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Comprehensive circRNA expression profile during ischemic postconditioning attenuating hepatic ischemia/reperfusion injury.

ABSTRACT: Ischemic postconditioning (IPO) attenuates hepatic ischemia/reperfusion (I/R) injury. The aim of this study was to explore the role of circular RNAs (circRNAs) in the protective mechanism of IPO. In this study, microarray hybridization analysis was performed to determine the circRNA expression profile. Briefly, a total of 1599 dysregulated circRNAs were detected. The competitive endogenous RNA (ceRNA) network, including 6 circRNAs, 47 miRNAs and 90 mRNAs, indicated that the potential "housekeeping" function of circRNAs is dysregulated in hepatic I/R injury. Based on the validation results of selected circRNAs, miRNAs and mRNAs following qRT-PCR amplification, the mmu_circRNA_005186-miR-124-3p-Epha2 pathway was constructed. Dual-luciferase reporter analysis showed that miR-124-3p interacted directly with mmu_circRNA_005186 and Epha2 through the predicted binding sites, which suggested that mmu_circRNA_005186, serving as a miRNA sponge for miR-124-3p, regulated the expression of Epha2. Functionally, we explored the mechanism of mmu_circRNA_005186 in LPS-treated RAW264.7 cells which simulated the inflammation in hepatic I/R injury. We found that mmu_circRNA_005186 silencing attenuated the LPS-induced inflammation and was associated with miR-124-3p upregulation and Epha2 downregulation. Our study is the first to show that circRNAs are closely related to hepatic I/R injury and IPO and suggests that targeting mmu_circRNA_005186-miR-124-3p-Epha2 pathway might attenuate hepatic I/R injury.

SUBMITTER: Zhang P

PROVIDER: S-EPMC6342922 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Ischemic postconditioning (IPoC) has been demonstrated to prevent myocardial ischemia?reperfusion injury (MIRI), but its cardioprotective effect is abrogated by hypercholesterolemia. The aim of the present study was to determine whether lycopene (LP), a type of carotenoid, can restore the cardioprotective effect of IPoC in hypercholesterolemic rats. Male Wistar rats were fed a cholesterol?enriched diet for 12 weeks to establish a hypercholesterolemic model. The rat hearts were isolated and subjected to 30 min ischemia and 60 min reperfusion using a Langendorff apparatus. LP was administered to the rats intraperitoneally for 5 consecutive days prior to ischemia and reperfusion. Myocardial pathological changes, infarct size and cell apoptosis were measured by hematoxylin and eosin, triphenyltetrazolium chloride and TUNEL staining, respectively. The changes in endoplasmic reticulum (ER) stress markers, the reperfusion injury salvage kinase (RISK) pathway and mitochondrial apoptosis?related proteins were detected by western blotting. Overall, the results demonstrated that low?dose LP in combination with IPoC ameliorated myocardial histopathological changes, reduced the infarct size and release of cardiac enzymes, and decreased cardiomyocyte apoptosis in hypercholesterolemic rats, but no beneficial effects were achieved by the same dose of LP or IPoC treatment were used alone. Furthermore, the combination of LP and IPoC inhibited the expression of glucose?regulated protein 78 and C/EBP homologous protein, increased the phosphorylation levels of AKT, ERK1/2 and glycogen synthase kinase?3?, repressed mitochondrial permeability transition pore opening, and reduced the expression of cytochrome c, cleaved caspase?9 and cleaved caspase?3. Collectively, these findings demonstrated that LP can restore the cardioprotective effects of IPoC on MIRI in hypercholesterolemic rats, and this restoration by LP was mediated by inhibition of ER stress and reactivation of the RISK pathway in hypercholesterolemic rat myocardium.

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Comprehensive circRNA expression profile during ischemic postconditioning attenuating hepatic ischemia/reperfusion injury.

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