Journal
BIOCHEMICAL PHARMACOLOGY
Volume 197, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2021.114839
Keywords
Intestinal ischemia-reperfusion; Autophagy; miR-146a-5p; TXNIP; PRKAA; mTOR
Categories
Funding
- National Natural Science Foundation of China [81950345]
- Natural Science Foundation of Gansu Province [21JR1RA069]
- Educational Technology Inno-vation Project of Gansu Province [2021CXZX-045]
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This study highlights the role of miR-146a-5p in regulating autophagy by targeting TXNIP and suggests that miR-146a-5p may be a novel drug target for intestinal I/R therapy.
Autophagy is being increasingly recognized as an important regulator of intestinal ischemia-reperfusion(I/R) injury, but its exact role is still debated. Emerging evidence suggests that miR-146a-5p is involved in the initiation and development of I/R injury, but its role in intestinal I/R injury remains unclear. The present study generated an intestinal I/R mouse model and an oxygen glucose deprivation/reoxygenation (OGD/R) Caco-2 cell model and found that autophagy was increased and contributed to the intestinal injury and cell death induced by I/R and OGD/R. In addition, in both I/R and OGD/R models, the miR-146a-5p expression level was decreased and accompanied by an increase in TXNIP expression. By transfecting cells with an miR-146a-5p inhibitor or mimic, we observed that miR-146a-5p inhibits autophagy during OGD/R by targeting TXNIP; this was confirmed by the dual luciferase reporter gene assay. Additionally, through overexpression and knockdown cell lines, we established that TXNIP regulates autophagy during intestinal I/R via the PRKAA/mTOR pathway. The interaction between TXNIP and p-PRKAA was verified by immunofluorescence co-localization and immunoprecipitation assays. Moreover, we confirmed that TXNIP is indispensable for miR-146a-5p-mediated cell protection. Finally, we observed that miR-146a-5p overexpression inhibits autophagy and attenuates intestinal I/R injury via the PRKAA/mTOR pathway by targeting TXNIP in vivo. In conclusion, this study highlights the role of miR-146a-5p in regulating autophagy by targeting TXNIP, suggesting that miR-146a-5p may be a novel drug target for intestinal I/R therapy.
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