Growing evidence suggests the crucial role of microRNAs (miRNAs) in regulating basic cell functions, and therefore participating in the pathologic development of diverse human diseases, including cardiac hypertrophy. Herein, we explained that miR-4458 was distinctly stimulated in Ang II-stimulated hypertrophic H9c2 cells. Intriguingly, miR-4458 inhibition led to exacerbated hypertrophic phenotypes in Ang II-treated H9c2 cells. In addition, the compensatory upregulation of miR-4458 in Ang II-treated H9c2 cells was ascribed to its transcriptional enhancement by NRF1, a transcription factor previously identified to be activated in early cardiac hypertrophy. Moreover, we discovered that miR-4458 served as a negative modulator in cardiac hypertrophy by prompting TFAM, a well-recognized myocardial protective protein. TTP, a RBP that always leads to degradation of recognized mRNAs, was predicted to interact with both miR-4458 and TFAM mRNA. Importantly, we verified that miR-4458 facilitated TFAM expression in cardiomyocytes by directly targeting TTP and releasing TTP-destabilized TFAM mRNA. On the whole, these findings demonstrated that NRF1-induced miR-4458 boosted TFAM via targeting TTP to dampen the exacerbation of cardiac hypertrophy, which indicates miR-4458 as a promising biomarker for the cardiac hypertrophy treatment.

中文翻译：

---

NRF1增强的miR-4458通过释放TTP抑制的TFAM减轻心脏肥大。

越来越多的证据表明，微小RNA（miRNA）在调节基本细胞功能中至关重要，因此参与了包括心脏肥大在内的各种人类疾病的病理发展。在本文中，我们解释了在Ang II刺激的肥大性H9c2细胞中，miR-4458得到了明显的刺激。有趣的是，在Ang II处理的H9c2细胞中，miR-4458的抑制作用导致了肥大的表型加剧。此外，在Ang II处理的H9c2细胞中miR-4458的代偿性上调归因于NRF1的转录增强，NRF1是先前在早期心脏肥大中被激活的转录因子。此外，我们发现miR-4458通过促进TFAM（一种公认的心肌保护蛋白）在心脏肥大中充当负调节剂。TTP，预计总是导致公认的mRNA降解的RBP与miR-4458和TFAM mRNA相互作用。重要的是，我们验证了miR-4458通过直接靶向TTP并释放TTP不稳定的TFAM mRNA来促进心肌细胞中TFAM的表达。总体而言，这些发现表明NRF1诱导的miR-4458通过靶向TTP抑制心脏肥大的恶化而增强了TFAM，这表明miR-4458作为心脏肥大治疗的有前途的生物标志物。