CLIC1 Inhibition Attenuates Vascular Inflammation, Oxidative Stress, and Endothelial Injury.
CLIC1 Inhibition Attenuates Vascular Inflammation, Oxidative Stress, and Endothelial Injury.
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CLIC1 抑制可减轻血管炎症、氧化应激和内皮损伤
DOI：
10.1371/journal.pone.0166790
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Zong L
中科院分区：
文献类型：
--
作者：
Xu Y;Zhu J;Hu X;Wang C;Lu D;Gong C;Yang J;Zong L
内皮功能障碍包括内皮氧化损伤和血管炎症，是动脉粥样硬化（AS）发病的关键起始步骤，也是该疾病的独立危险因素。细胞内氯离子通道1 （CLIC1）是一种新的变质蛋白，作为细胞氧化的传感器并参与炎症反应。在本研究中，我们假设CLIC1在AS中起重要作用。载脂蛋白e缺乏小鼠给予正常饮食或高脂肪高胆固醇饮食8周。过表达的CLIC1与动脉粥样硬化斑块的加速发展、氧化应激的放大和体内炎症细胞因子的释放有关。我们随后通过体外实验检查了潜在的分子机制。H2O2处理培养的人脐静脉内皮细胞（HUVECs）诱导内皮细胞氧化损伤并增强CLIC1表达。通过基因敲除（CLIC1−/−）或使用特异性抑制剂indanyloxyacetic acid-94 （iaaa94）抑制CLIC1的表达可减少ROS的产生，提高SOD酶活性，并显著降低MDA水平。在蛋白水平上，CLIC1−/−HUVECs的TNF-α和IL-1β以及ICAM-1和VCAM-1的表达显著降低。H2O2促进CLIC1向细胞膜转移并插入脂质膜，而IAA94抑制H2O2诱导的CLIC1膜易位。相比之下，在正常HUVECs中，大多数CLIC1没有聚集在细胞膜上，这一发现与细胞质氯离子浓度的变化是一致的。本研究首次证实了体外和体内AS发育过程中CLIC1的过表达，并能调节炎症细胞因子的积累和氧化应激的产生。我们的研究结果还强调，内皮功能的失调可能与内皮细胞中CLIC1的膜易位和活性氯选择离子通道有关。
Endothelial dysfunction, which includes endothelial oxidative damage and vascular inflammation, is a key initiating step in the pathogenesis of atherosclerosis (AS) and an independent risk factor for this disorder. Intracellular chloride channel 1 (CLIC1), a novel metamorphic protein, acts as a sensor of cell oxidation and is involved in inflammation. In this study, we hypothesize that CLIC1 plays an important role in AS. Apolipoprotein E-deficient mice were supplied with a normal diet or a high-fat and high-cholesterol diet for 8 weeks. Overexpressed CLIC1 was associated with the accelerated atherosclerotic plaque development, amplified oxidative stress, and in vivo release of inflammatory cytokines. We subsequently examined the underlying molecular mechanisms through in vitro experiments. Treatment of cultured human umbilical vein endothelial cells (HUVECs) with H2O2 induced endothelial oxidative damage and enhanced CLIC1 expression. Suppressing CLIC1 expression through gene knocked-out (CLIC1−/−) or using the specific inhibitor indanyloxyacetic acid-94 (IAA94) reduced ROS production, increased SOD enzyme activity, and significantly decreased MDA level. CLIC1−/− HUVECs exhibited significantly reduced expression of TNF-α and IL-1β as well as ICAM-1 and VCAM-1 at the protein levels. In addition, H2O2 promoted CLIC1 translocation to the cell membrane and insertion into lipid membranes, whereas IAA94 inhibited CLIC1 membrane translocation induced by H2O2. By contrast, the majority of CLIC1 did not aggregate on the cell membrane in normal HUVECs, and this finding is consistent with the changes in cytoplasmic chloride ion concentration. This study demonstrates for the first time that CLIC1 is overexpressed during AS development both in vitro and in vivo and can regulate the accumulation of inflammatory cytokines and production of oxidative stress. Our results also highlight that deregulation of endothelial functions may be associated with the membrane translocation of CLIC1 and active chloride-selective ion channels in endothelial cells.
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影响因子：
--
作者：
Goodchild, Sophia C;Curmi, Paul M G;Brown, Louise J
通讯作者：
Brown, Louise J
影响因子：
3.4
作者：
Chen, Chi-De;Wang, Chia-Siu;Lin, Kwang-Huei
通讯作者：
Lin, Kwang-Huei
影响因子：
9.5
作者：
Kaelsch, Thorsten;Elmas, Elif;Dempfle, Carl-Erik
通讯作者：
Dempfle, Carl-Erik
影响因子：
2.4
作者：
Kim S;Ma L;Unruh J;McKinney S;Yu CR
通讯作者：
Yu CR
DOI：
10.1161/01.atv.13.2.197
发表时间：
1993-02-01
期刊：
ARTERIOSCLEROSIS AND THROMBOSIS
影响因子：
--
作者：
LI, H;CYBULSKY, MI;LIBBY, P
通讯作者：
LIBBY, P