Lipophilic but not hydrophilic statin functionally inhibit volume-activated chloride channels by inhibiting NADPH oxidase in monocytes.
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.
Department of Otorhinolaryngology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, China.
Zhi-Jie
ZJ
Fu
Department of Cardiovascular Disease, Jinan Central Hospital Affiliated to Shandong University, Shandong, Jinan 250013, China.
Xue-Zhen
XZ
Zhong
Department of Cardiology, The Second Hospital of Shandong University, Jinan 250033, China.
Wei-Hong
WH
Ma
Department of Pharmacy, QiLu Hospital, Shandong University, Jinan 250012, China. Electronic address: zhangwendong_ql@163.com.
Wen-Dong
WD
Zhang
Department of Pharmacy, QiLu Hospital, Shandong University, Jinan 250012, China.
Cheng-Yao
CY
Shi
D000818:Animals; D002478:Cells, Cultured; D018118:Chloride Channels / Q000187:drug effects* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D007038:Hypotonic Solutions / Q000737:chemistry; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008055:Lipids / Q000737:chemistry; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009997:Osmotic Pressure; D000067996:RAW 264.7 Cells; D019821:Simvastatin / Q000737:chemistry* / Q000494:pharmacology*
D018118:Chloride Channels; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007038:Hypotonic Solutions; D008055:Lipids; D019821:Simvastatin; D019255:NADPH Oxidases
Inflammation; Monocytes; Pravastatin; Reactive oxygen species; Simvastatin; Volume-activated chloride channel