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首页> 外文期刊>American Journal of Physiology >Signaling by eNOS through a superoxide-dependent p42/44 mitogen-activated protein kinase pathway.
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Signaling by eNOS through a superoxide-dependent p42/44 mitogen-activated protein kinase pathway.

机译：eNOS通过超氧化物依赖的p42 / 44丝裂原激活的蛋白激酶途径进行信号传递。

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摘要

Expression of endothelial nitric oxide synthase (eNOS) in transfected U-937 cells upregulates phorbol 12-myristate 13-acetate (PMA)-induced tumor necrosis factor-alpha (TNF-alpha) production through a superoxide (O(2)(-))-dependent mechanism. Because mitogen-activated protein kinases (MAPK) have been shown to participate in both reactive oxygen species signaling and TNF-alpha regulation, their possible role in eNOS-derived O(2)(-) signal transduction was examined. A redox-cycling agent, phenazine methosulfate, was found to both upregulate TNF-alpha (5.8 +/- 1.0 fold; P 0.01) and increase the phosphorylation state of p42/44 MAPK (3.1 +/- 0.2 fold; P = 0.01) in PMA-differentiated U-937 cells. Although S-nitroso-N-acetylpenicillamine, a nitric oxide (NO) donor, also increased TNF-alpha production, NO exposure led to phosphorylation of p38 MAPK, not p42/44 MAPK. Upregulation of TNF-alpha production by eNOS transfection was associated with increases in activated p42/44 MAPK (P = 0.001), whereas levels of phosphorylated p38 MAPK were unaffected. Furthermore, cotransfection with Cu/Zn superoxide dismutase, which blocks TNF-alpha upregulation by eNOS, also abolished the effects on p42/44 MAPK. Expression of Gln(361)eNOS, a mutant that produces O(2)(-) but not NO, still resulted in p42/44 MAPK phosphorylation. In contrast, two NADPH binding site deletion mutants of eNOS that lack oxidase activity had no effect on p42/44 MAPK. Finally, PD-98059, a p42/44 MAPK pathway inhibitor, blocked TNF-alpha upregulation by eNOS (P = 0.02). Thus O(2)(-) produced by eNOS increases TNF-alpha production via a mechanism that involves p42/44 MAPK activation.
机译：内皮一氧化氮合酶（eNOS）在转染的U-937细胞中的表达上调了佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）诱导的肿瘤坏死因子-α（TNF-alpha）通过超氧化物的产生（O（2）（-） ）依赖机制。因为已显示有丝分裂原激活的蛋白激酶（MAPK）参与活性氧信号和TNF-α调节，所以检查了它们在eNOS衍生的O（2）（-）信号转导中的可能作用。发现氧化还原循环剂甲基硫酸吩嗪既上调TNF-α（5.8 +/- 1.0倍; P 0.01），又增加p42 / 44 MAPK的磷酸化状态（3.1 +/- 0.2倍; P = 0.01）在PMA分化的U-937细胞中。尽管一氧化氮（NO）供体S-亚硝基-N-乙酰青霉胺也增加了TNF-α的产生，但NO暴露导致p38 MAPK而不是p42 / 44 MAPK磷酸化。 eNOS转染导致的TNF-α产生上调与激活的p42 / 44 MAPK升高有关（P = 0.001），而磷酸化的p38 MAPK的水平不受影响。此外，与铜/锌超氧化物歧化酶的共转染（可阻止eNOS抑制TNF-α上调）也消除了对p42 / 44 MAPK的影响。 Gln（361）eNOS，产生O（2）（-）但不产生NO的突变体的表达仍然导致p42 / 44 MAPK磷酸化。相反，缺少氧化酶活性的eNOS的两个NADPH结合位点缺失突变体对p42 / 44 MAPK没有影响。最后，p-42 / 44 MAPK途径抑制剂PD-98059阻止了eNOS对TNF-α的上调作用（P = 0.02）。因此，eNOS产生的O（2）（-）通过涉及p42 / 44 MAPK激活的机制增加了TNF-α的产生。

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