Ge Hongyao, Du Zhenyu, Liu Weizhe, Wang Letian, Li Junyang, Yang Gaoshan, Li Aiying
Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Hebei Key Laboratory of Chinese Medicine Research on Cardio-cerebrovascular Disease, Shijiazhuang, Hebei, China.
Front Pharmacol. 2025 May 2;16:1578877. doi: 10.3389/fphar.2025.1578877. eCollection 2025.
Myocardial fibrosis (MF) is a key pathological change in heart failure, and lactate a product of glycolysis, is an important component affecting the process of MF. miRNAs derived from () have been shown to effectively treat cardiac remodeling. However, whether -derived Gen-miR-5 can effectively improve MF remains to be elucidated. This study seeks to explore the pharmacological effects and underlying molecular mechanisms of Gen-miR-5 in the context of Angiotensin II (Ang II) -induced MF.
A mouse model of MF was established by subcutaneous infusion of Ang II using osmotic pumps, and then administration of Gen-miR-5 by injection. The effects of Gen-miR-5 in reducing MF and exerting cardioprotective actions were evaluated through pathological morphological analysis and echocardiography. The targeting effect of Gen-miR-5 on PFKP was assessed through dual-luciferase reporter gene assays. Cardiac fibroblasts (CFs) migration abilities were evaluated through wound healing assay and transwell assays. Additionally, the role of Gen-miR-5 in fibroblast activation was investigated using gain- and loss-of-function experiments, and immunofluorescence.
This study identified six novel specific miRNAs in , among which Gen-miR-5 can be absorbed by mice, stably exists in cardiac tissue, and targets the PFKP 3' UTR to exert cross-kingdom regulatory effects. PFKP, as a key rate-limiting enzyme in the glycolytic pathway, increases lactate accumulation and promotes the proliferation and migration of CFs, thereby facilitating the development of MF. In contrast, Gen-miR-5 alleviates MF by inhibiting this process.
In conclusion, we have elucidated for the first time the pharmacological effects of Gen-miR-5, derived from , in inhibiting MF. Gen-miR-5 exerts its cardioprotective effects by targeting and inhibiting the expression of the key glycolytic enzyme PFKP, induced by Ang II, regulating lactate metabolism in fibroblast, and preventing the transformation of fibroblasts into myofibroblasts, ultimately alleviating MF. This study demonstrates that Gen-miR-5 is a potential therapeutic agent for improving cardiac remodeling.
心肌纤维化（MF）是心力衰竭的关键病理变化，而乳酸作为糖酵解产物，是影响MF进程的重要成分。源自（）的微小RNA（miRNA）已被证明可有效治疗心脏重塑。然而，源自的Gen-miR-5是否能有效改善MF仍有待阐明。本研究旨在探讨Gen-miR-5在血管紧张素II（Ang II）诱导的MF背景下的药理作用及潜在分子机制。
通过使用渗透泵皮下输注Ang II建立MF小鼠模型，然后通过注射给予Gen-miR-5。通过病理形态学分析和超声心动图评估Gen-miR-5在减轻MF和发挥心脏保护作用方面的效果。通过双荧光素酶报告基因测定评估Gen-miR-5对磷酸果糖激酶-1（PFKP）的靶向作用。通过伤口愈合试验和Transwell试验评估心脏成纤维细胞（CFs）的迁移能力。此外，使用功能获得和功能丧失实验以及免疫荧光研究Gen-miR-5在成纤维细胞活化中的作用。
本研究在（）中鉴定出六种新的特异性miRNA，其中Gen-miR-5可被小鼠吸收，稳定存在于心脏组织中，并靶向PFKP的3'非翻译区发挥跨界调节作用。PFKP作为糖酵解途径中的关键限速酶，增加乳酸积累并促进CFs的增殖和迁移，从而促进MF的发展。相比之下，Gen-miR-5通过抑制这一过程减轻MF。
总之，我们首次阐明了源自（）的Gen-miR-5在抑制MF方面的药理作用。Gen-miR-5通过靶向并抑制由Ang II诱导的关键糖酵解酶PFKP的表达，调节成纤维细胞中的乳酸代谢，并防止成纤维细胞转化为肌成纤维细胞，最终减轻MF，发挥其心脏保护作用。本研究表明Gen-miR-5是改善心脏重塑的潜在治疗剂。
