Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, P.R. China.
School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P.R. China.
Cell Prolif. 2022 May;55(5):e13221. doi: 10.1111/cpr.13221. Epub 2022 Mar 30.
Myocardial infarction (MI) commonly occurs in patients with coronary artery disease and have high mortality. Current clinical strategies for MI still limited to reducing the death of myocardial cells but failed to replace these cells. This study aimed to investigate the role of fibroblast growth factor 6 (FGF6) in enhancing the proliferative potential of cardiomyocytes (CMs) after ischemic injury via the Hippo pathway.
Expression of FGF6 protein was analysed in mice with MI induced by ligation of the left anterior descending coronary artery. Activation of the Hippo pathway and the proliferation potential were examined in ischemic CMs, treated with FGF6 protein or transfected with an adeno-virus carrying FGF6 sh-RNA. Immunofluorescence staining and western blotting were performed to assess the relationship between FGF6 and the Hippo pathway.
We found that FGF6 expression was significantly increased in the MI mouse model. Knockdown of FGF6 synthesis resulted in poorer heart function after MI. By contrast, treatment with recombinant human FGF6 protein improved heart function, reduced infarct size, and promoted cardiac repair. Additionally, FGF6 restrains the activation of the Hippo pathway and subsequently promotes nuclear accumulation of YAP. This was largely counteracted by treatment with extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor U0126.
FGF6 inhibits the Hippo pathway via ERK1/2, and facilitates nuclear translocation of YAP, and thereby promotes cardiac repair after MI.
心肌梗死（MI）常发生于冠状动脉疾病患者，且死亡率较高。目前 MI 的临床策略仍局限于减少心肌细胞死亡，但未能替代这些细胞。本研究旨在通过 Hippo 通路探讨成纤维细胞生长因子 6（FGF6）在增强缺血性损伤后心肌细胞（CMs）增殖潜能中的作用。
分析结扎左前降支诱导的 MI 小鼠模型中 FGF6 蛋白的表达。用 FGF6 蛋白处理或转染携带 FGF6 sh-RNA 的腺病毒，检测缺血性 CMs 中 Hippo 通路的激活和增殖潜能。通过免疫荧光染色和 Western blot 检测 FGF6 与 Hippo 通路之间的关系。
我们发现 FGF6 表达在 MI 小鼠模型中显著增加。FGF6 合成的敲低导致 MI 后心脏功能更差。相比之下，用重组人 FGF6 蛋白治疗可改善心脏功能、减少梗死面积并促进心脏修复。此外，FGF6 抑制 Hippo 通路的激活，随后促进 YAP 的核内积累。这在很大程度上被细胞外信号调节激酶 1/2（ERK1/2）抑制剂 U0126 所拮抗。
FGF6 通过 ERK1/2 抑制 Hippo 通路，促进 YAP 的核转位，从而促进 MI 后心脏修复。
