Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent.
Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent.
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DOI：
10.1002/hep.25938
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发表时间：
2012-12
期刊：
影响因子：
13.5
通讯作者：
Brenner, David A.
中科院分区：
文献类型：
--
作者：
Aoyama, Tomonori;Paik, Yong-Han;Watanabe, Sumio;Laleu, Benoit;Gaggini, Francesca;Fioraso-Cartier, Laetitia;Molango, Sophie;Heitz, Freddy;Merlot, Cedric;Szyndralewiez, Cedric;Page, Patrick;Brenner, David A.
NADPH氧化酶（NOX）在肝纤维化过程中在肝星状细胞（HSCs）中产生活性氧物质（ROS）。对促纤维化激动剂，如血管紧张素II（Ang II）作出反应时，NOX1成分形成一种包含Rac1的活性复合物。超氧化物歧化酶1（SOD1）与NOX - Rac1复合物相互作用以刺激NOX活性。在活化的肝星状细胞/肌成纤维细胞中，NOX4也因基因表达增加而被诱导。在此，我们研究增强活性的SOD1 G37R突变体（SODmu）的作用以及双重NOX1/4抑制剂GKT137831对肝星状细胞和肝纤维化的影响。
为诱导肝纤维化，野生型（WT）和SOD1mu小鼠用四氯化碳（CCl₄）或胆管结扎（BDL）进行处理。然后，为了阐明NOX - SOD1介导的ROS产生在肝星状细胞活化和肝纤维化中的作用，用一种NOX1/4抑制剂处理小鼠。通过组织学以及硫代巴比妥酸反应物（TBARS）和NOX相关基因的测量来评估纤维化和ROS产生。对从野生型、SODmu和NOX1敲除（KO）小鼠中分离出的原代培养肝星状细胞进行ROS产生、Rac1活性和NOX基因表达的评估。
SOD1mu小鼠的肝纤维化增加，并且SOD1mu肝星状细胞中的ROS产生和Rac1活性增加。NOX1/4抑制剂GKT137831减轻了SOD1mu和野生型小鼠的肝纤维化以及ROS产生，还降低了纤维化和NOX基因的mRNA表达。用GKT137831处理抑制了SOD1mu和野生型肝星状细胞中的ROS产生以及NOX和纤维化基因表达，但不抑制Rac1活性。血管紧张素II和转化生长因子β都上调NOX4，但血管紧张素II需要NOX1。
SOD1mu通过肝星状细胞中的Rac1诱导NOX1过度活化，导致NOX4上调增强、ROS产生以及肝纤维化。针对NOX1/4的治疗可能是肝纤维化的一种新疗法。
NADPH oxidase (NOX) generates reactive oxygen species (ROS) in hepatic stellate cells (HSCs) during liver fibrosis. In response to fibrogenic agonists, such as angiotensin II (Ang II), the NOX1 components form an active complex including Rac1. Superoxide dismutase 1 (SOD1) interacts with the NOX-Rac1 complex to stimulate NOX activity. NOX4 is also induced in activated HSCs/myofibroblast by increased gene expression. Here, we investigate the role of an enhanced activity SOD1 G37R mutation (SODmu) and the effects of GKT137831, a dual NOX1/4 inhibitor, on HSCs and liver fibrosis. To induce liver fibrosis, wild-type (WT) and SOD1mu mice were treated with carbon tetrachloride (CCl4) or bile duct ligation (BDL). Then, to address the role of NOX-SOD1-mediated ROS production in HSC activation and liver fibrosis, mice were treated with a NOX1/4 inhibitor. Fibrosis and ROS generation was assessed by histology and measurement of TBARS and NOX related genes. Primary cultured HSCs isolated from WT, SODmu, and NOX1 knock-out (KO) mice were assessed for ROS production, Rac1 activity, and NOX gene expression. Liver fibrosis was increased in SOD1mu mice, and ROS production and Rac1 activity were increased in SOD1mu HSCs. The NOX1/4 inhibitor GKT137831 attenuated liver fibrosis and ROS production in both SOD1mu and WT mice as well as mRNA expression of fibrotic and NOX genes. Treatment with GKT137831 suppressed ROS production and NOX and fibrotic gene expression, but not Rac1 activity, in SOD1mut and WT HSCs. Both Ang II and TGFb upregulated NOX4, but AngII required NOX1. SOD1mu induces excessive NOX1 activation through Rac1 in HSCs, causing enhanced NOX4 upregulation, ROS generation, and liver fibrosis. Treatment targeting NOX1/4 may be a new therapy for liver fibrosis.
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DOI：
10.1152/ajpgi.00162.2009
发表时间：
2009-10-01
影响因子：
4.5
作者：
Colmenero, Jordi;Bataller, Ramon;Gines, Pere
通讯作者：
Gines, Pere
DOI：
10.1111/j.1600-6143.2008.02463.x
发表时间：
2009-01
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Djamali A;Vidyasagar A;Adulla M;Hullett D;Reese S
通讯作者：
Reese S
影响因子：
25.7
作者：
Guimaraes, Eduardo L. M.;Empsen, Christophe;van Grunsven, Leo A.
通讯作者：
van Grunsven, Leo A.
影响因子：
13.5
作者：
Aoyama, Tomonori;Ikejima, Kenichi;Watanabe, Sumio
通讯作者：
Watanabe, Sumio
影响因子：
15.9
作者：
Bataller, R;Schwabe, RF;Brenner, DA
通讯作者：
Brenner, DA