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首页> 外文期刊>American Journal of Physiology >Defects in cGMP-PKG pathway contribute to impaired NO-dependent responses in hepatic stellate cells upon activation.
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Defects in cGMP-PKG pathway contribute to impaired NO-dependent responses in hepatic stellate cells upon activation.

机译：激活后，肝星状细胞中cGMP-PKG途径的缺陷会导致NO依赖性反应受损。

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摘要

NO antagonizes hepatic stellate cell (HSC) contraction, although activated HSC in cirrhosis demonstrate impaired responses to NO. Decreased NO responses in activated HSC and mechanisms by which NO affects activated HSC remain incompletely understood. In normal rat HSC, the NO donor diethylamine NONOate (DEAN) significantly increased cGMP production and reduced serum-induced contraction by 25%. The guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) abolished 50% of DEAN effects, whereas the cGMP analog 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP) reiterated half the observed DEAN response, suggesting both cGMP-dependent protein kinase G (PKG)-dependent and -independent mechanisms of NO-mediated antagonism of normal HSC contraction. However, NO donors did not increase cGMP production from in vivo activated HSC from bile duct-ligated rats and showed alterations in intracellular Ca(2+) accumulation suggesting defective cGMP-dependent effector pathways. The LX-2 cell line also demonstrated lack of cGMP generation in response to NO and a lack of effect of ODQ and 8-BrcGMP in modulating the NO response. However, cGMP-independent effects in response to NO were maintained in LX-2 and were associated with S-nitrosylation of proteins, an effect reiterated in primary HSC. Adenovirus-based overexpression of PKG significantly attenuated contraction of LX-2 by 25% in response to 8-BrcGMP. In summary, these studies demonstrate that NO affects HSC through cGMP-dependent and -independent pathways. The HSC activation process is associated with maintenance of cGMP-independent actions of NO but defects in cGMP-PKG-dependent NO signaling that are improved by PKG gene delivery in LX-2 cells. Activating targets downstream from NO-cGMP in activated HSC may represent a novel therapeutic target for portal hypertension.
机译：NO拮抗肝星状细胞（HSC）的收缩，尽管肝硬化中激活的HSC表现出对NO的反应受损。激活的HSC中NO应答减少以及NO影响激活的HSC的机制仍不完全清楚。在正常大鼠HSC中，NO供体二乙胺NONOate（DEAN）显着增加了cGMP的产生，并将血清诱导的收缩降低了25％。鸟苷酸环化酶（sGC）抑制剂1H- [1,2,4]恶二唑-[4,3-a]喹喔啉-1-酮（ODQ）消除了50％的DEAN效应，而cGMP类似物8-溴鸟苷3'， 5'-环一磷酸酯（8-BrcGMP）重申了所观察到的DEAN反应的一半，表明cGMP依赖性蛋白激酶G（PKG）依赖性和非NO介导的HSC正常收缩拮抗机制均如此。但是，没有捐助者没有增加胆管结扎大鼠体内激活HSC的cGMP产生，并显示胞内Ca（2+）积累的变化，表明cGMP依赖的效应子途径有缺陷。 LX-2细胞系还显示出对NO的响应缺乏cGMP生成，并且在调节NO响应方面也缺乏ODQ和8-BrcGMP的作用。然而，在LX-2中，对NO的cGMP依赖性效应得以维持，并与蛋白质的S-亚硝基化有关，这一效应在原代HSC中得到了重申。基于腺病毒的PKG过表达，可显着降低LX-2的收缩25％，以响应8-BrcGMP。总之，这些研究表明，NO通过cGMP依赖性和非依赖性途径影响HSC。 HSC活化过程与NO的cGMP非依赖性作用的维持有关，但LX-2细胞中PKG基因的递送改善了cGMP-PKG依赖性NO信号的缺陷。在激活的HSC中，激活NO-cGMP下游的靶标可能代表门脉高压的新治疗靶标。

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