Ye J, Laychock S G
Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, the State University of New York, Buffalo 14214, USA.
Endocrinology. 1998 Oct;139(10):4155-63. doi: 10.1210/endo.139.10.6244.
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.
在大鼠分离的胰岛中研究了血红素加氧酶（HO）-1的表达。新鲜分离的胰岛未显示HO-1表达的证据。培养20小时后，对照胰岛中的HO-1有少量增加，白细胞介素-1β（IL-1β）诱导HO-1表达高于对照水平。N（G）-单甲基-L-精氨酸抑制IL-1β诱导的HO-1增加。硝普钠产生的一氧化氮也增加了HO-1表达。氯化钴（CoCl2）诱导HO-1表达呈浓度和时间依赖性增加，但对热休克蛋白70的表达无此作用。氯化钴（CoCl2）保护胰岛免受IL-1β对葡萄糖刺激的胰岛素释放和葡萄糖氧化的抑制作用。氯化镍不能模拟CoCl2的作用。HO-1活性抑制剂锌原卟啉IX（ZnPP）可阻止CoCl2对IL-1β诱导的胰岛素释放的保护作用，但不影响HO-1表达或对单独IL-1β的抑制反应。ZnPP也抑制血红素对IL-1β处理的胰岛的保护作用。CoCl2抑制胰岛对IL-1β反应中亚硝酸盐生成的显著增加。增加HO表达和活性的钴原卟啉IX（CoPP）也保护胰岛免受IL-1β的抑制作用，尽管IL-1β在很大程度上阻断了CoPP诱导的HO-1表达增加。在βHC9细胞中，CoCl2增加HO-1表达和HO活性，而CoPP直接激活HO。ZnPP抑制基础和CoCl2刺激的HO活性。因此，响应CoCl2、CoPP和血红素而增加的HO-1表达和/或HO活性似乎介导了胰岛对IL-1β的保护反应。HO-1可能对β细胞具有保护作用，这是因为其可清除游离血红素、终产物胆红素的抗氧化作用，或一氧化碳的生成，一氧化碳可能具有促进胰岛素分泌和抑制一氧化氮合酶的作用。
