancreatic islets. Freshly isolated islets showed no evidence of HO-1 expression. After a 20-h culture, there was a small increase in HO-1 in control islets, and interleukin-1beta (IL-1beta) induced HO-1 expression above control levels. N(G)-monomethyl-L-arginine inhibited the IL-1beta-induced increase in HO-1. Sodium nitroprusside-generated nitric oxide also increased HO-1 expression. CoCl2 induced a concentration- and time-dependent increase in HO-1, but not heat shock protein 70, expression. Cobalt chloride (CoCl2) protected islets from the inhibitory effects of IL-1beta on glucose-stimulated insulin release and glucose oxidation. Nickel chloride did not mimic the effects of CoCl2. An inhibitor of HO-1 activity, zinc-protoporphyrin IX (ZnPP), prevented the protective effect of CoCl2 on insulin release with IL-1beta but did not affect HO-1 expression or the inhibitory response to IL-1beta alone. ZnPP also inhibited the protective effect of hemin in IL-1beta-treated islets. CoCl2 inhibited the marked increase in islet nitrite production in response to IL-1beta. Cobalt-protoporphyrin IX (CoPP), which increased HO expression and activity, also protected islets from the inhibitory effects of IL-1beta, even though IL-1beta largely blocked the CoPP-induced increase in HO-1 expression. In betaHC9 cells, CoCl2 increased HO-1 expression and HO activity, whereas CoPP directly activated HO. ZnPP inhibited basal and CoCl2-stimulated HO activity. Thus, increased HO-1 expression and/or HO activity in response to CoCl2, CoPP, and hemin, seems to mediate protective responses of pancreatic islets against IL-1beta. HO-1 may be protective of beta-cells because of the scavenging of free heme, the antioxidant effects of the end-product bilirubin, or the generation of carbon monoxide, which might have insulin secretion-promoting effects and inhibitory effects on nitric oxide synthase.

Haem oxygenase augments porcine granulosa cell apoptosis in vitro

“…However, the proportion of apoptotic cells was not altered by treatment with haemin in weakly associated PGCs. Because haemin and ZnPP IX were used previously as, respectively, a haem oxygenase substrate and a haem oxygenase inhibitor, to investigate the effect of haem oxygenase on various phenomena in many organs (Eyssen-Hernandez et al 1996, Ye & Laychock 1998, Duckers et al 2001, Alexandreanu & Lawson 2003, we used both compounds in this study. Although high concentrations of ZnPP IX decrease both haem oxygenase and NOS activities, it had been reported previously that, in concentrations lower than 1 µM, it was able to inhibit haem oxygenase activity but did not affect NOS activity (Appleton et al 1999).…”

“…In murine fibroblasts, HO-1 shows a protective role against cell apoptosis induced by serum deprivation, by reducing intracellular iron concentrations (Ferris et al 1999). Furthermore, in rat cultured pancreatic islets, haem oxygenase provides a protective role against the actions of IL--induced NO, which induces cell apoptosis and inhibits insulin release (Ye & Laychock 1998). Conversely, adenovirus-mediated transfer of HO-1 stimulates apoptosis in rat vascular smooth muscle cells through bilirubin, a product of the catalysis of haem by haem oxygenase (Liu et al 2000).…”

“…In rat cultured pancreatic islets, it provides a protective role against the actions of IL-1 that induce cell apoptosis and inhibit insulin release (Ye & Laychock 1998). In rat adrenals, treatment with tin protoporphyrin IX (SnPP IX), a haem oxygenase inhibitor, attenuates serum corticosterone concentrations by inhibiting the activities of both microsomal 21 -hydroxylase and mitochondrial 11 -hydroxylase (Maines & Trakshel 1992).…”

Heme Oxygenase-1 Is a cGMP-Inducible Endothelial Protein and Mediates the Cytoprotective Action of Nitric Oxide

“…18,19 In addition to its general anti-inflammatory function, 20 HO-1 specifically prevents chronic rejection or arteriosclerosis of transplants, according to recent investigations, 21,22 and enhances the resistance of pancreatic islet cells to cytokine-mediated injury. 23 Moreover, the first human case of HO-1 deficiency, which has been reported to be due to a genetic disorder, shows severe persistent endothelial damage and increased tissue vulnerability to oxidant injury besides growth retardation and anemia. 24 Although induction of HO-1 by NO has been reported in endothelial and vascular smooth muscle cells, the underlying signaling pathway, particularly with regard to a possible participation of cGMP, is unclear.…”

Cytokine- or chemically derived nitric oxide alters the expression of proteins detected by two-dimensional gel electrophoresis in neonatal rat islets of Langerhans.

“…This inhibitory effect of IL-1␤ on protein synthesis is reproduced by exposure of cells to NO donors (6) and is eliminated using the arginine analog NMMA (6,32). In rat islets, IL-1␤ has been shown to increase the expression of proteins such as iNOS (14)(15)(16), heat shock protein (HSP) 70 (33)(34)(35)(36), manganese superoxide dismutase (MnSOD) (36), and heme oxygenase (34,36,37). Upregulation of expression of some of these proteins by IL-1␤ may be ␤-cell specific (36,38,39) and has recently been confirmed to occur in fluorescence-activated cell sorter (FACS)-purified rat ␤-cells (40).…”