NO-mediated activation of heme oxygenase: Endogenous cytoprotection against oxidative stress to endothelium
NO-mediated activation of heme oxygenase: Endogenous cytoprotection against oxidative stress to endothelium
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DOI：
10.1152/ajpheart.1996.270.1.h107
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发表时间：
1996-01-01
影响因子：
4.8
通讯作者：
Winslow, RM
中科院分区：
文献类型：
--
作者：
Motterlini, R;Foresti, R;Winslow, RM
我们研究了一氧化氮（NO）对应激蛋白血红素氧合酶的诱导及其在血管内皮细胞暴露于过氧化氢中的保护作用的影响。用NO释放化合物（0.1-1 mM）硝普钠（SNP）、S-亚硝基-N-乙酰青霉胺（SNAP）和3-吗啉代壬亚胺（SIN-1）处理猪主动脉内皮细胞6 h导致血红素加氧酶活性的浓度依赖性增加。在1 mM时，血红素加氧酶的活性与对照值相比，SNP增加了8.5倍，SNAP增加了5.8倍，SIN-1增加了5.7倍。相比之下，内皮细胞暴露于100 μ M 8-溴鸟苷3 '，5'-环一磷酸，一种组织渗透性类似物，模仿鸟苷3 '，5'-环一磷酸的行动，没有表现出血红素加氧酶活性的任何变化。通过细菌脂多糖（250 ng/ml）和干扰素-γ（100 U/ml）的协同作用激活诱导型NO合酶也使内皮血红素加氧酶活性增加3.2倍（P < 0.05 vs对照）。亚甲基蓝（1 μ M），一氧化氮合酶和鸟苷酸环化酶活性的抑制剂，完全消除了这种影响。预先暴露于SNAP和SIN-1的细胞表现出对过氧化氢（250 μ M）介导的细胞毒性的显著保护（P < 0.05）。相反，SNP没有表现出任何保护作用，可能是因为在其化学分解过程中释放了催化铁。事实上，铁螯合剂去铁胺（5 mM）完全抑制了SNP介导的细胞毒性，并部分减弱了血红素加氧酶的活性，使其达到与SIN-1和SNAP介导的水平相同的水平。这些结果表明，NO是一个决定因素，在血红素加氧酶的活性的调制，导致一个主要的抗氧化应激的内皮细胞。
We investigated the effect of nitric oxide (NO) on the induction of the stress protein heme oxygenase and its protective role in vascular endothelial cells exposed to hydrogen peroxide. Treatment of porcine aortic endothelial cells for 6 h with the NO-releasing compounds (0.1-1 mM) sodium nitroprusside (SNP), S-nitroso-N-acetylpenicillamine (SNAP), and 3-morpholinosydnonimine (SIN-1) resulted in a concentration-dependent increase in heme oxygenase activity. At 1 mM, the activity of heme oxygenase was augmented 8.5-fold with SNP, 5.8-fold with SNAP, and 5.7-fold with SIN-1 over the control value. In contrast, endothelial cells exposed to 100 mu M 8-bromoguanosine 3',5'-cyclic monophosphate, a tissue-permeable analogue that mimics the action of guanosine 3',5'-cyclic monophosphate, did not show any change in heme oxygenase activity. Activation of the inducible NO synthase by the synergistic action of bacterial lipopolysaccharide (250 ng/ml) and interferon-gamma (100 U/ml) also increased endothelial heme oxygenase activity by 3.2-fold (P < 0.05 vs control). Methylene blue (1 mu M), an inhibitor of both NO synthase and guanylate cyclase activities, completely abolished this effect. Cells previously exposed to SNAP and SIN-1 exhibited a significant protection against the cytotoxicity mediated by hydrogen peroxide (250 mu M) (P < 0.05). Conversely, SNP did not show any protective effects, possibly because of catalytic iron released during its chemical decomposition. In fact, the iron chelator deferoxamine (5 mM) completely suppressed the SNP-mediated cytotoxicity and partially attenuated the activity of heme oxygenase to a level equal to that mediated by SIN-1 and SNAP. These results indicate that NO is a determinant in the modulation of the activity of heme oxygenase leading to a major resistance of the endothelium to oxidative stress.