LncRNA TUG1 competitively binds to miR‐340 to accelerate myocardial ischemia‐reperfusion injury

Abstract

The aberrant expression of long noncoding RNA (lncRNA) taurine-upregulated gene 1 (TUG1) has been previously associated with myocardial ischemia-reperfusion injury (MIRI), but the underlying molecular mechanisms remain elusive. The current study aimed to clarify the functional role of TUG1/microRNA (miR)-340/histone deacetylase 4 (HDAC4)/β-catenin/glucose transporter type 1 (GLUT1) axes in MIRI. The database-based analyses performed predicted the downstream factors of lncRNA TUG1. In the MIRI mouse models and hypoxia/reoxygenation (H/R)-induced cardiomyocyte models, the expression of TUG1/miR-340/HDAC4/β-catenin/GLUT1 was manipulated to examine their effects on the infarction area, cardiomyocyte viability and apoptosis employing the Evans blue/TTC double staining, CCK-8 and TUNEL assays. Furthermore, the dual luciferase reporter and RIP assays verified the binding affinity of miR-340 to TUG1 and HDAC4. Subsequently, a negative correlation between miR-340 and TUG1 or HDAC4 expression was identified in myocardial tissues of MIRI mice and H/R-induced cardiomyocyte models, along with a positive correlation between TUG1 and HDAC4. Additionally, it was established that TUG1 bound to miR-340, and miR-340 targeted HDAC4. TUG1 upregulated HDAC4 expression, thereby promoting MIRI in the mouse models. HDAC4 was proven to repress the expression of β-catenin and its target gene GLUT1. Moreover, the in vivo experiments validated that the inhibition of TUG1/miR-340/HDAC4/β-catenin/ GLUT1 axes alleviated MIRI in mice. Collectively, the current study uncovered the role of TUG1/miR-340/HDAC4/β-catenin/GLUT1 axes in MIRI mouse models and H/R-induced cardiomyocyte models which may be a potential therapeutic target for MIRI treatment.

The various regulatory functions of long noncoding RNAs in apoptosis, cell cycle, and cellular senescence

“…GLUT1 inhibits mitochondrial dysfunction and diminishes structural remodeling during pressure overload. Besides, the in vivo experiments in mice validated that the suppression of TUG1/miR‐340/HDAC4/β‐catenin/GLUT1 axes directed the reduction of MIRI 38 …”

“…Silencing of TUG1 led to inhibition of cervical cancer cell proliferation mediated by miR‐381‐3/MDM2 107 . TUG1 elevation is also relevant in myocardial ischemia–reperfusion injury (MIRI) 38 . TUG1 binds to miR340, and then it acts like a sponge.…”

miR-340-5p Mediates Cardiomyocyte Oxidative Stress in Diabetes-Induced Cardiac Dysfunction by Targeting Mcl-1

“…Accumulating evidence suggests that miR-340-5p increases the expression levels of Bim, Bax, and cleaved caspase 3 but decreases the expression of Bcl-2, thereby contributing to increased apoptosis [ 12 , 13 , 30 ]. However, another study has reported that microRNA-340-5p plays a protective role in hypoxia/reoxygenation-induced apoptosis in an acute myocardial infarction model [ 46 ]. The difference in the response period for the animal model should be considered because the development of cardiomyopathy is chronic and progressive.…”

LncRNA TUG1 attenuates ischaemia‐reperfusion‐induced apoptosis of renal tubular epithelial cells by sponging miR‐144‐3p via targeting Nrf2

“…[43][44][45] TUG1 was recently reported to play important roles in ischaemia-induced oxidative damage including in kidney, cardiac or cerebrum. 14,46,47 MiR-144-3p was confirmed to be a target of TUG1 in tumour models, 18,19 however, among all these studies related to oxidative damage, miR-144-3p was never studied as a target of TUG1. Our results show that the expression of lncRNA-TUG1 is significantly upregulated in renal IRI, and we also confirmed that TUG1 can directly bind to miR-144-3p, and their expression levels are negatively correlated.…”