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

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.

MicroRNA‐29b‐3p reduces intestinal ischaemia/reperfusion injury via targeting of TNF receptor‐associated factor 3

“…As mentioned above, apoptosis and inflammation are important mechanisms associated with II/R injury. TUNEL staining is one major method to detect cell apoptosis, and pro‐inflammatory factors including IL‐1β, IL‐6, and TNF‐α can reflect inflammatory response (Y. Li, Wen, et al, ; Y. Li, Xu, et al, ; Zu, Zhou, Che, & Zhang, ). In this study, our results showed that the numbers of apoptotic cells and the mRNA levels of IL‐1β, IL‐6, and TNF‐α were significantly increased after 4 hr of hypoxia and 120 min of reoxygenation in IEC‐6 cells and ischaemia for 45 min and reperfusion for 90 min in mice compared with control group or sham group, which were reduced with the prolongation of reoxygenation or reperfusion time compared with 120 min of reoxygenation in vitro or reperfusion for 90 min in vivo.…”

“…Previous studies have shown that miRNAs can control the pathological process of II/R injury (Y. Hu et al, ; Z. Li et al, ; Y. Li, Wen, et al, ; Y. Li, Xu, et al, ). In addition, some miRNAs including miR‐375 and miR‐371 have been confirmed as the markers for clinical diagnosis and treatment of diseases (Piano et al, ; Salvatori et al, ).…”

“…Excessive ROS can cause cell apoptosis, destroy intestinal epithelial homeostasis, and induce cell death (Filpa et al, ). Many groups have shown that cell apoptosis is one major mode of cell death caused by II/R (Ikeda et al, ; Y. Li, Wen, et al, ; Y. Li, Xu, et al, ; Wen et al, ), and uncontrolled inflammatory response is an important mechanism to cause SIRS. Thus, exploration of drug targets in inhibiting inflammation and apoptosis is very important to mitigate II/R injury.…”

“…MicroRNAs (miRNAs) are important endogenous regulators leading to RNA degradation and/or inhibition of protein synthesis (He et al, ; Y. Hu et al, ; Z. Liu et al, ). Recent studies have shown that some miRNAs including miR‐378, miR‐351‐5P, and miR‐665‐3p play important roles in regulating II/R injury (Y. Hu et al, ; Z. Li et al, ; Y. Li, Wen, et al, ; Y. Li, Xu, et al, ). MiR‐378 can protect against II/R injury via inhibiting intestinal mucosal cell apoptosis (Y. Li, Wen, et al, ; Y. Li, Xu, et al, ).…”

“…Recent studies have shown that some miRNAs including miR‐378, miR‐351‐5P, and miR‐665‐3p play important roles in regulating II/R injury (Y. Hu et al, ; Z. Li et al, ; Y. Li, Wen, et al, ; Y. Li, Xu, et al, ). MiR‐378 can protect against II/R injury via inhibiting intestinal mucosal cell apoptosis (Y. Li, Wen, et al, ; Y. Li, Xu, et al, ). Inhibition of miR‐351‐5p can alleviate II/R‐induced intestinal oxidative stress, inflammation, and apoptosis via targeting MAPK13 and sirtuin‐6 (Y. Hu et al, ).…”