LncRNA FOXD3-AS1 aggravates myocardial ischemia/reperfusion injury by inactivating the Redd1/AKT/GSK3β/Nrf2 signaling pathway via the miR-128/TXNIP axis.

Long noncoding RNA forkhead box D3-antisense RNA 1 (FOXD3-AS1) is associated with cardiovascular diseases, but its roles in myocardial ischemia/reperfusion (I/R) injury and the related signaling pathway have not been fully reported. We aimed to investigate the roles and mechanism of action of FOXD3-AS1 in myocardial I/R injury. An in vivo myocardial I/R injury mouse model and an in vitro hypoxia/reoxygenation (H/R) cardiomyocyte model was established. Quantitative reverse transcription-polymerase chain reaction, western blotting, and immunofluorescent assays were performed to examine the expression levels of FOXD3-AS1, microRNA (miR)-128, thioredoxin-interacting protein/regulation of development and DNA damage response 1/protein kinase B/glycogen synthase kinase 3β/nuclear factor erythroid 2-related factor 2 (TXNIP/Redd1/AKT/GSK3β/Nrf2) pathway-related proteins and apoptosis-related proteins. The interactions between FOXD3-AS1 and miR-128 and miR-128 and TXNIP were analyzed by Spearman's correlation test, predicted by ENCORI, and verified by dual-luciferase reporter assay. In addition, the levels of cardiac injury markers and oxidative stress markers were evaluated by corresponding kits. Cell Counting Kit-8 assays and flow cytometry were performed to assess cell viability and apoptosis. Hematoxylin and eosin staining was applied to observe the effect of FOXD3-AS1 on the morphology of myocardial I/R injured tissues. The results showed that the FOXD3-AS1 and TXNIP were highly expressed, whereas miR-128 was expressed at low levels in I/R myocardial tissues and H/R-induced H9c2 cells. FOXD3-AS1 directly targeted miR-128 to reduce its expression. TXNIP was confirmed as a downstream target of miR-128. Knockdown of FOXD3-AS1 led to the alleviation of I/R injury in vivo and in vitro. FOXD3-AS1 enhanced the expression of TXNIP by sponging miR-128, which inhibited the Redd1/AKT/GSK3β/Nrf2 pathway. Both inhibition of miR-128 and overexpression of TXNIP reversed the cardioprotective effect of FOXD3-AS1 small interfering RNA in H/R-induced H9c2 cells.