MicroRNA-378 protects against intestinal ischemia/reperfusion injury via a mechanism involving the inhibition of intestinal mucosal cell apoptosis

Yunsheng Li,Jing Tang,Kexuan Liu,Xi Yao,Jiantong Shen,Weifeng Liu,Cai Li,Shihong Wen,Wentao Deng

doi:10.1038/cddis.2017.508

Abstract

Intestinal ischemia/reperfusion (I/R) injury remains a major clinical event and contributes to high morbidity and mortality rates, but the underlying mechanisms remain elusive. Recent studies have demonstrated that microRNAs (miRNAs) have important roles in organ I/R injury, but the changes and potential roles of miRNAs in intestinal I/R-induced intestinal injury are unclear. This study was designed to analyze the miRNA expression profiles in intestinal mucosa after I/R injury and to explore the role of target miRNA during this process. Using miRNA microarray analysis, we found changes of 19 miRNAs from the expression profile of miRNAs in a mouse model of intestinal I/R and further verified them by RT-qPCR. Here, we report that miR-378 is one of the markedly decreased miRNAs and found the putative target mRNA that is linked to cell death after applying the TargetScan, miRanda, CLIP-Seq and miRDB prediction algorithms. Our results show that the overexpression of miR-378 significantly ameliorated intestinal tissue damage in wild-type and transgenic mice and oxygen glucose deprivation/reperfusion-challenged IEC-6 cell injury. Moreover, miR-378 overexpression reduced intestinal epithelial cell apoptosis in both in vivo and in vitro ischemic models and attenuated cleaved caspase-3 expression. Collectively, our results revealed that the suppression of caspase-3 activation by miRNA-378 overexpression may be involved in the protective effects of intestinal ischemic damage. MiRNA-378 may serve as a key regulator and therapeutic target in intestinal I/R injury.

Highlights

Intestinal ischemia/reperfusion (I/R) injury is a potentially serious consequence of acute mesenteric ischemia, hemorrhagic, traumatic or septic shock, severe burns or some surgical procedures, including small bowel transplantation and aortic aneurysm repair.[1]
Representative intestine sections (n = 8 per group) revealed that 60 min of ischemia and 120 min of reperfusion caused significant intestinal mucosal damage that was primarily manifested as severe edema of the mucosal villi, infiltration of inflammatory cells and increased gaps between epithelial cells
MiR-378 is one of these markedly decreased miRNAs and was found to be the putative target messenger RNAs (mRNAs) linked to cell death based on the application of the TargetScan, miRanda, CLIP-Seq and miRDB prediction algorithms

Summary

Introduction

Intestinal ischemia/reperfusion (I/R) injury is a potentially serious consequence of acute mesenteric ischemia, hemorrhagic, traumatic or septic shock, severe burns or some surgical procedures, including small bowel transplantation and aortic aneurysm repair.[1]. The factors contributing to intestinal I/R injury were complex, including microvascular dysfunction,[3] reactive oxygen species over-production,[4,5] inflammation[6,7] and even intestinal epithelial cell death. Through imperfect sequence-specific binding to the 3’-untranslated region (UTR) of target messenger RNAs (mRNAs), miRNAs downregulate gene expression by degrading target mRNAs and/or inhibiting protein synthesis.[16,17] it has been found to be crucial for the development and maintenance of physiological homeostasis, but have been causally implicated in tissue injury and repair.[18,19,20] Recent studies showed that characteristic changes of miRNAs have important roles in cardiac,[21] cerebral,[22] renal[23] I/R injury, which are associated with cell apoptosis, oxidative stress and inflammation. We aimed to analyze miRNAs expression profiles in intestinal mucosa

Objectives

Methods

Results

Conclusion