LncRNA Nuclear Factor of Activated T Cells Knockdown Alleviates Hypoxia/Reoxygenation-induced Cardiomyocyte Apoptosis by Upregulating HIF-1α Expression

Abstract

Acute myocardial infarction (AMI) has become the most common cause of death in the developed countries. However, its pathogenesis is poorly understood. Increasing studies have revealed that lncRNAs are important modulators of AMI development. This study aimed to explore the function of lncRNA noncoding repressor of nuclear factor of activated T cells (NRON) in hypoxia/reoxygenation (H/R)-stimulated H9c2 cells. NRON expression in peripheral blood of AMI patients and H/R-stimulated H9c2 cells was measured by quantitative real-time polymerase chain reaction. H9c2 cells were transfected with si-NRON or cotransfected with si-NRON and si-hypoxia-inducible factor-1 alpha (HIF-1α). The viability and apoptosis of these cells were evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assay and flow cytometer, respectively. In addition, HIF-1α, AKT/mTOR signal pathways and ERK1/2 were detected by western blot. NRON knockdown in the myocardial infarction mouse model was conducted through adeno-associated virus injection, and cardiac function was evaluated by motion-mode echocardiography. The results showed that NRON was highly expressed in peripheral blood of AMI patients and H/R-stimulated H9c2 cells. NRON knockdown promoted cell viability and inhibited cell apoptosis of H/R-stimulated H9c2 cells. Meanwhile, NRON knockdown also significantly attenuated heart damage and improved cardiac function in an AMI mouse model. Furthermore, compared with si-normal control, NRON knockdown increased the levels of HIF-1α, p-AKT, p-mTOR, and p-ERK1/2. HIF-1α knockdown reversed the effects of NRON knockdown in H/R-stimulated-H9c2 cells damage. Overall, our study revealed that NRON knockdown alleviated H/R-induced cardiomyocyte apoptosis by upregulating HIF-1α expression, suggesting that NRON might be a novel therapeutic target for AMI.