Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A & M Health Science Center, Scott & White, Central Texas Veterans Health Care System , Temple, TX , USA.
Free Radic Res. 2014 Mar;48(3):282-91. doi: 10.3109/10715762.2013.865839. Epub 2013 Dec 10.
Oxidative stress, defined as an excess production of reactive oxygen species (ROS), is shown to play an important role in the pathophysiology of cardiac remodeling including cell death and contractile dysfunction. Therefore, the balance between ROS production and removal of excess ROS is essential in maintaining the redox state and homeostasis balance in the cell. The increased ROS further activates nuclear factor-κB (NF-κB), a redox-sensitive transcription factor and promotes cell death. Recently, microRNAs (miRNAs) have been identified as critical regulators of various pathophysiological processes of cardiac remodeling; however, NF-κB-mediated miRNA's role in cardiomyocytes under oxidative stress remains undetermined. The miR-21 has been implicated in diverse cardiac remodeling; but, NF-κB-mediated miR-21 modulation in oxidative stress is currently unknown. Neonatal cardiomyocytes were transfected with IκBα mutant, miR-21 mimetic, and inhibitors separately, and were challenged with H2O2. The target gene, programmed cell death 4 (PDCD4), ROS activity, and NF-κB translocation were analyzed. Our results indicated that NF-κB positively regulated miR-21 expression under oxidative stress, and PDCD4 was a direct target for miR-21. NF-κB further regulated the expression of PDCD4 in H2O2-induced oxidative stress. Moreover, H2O2-induced ROS activity and cardiomyocytes apoptosis were partly protected by overexpression of miR-21 and displayed an important role in ROS-mediated cardiomyocytes injury. We evaluated a critical role of NF-κB-mediated miR-21 modulation in H2O2-induced oxidative stress in cardiomyocytes by targeting PDCD4. Our data may provide a new insight of miR-21's role in cardiac diseases primarily mediated by ROS.
氧化应激，定义为活性氧（ROS）的过度产生，被证明在心脏重构的病理生理学中起着重要作用，包括细胞死亡和收缩功能障碍。因此，ROS 产生和清除过量 ROS 之间的平衡对于维持细胞中的氧化还原状态和内稳态平衡至关重要。增加的 ROS 进一步激活核因子-κB（NF-κB），一种氧化还原敏感的转录因子，并促进细胞死亡。最近，microRNAs（miRNAs）已被确定为心脏重构的各种病理生理过程的关键调节剂；然而，NF-κB 介导的 miRNA 在氧化应激下的心肌细胞中的作用仍未确定。miR-21 已被牵涉到多种心脏重构中；但是，NF-κB 介导的 miR-21 在氧化应激中的调节目前尚不清楚。分别用 IκBα 突变体、miR-21 模拟物和抑制剂转染新生心肌细胞，并用 H2O2 处理。分析靶基因、程序性细胞死亡 4（PDCD4）、ROS 活性和 NF-κB 易位。我们的结果表明，NF-κB 在氧化应激下正向调节 miR-21 的表达，PDCD4 是 miR-21 的直接靶标。NF-κB 进一步调节 H2O2 诱导的氧化应激中 PDCD4 的表达。此外，miR-21 的过表达部分保护了 H2O2 诱导的 ROS 活性和心肌细胞凋亡，并在 ROS 介导的心肌细胞损伤中发挥重要作用。我们通过靶向 PDCD4 评估了 NF-κB 介导的 miR-21 调节在 H2O2 诱导的氧化应激中对心肌细胞的关键作用。我们的数据可能为 ROS 主要介导的心脏疾病中 miR-21 的作用提供新的见解。
