Lipophilic but not hydrophilic statin functionally inhibit volume-activated chloride channels by inhibiting NADPH oxidase in monocytes.
Lipophilic but not hydrophilic statin functionally inhibit volume-activated chloride channels by inhibiting NADPH oxidase in monocytes.
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DOI：
10.1016/j.bbrc.2016.11.007
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发表时间：
2016-12
影响因子：
3.1
通讯作者：
Zhi-jie Fu;Xue-Zhen Zhong;Wei-hong Ma;Wen-dong Zhang;Cheng-Yao Shi
中科院分区：
文献类型：
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作者：
Zhi-jie Fu;Xue-Zhen Zhong;Wei-hong Ma;Wen-dong Zhang;Cheng-Yao Shi
容量激活的 Cl−通道 (VACC) 可以被低渗溶液激活，并且已在许多细胞类型中得到鉴定。在这里，我们研究了不同他汀类药物对单核细胞 VACC 的影响。全细胞膜片钳记录表明，低渗溶液会在人外周单核细胞和 RAW 264.7 细胞中诱导 5-硝基-2-（3-苯基丙氨基）苯甲酸 (NPPB)- 和 4,4'-二异硫氰酸芪-2, 2'-二磺酸 (DIDS) 敏感的 VACC 电流。 VACC电流被亲脂性他汀类药物（辛伐他汀）抑制，但不被亲水性辛伐他汀酸和普伐他汀抑制。低分子量超氧阴离子清除剂（钛试剂，1 mM）和 NADPH 氧化酶抑制剂（DPI 10 μM）能够消除 VACC 电流。低渗溶液增加了二氯二氢荧光素 (DCF) 荧光检测到的活性氧 (ROS)，而钛试剂和 DPI 则消除了活性氧 (ROS)。 NPPB、DIDS 和辛伐他汀降低 DCF 的荧光，但普伐他汀不降低。当用 Tiron 或 DPI 预处理时，辛伐他汀不能进一步降低 VACC 电流，而外源性 H2O2（100 μM）则增加了 VACC 电流并克服了辛伐他汀对 VACC 电流的阻断。从功能上讲，低渗溶液增加了 TNF-α mRNA 的表达，而提隆、DPI、NPPB、DIDS 和辛伐他汀可以降低 TNF-α mRNA 的表达，但普伐他汀则不能。然而，当用替隆、DPI、NPPB或DIDS预处理时，辛伐他汀不能进一步降低TNF-α的表达。我们得出的结论是，亲脂性（辛伐他汀）而不是亲水性他汀可以抑制 VACC，并通过抑制 NADPH 氧化酶来减少单核细胞中低渗透压诱导的炎症。
Volume-activated Cl−channels (VACCs) can be activated by hypotonic solutions and have been identified in many cell types. Here, we investigated the effects of different statins on VACCs in monocytes. Whole-cell patch clamp recordings demonstrated that a hypotonic solution induced 5-nitro-2- (3-phenylpropylamino) benzoic acid (NPPB)- and 4,4′-diisothiocyanatostilbene-2, 2′-disulfonic acid (DIDS)-sensitive VACC currents in human peripheral monocytes and RAW 264.7 cells. The VACC currents were inhibited by the lipophilic statin (simvastatin) but not by the hydrophilic simvastatin acid and pravastatin. A low-molecular-weight superoxide anion scavenger (tiron, 1 mM) and inhibitor of NADPH oxidase (DPI 10 μM) was able to abolish the VACC currents. A hypotonic solution increased the reactive oxygen species (ROS) detected by the fluorescence of dichlorodihydrofluorescein (DCF), which was abolished by tiron and DPI. NPPB, DIDS, and simvastatin but not pravastatin decreased the fluorescence of DCF. Simvastatin could not further decrease VACC currents when pretreated with tiron or DPI, whereas exogenous H2O2(100 μM), increased the VACC currents and overcame the blockade of VACC currents by simvastatin. Functionally, hypotonic solution increased the TNF-α mRNA expression, which could be decreased by tiron, DPI, NPPB, DIDS and simvastatin but not pravastatin. However, simvastatin could not decrease the TNF-α expression further when pretreatment with tiron, DPI, NPPB or DIDS. We conclude that lipophilic (simvastatin) rather than hydrophilic statin inhibit VACCs and decrease hyposmolality induced inflammation in monocytes by inhibiting NADPH oxidase.