Abstract
Intestinal ischemia/reperfusion (I/R) can lead to tissue damage associated with inflammation and mucosal apoptosis. Ischemic postconditioning (IPostC), a series of repeated, brief, intermittent periods of ischemia and reperfusion, has beneficial effects against I/R-induced injury in the heart and intestine, although the underlying mechanisms for these effects remain unclear. We evaluated the involvement of microRNA-21 (miR-21) in the protective effects of IPostC in a rat model of I/R induced by superior mesenteric artery occlusion and reopening. IPostC decreased I/R injury and suppressed apoptosis in the intestinal tissues concomitant with the induction of hypoxia inducible factor 1 alpha (HIF-1α) and the upregulation of miR-21. In vitro experiments in the intestinal epithelial cell line IEC-6 showed that hypoxia induced miR-21 and this effect was abolished by silencing HIF1-α, confirming the induction of miR-21 by HIF1-α, HIF1-α or miR-21 inhibition exacerbated I/R induced apoptosis, and programmed cell death 4 (PDCD4) and Fas-L was involved in miR-21 mediated anti-apoptotic effects on intestinal epithelial cells. Knockdown of miR-21 or inhibition of HIF1-α abolished the IPostC-mediated attenuation of intestinal injury and apoptosis and the downregulation of PDCD4 and Fas-L. A potential mechanism underlying the protective effect of IPostC may therefore involve the induction of miR-21 by HIF1-α and the attenuation of apoptosis via the downregulation of PDCD4 and Fas-L.
Highlights
Several microRNAs have been implicated in the regulation of I/R injury6. miR-21 is upregulated by Ischemic postconditioning (IPostC) and has a protective effect against I/R injury in the heart through target programmed cell death 4 (PDCD4)[10]
We examined the involvement of HIF-1α and miR-21 in the progression of intestinal I/R in a rat model and explored the molecular mechanisms underlying the protective effects of IPostC after intestinal I/R
Quantification of apoptosis demonstrated an approximately 7.5-fold increase in the apoptotic index in the I/R group compared with the index in the sham group (31.3 ± 3.3% vs 4.3 ± 0.7%; P < 0.01), with a decrease in the IPostC group
Summary
Several microRNAs (miRNAs) have been implicated in the regulation of I/R injury6. miR-21 is upregulated by IPostC and has a protective effect against I/R injury in the heart through target programmed cell death 4 (PDCD4)[10]. MiR-21 is upregulated by IPostC and has a protective effect against I/R injury in the heart through target programmed cell death 4 (PDCD4)[10]. MiR-21 has been shown to be upregulated by IPostC in the myocardium, alleviating I/R-induced cardiomyocyte apoptosis through www.nature.com/scientificreports/. The expression of HIF-1α was significantly increased in the ischemic intestinal mucosa[15]. Little is known as to how the role of HIF-1α and miR-21 in IPostC protects against intestinal ischemia/reperfusion injury. We examined the involvement of HIF-1α and miR-21 in the progression of intestinal I/R in a rat model and explored the molecular mechanisms underlying the protective effects of IPostC after intestinal I/R
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