Wang Min, Lu Rui, Peng Liang, Xu Ling-Ling, He Shang-Fei, Guo Tao, Lu Ming-Jun, Luo Yi, Cui Tong-Tao
Department of Cardiology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Department of Gastroenterology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Shock. 2025 Apr 1;63(4):656-663. doi: 10.1097/SHK.0000000000002546. Epub 2025 Jan 28.
The global prevalence of heart failure is still growing, which imposes a heavy economic burden. The role of microRNA-146b (miR-146b) in HF remains largely unknown. This study aims to explore the role and mechanism of miR-146b in HF. Method: We applied reverse transcription-polymerase chain reaction to search for differential microRNAs between myocardial tissues of heart failure patients and controls. We also used reverse transcription-polymerase chain reaction to detect the miR-146b expression in primary neonatal mouse cardiomyocytes and mice models of doxorubicin-induced HF. In vivo experiments, echocardiography was performed at baseline and weeks 6. After that we harvested mice's heart and evaluated the cardiomyocyte with hematoxylin and eosin (HE), Masson trichrome staining, and TUNEL staining. Through bioinformatics analysis, we found HIF-1α might be the target gene of miR-146b, which validated by luciferase reporter gene assay. Subsequently, mRNA and protein expression levels of HIF-1α were detected by overexpression or inhibition of miR-146b in primary neonatal mouse cardiomyocytes. Results: We found that miR-146b expression was decreased in myocardial tissues of HF patients compared with controls ( P < 0.01). MiR-146b levels were notably downregulated in HF models. MiR-146b knockout mice showed a more pronounced decrease in cardiac function and more severe myocardial fibrosis and apoptosis than wild type. Meanwhile, over expression or repression of miR-146b in primary neonatal mouse cardiomyocytes could inhibit or upregulate HIF-1α mRNA and protein expression. Conclusion : Our study shows that miR-146b may be a protective factor for cardiomyocytes by modulating HIF-1α.
心力衰竭的全球患病率仍在上升，这带来了沉重的经济负担。微小RNA - 146b（miR - 146b）在心力衰竭中的作用在很大程度上仍不清楚。本研究旨在探讨miR - 146b在心力衰竭中的作用及机制。方法：我们应用逆转录 - 聚合酶链反应来寻找心力衰竭患者与对照组心肌组织之间差异表达的微小RNA。我们还使用逆转录 - 聚合酶链反应检测原代新生小鼠心肌细胞和阿霉素诱导的心力衰竭小鼠模型中miR - 146b的表达。在体内实验中，于基线和第6周进行超声心动图检查。之后采集小鼠心脏，并用苏木精 - 伊红（HE）染色、Masson三色染色和TUNEL染色评估心肌细胞。通过生物信息学分析，我们发现缺氧诱导因子 - 1α（HIF - 1α）可能是miR - 146b的靶基因，这通过荧光素酶报告基因实验得到验证。随后，在原代新生小鼠心肌细胞中通过过表达或抑制miR - 146b来检测HIF - 1α的mRNA和蛋白表达水平。结果：我们发现与对照组相比，心力衰竭患者心肌组织中miR - 146b的表达降低（P < 0.01）。在心力衰竭模型中，miR - 146b水平显著下调。与野生型相比，miR - 146b基因敲除小鼠的心脏功能下降更明显，心肌纤维化和细胞凋亡更严重。同时，在原代新生小鼠心肌细胞中过表达或抑制miR - 146b可抑制或上调HIF - 1α的mRNA和蛋白表达。结论：我们的研究表明，miR - 146b可能通过调节HIF - 1α对心肌细胞起保护作用。
