MicroRNA-351-5p aggravates intestinal ischaemia/reperfusion injury through the targeting of MAPK13 and Sirtuin-6

被引:32
作者
Hu, Yupeng [1 ]
Tao, Xufeng [1 ]
Han, Xu [1 ]
Xu, Lina [1 ]
Yin, Lianhong [1 ]
Sun, Huijun [1 ]
Qi, Yan [1 ]
Xu, Youwei [1 ]
Peng, Jinyong [1 ]
机构
[1] Dalian Med Univ, Coll Pharm, Dalian, Peoples R China
关键词
ISCHEMIA-REPERFUSION INJURY; NF-KAPPA-B; INFLAMMATORY RESPONSES; PROTEIN-KINASE; CONCISE GUIDE; LUNG INJURY; P38; MAPK; OVEREXPRESSION; APOPTOSIS; INHIBITION;
D O I
10.1111/bph.14428
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
BACKGROUND AND PURPOSE Intestinal ischaemia-reperfusion (II/R) injury is a serious clinical problem. Here we have investigated novel mechanisms and new drug targets in II/R injury by searching for microRNAs regulating such injury. EXPERIMENTAL APPROACH We used hypoxia/reoxygenation (H/R) of IEC-6 cell cultures and models of II/R models in rats and mice. Microarray assays were used to identify target miRNAs from rat intestinal. Real-time PCR, Western blot and dual luciferase reporter assays, and agomir and antagomir in vitro and in vivo were used to assess the effects of the target miRNA on II/R injury. KEY RESULTS The miR-351-5p was differentially expressed in our models and it targeted MAPK13 and sirtuin-6. This miRNA reduced levels of sirtuin-6 and AMP-activated protein kinase phosphorylation, and activated forkhead box O3 (FoxO3 alpha) phosphorylation to cause oxidative stress. Also, miR-351-5p markedly reduced MAPK13 level, activated polycystic kidney disease 1/NF-kappa B signal and increased NF-kappa B (p65). Moreover, miR-351-5p up-regulated levels of Bcl2-associated X, cytochrome c, apoptotic peptidase activating factor 1, cleaved-caspase 3 and cleaved-caspase 9 by reducing sirtuin-6 levels to promote apoptosis. In addition, miR-351-5p mimic in IEC-6 cells and agomir in mice aggravated these effects, and miR-351-5p inhibitor and antagomir in mice alleviated these actions. CONCLUSIONS AND IMPLICATIONS Our data showed that miR-351-5p aggravated II/R injury by promoting intestinal mucosal oxidative stress, inflammation and apoptosis by targeting MAPK13 and sirtuin-6. These data provide new insights into the mechanisms regulating II/R injury, and of miR-351-5p could be considered as a novel therapeutic target for such injury.
引用
收藏
页码:3594 / 3609
页数:16
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