Department of Cardiology II, Cangzhou Teaching Hospital of Tianjin Medical University, Cangzhou City, P. R. China; and.
Heart Center of the Second Affiliated Hospital of Baotou Medical College, Inner Mongolia Autonomous Region, Baotou City, P. R. China.
J Cardiovasc Pharmacol. 2022 Apr 1;79(4):479-488. doi: 10.1097/FJC.0000000000001198.
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.
急性心肌梗死（AMI）已成为发达国家最常见的死亡原因。然而，其发病机制尚不清楚。越来越多的研究表明，lncRNAs 是 AMI 发展的重要调节因子。本研究旨在探讨核因子活化 T 细胞的非编码抑制因子（NRON）长非编码 RNA 在缺氧/复氧（H/R）刺激的 H9c2 细胞中的作用。通过实时定量聚合酶链反应测定 AMI 患者外周血和 H/R 刺激的 H9c2 细胞中 NRON 的表达。用 si-NRON 转染 H9c2 细胞或与 si-hypoxia-inducible factor-1 alpha（HIF-1α）共转染。通过 MTT（3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐）测定法和流式细胞术分别评估这些细胞的活力和凋亡。此外，通过 Western blot 检测 HIF-1α、AKT/mTOR 信号通路和 ERK1/2。通过腺相关病毒注射在心肌梗死小鼠模型中进行 NRON 敲低，并通过运动模式超声心动图评估心脏功能。结果表明，NRON 在 AMI 患者外周血和 H/R 刺激的 H9c2 细胞中表达水平较高。NRON 敲低可促进 H/R 刺激的 H9c2 细胞活力并抑制细胞凋亡。同时，NRON 敲低还可显著减轻 AMI 小鼠模型中的心脏损伤并改善心脏功能。此外，与 si-正常对照相比，NRON 敲低可增加 HIF-1α、p-AKT、p-mTOR 和 p-ERK1/2 的水平。HIF-1α 敲低逆转了 NRON 敲低对 H/R 刺激的 H9c2 细胞损伤的作用。总的来说，我们的研究表明，NRON 敲低通过上调 HIF-1α 表达减轻 H/R 诱导的心肌细胞凋亡，提示 NRON 可能是 AMI 的一种新的治疗靶点。
