Signaling by eNOS through a superoxide-dependent p42/44 mitogen-activated protein kinase pathway.
Signaling by eNOS through a superoxide-dependent p42/44 mitogen-activated protein kinase pathway.
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eNOS 通过超氧化物依赖性 p42/44 丝裂原激活蛋白激酶途径发出信号。
DOI：
10.1152/ajpcell.2001.281.2.c544
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
Danner,RL
中科院分区：
文献类型：
--
作者：
Wang,W;Wang,S;Nishanian,EV;DelPilarCintron,A;Wesley,RA;Danner,RL
Expression of endothelial nitric oxide synthase (eNOS) in transfected U-937 cells upregulates phorbol 12-myristate 13-acetate (PMA)-induced tumor necrosis factor-α (TNF-α) production through a superoxide (O)-dependent mechanism. Because mitogen-activated protein kinases (MAPK) have been shown to participate in both reactive oxygen species signaling and TNF-α regulation, their possible role in eNOS-derived Osignal transduction was examined. A redox-cycling agent, phenazine methosulfate, was found to both upregulate TNF-α (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. AlthoughS-nitroso-N-acetylpenicillamine, a nitric oxide (NO) donor, also increased TNF-α production, NO exposure led to phosphorylation of p38 MAPK, not p42/44 MAPK. Upregulation of TNF-α 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-α upregulation by eNOS, also abolished the effects on p42/44 MAPK. Expression of Gln361eNOS, a mutant that produces Obut 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-α upregulation by eNOS (P= 0.02). Thus Oproduced by eNOS increases TNF-α production via a mechanism that involves p42/44 MAPK activation.
