Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL, USA.
Sci Rep. 2021 Jun 7;11(1):11977. doi: 10.1038/s41598-021-90583-y.
Although recent advances in the treatment of acute coronary heart disease have reduced mortality rates, few therapeutic strategies exist to mitigate the progressive loss of cardiac function that manifests as heart failure. Nuclear factor, erythroid 2 like 2 (Nfe2l2, Nrf2) is a transcriptional regulator that is known to confer transient myocardial cytoprotection following acute ischemic insult; however, its sustained activation paradoxically causes a reductive environment characterized by excessive antioxidant activity. We previously identified a subset of 16 microRNAs (miRNA) significantly diminished in Nrf2-ablated (Nrf2) mouse hearts, leading to the hypothesis that increasing levels of Nrf2 activation augments miRNA induction and post-transcriptional dysregulation. Here, we report the identification of distinct miRNA signatures (i.e. "reductomiRs") associated with Nrf2 overexpression in a cardiac-specific and constitutively active Nrf2 transgenic (caNrf2-Tg) mice expressing low (TgL) and high (TgH) levels. We also found several Nrf2 dose-responsive miRNAs harboring proximal antioxidant response elements (AREs), implicating these "reductomiRs" as putative meditators of Nrf2-dependent post-transcriptional regulation. Analysis of mRNA-sequencing identified a complex network of miRNAs and effector mRNAs encoding known pathological hallmarks of cardiac stress-response. Altogether, these data support Nrf2 as a putative regulator of cardiac miRNA expression and provide novel candidates for future mechanistic investigation to understand the relationship between myocardial reductive stress and cardiac pathophysiology.
尽管急性冠状动脉心脏病治疗的最新进展降低了死亡率，但几乎没有治疗策略可以减轻心力衰竭表现为心脏功能进行性丧失。核因子，红系 2 样 2（Nfe2l2，Nrf2）是一种转录调节剂，已知在急性缺血性损伤后可提供短暂的心肌细胞保护作用；然而，其持续激活反而会导致以过度抗氧化活性为特征的还原性环境。我们之前发现了一组 16 个 microRNA（miRNA）在 Nrf2 缺失（Nrf2）小鼠心脏中显著减少，这导致了这样一种假设，即增加 Nrf2 激活水平会增加 miRNA 的诱导和转录后失调。在这里，我们报告了在心脏特异性和组成型激活 Nrf2 转基因（caNrf2-Tg）小鼠中，与 Nrf2 过表达相关的不同 miRNA 特征（即“还原 microRNA”）的鉴定，这些小鼠表达低（TgL）和高（TgH）水平的 Nrf2。我们还发现了几个具有近端抗氧化反应元件（ARE）的 Nrf2 剂量反应性 miRNA，暗示这些“还原 microRNA”可能是 Nrf2 依赖的转录后调节的介体。mRNA 测序分析鉴定了 miRNA 和编码已知心脏应激反应病理特征的效应 mRNA 的复杂网络。总的来说，这些数据支持 Nrf2 作为心脏 miRNA 表达的潜在调节剂，并为未来的机制研究提供了新的候选基因，以了解心肌还原性应激与心脏病理生理学之间的关系。
