Bone marrow–derived mesenchymal stem cells (BMSCs) have therapeutic potential for certain heart diseases. Previous studies have shown that stem cells inhibit cardiac hypertrophy; however, it is necessary to explore the mechanisms underlying this effect. This study aimed to investigate the possible mechanism underlying the inhibitory effect of BMSCs on cardiomyocyte hypertrophy. We induced cardiomyocyte hypertrophy in cultured rat cells through isoproterenol (ISO) treatment with or without BMSC coculture. A microarray was performed to analyze messenger RNA expression in response to ISO treatment and BMSC coculture. Pathway enrichment analysis showed that the expression of differential genes was closely related to the 5′‐adenosine monophosphate‐activated protein kinase (AMPK) signaling pathway and that the expression of forkhead box O 1 (FoxO1) was significantly increased in the presence of BMSCs. Furthermore, we determined the expression levels of p‐AMPK/AMPK and p‐FoxO1/FoxO1 by western blot analysis. The expression of p‐AMPK/AMPK was upregulated, whereas that of p‐FoxO1/FoxO1 was downregulated upon coculturing with BMSCs. The AMPK‐specific antagonist Compound C inhibited the downregulation of p‐FoxO1/FoxO1 induced by the BMSC coculture. Furthermore, treatment with the specific FoxO1 antagonist AS1842856 reduced the inhibitory effects of BMSCs on cardiomyocyte hypertrophy in vivo and in vitro. Our present study demonstrates the inhibition of cardiomyocyte hypertrophy by BMSCs, which occurs partly through the AMPK–FoxO1 signaling pathway.

中文翻译：

---

骨髓间充质干细胞通过增强FoxO1转录抑制心脏肥大


骨髓间充质干细胞（BMSC）具有治疗某些心脏病的潜力。此前的研究表明，干细胞可以抑制心脏肥大；然而，有必要探索这种效应背后的机制。本研究旨在探讨BMSCs抑制心肌细胞肥大的可能机制。我们通过异丙肾上腺素 (ISO) 处理（有或没有 BMSC 共培养）诱导培养的大鼠细胞心肌细胞肥大。通过微阵列分析 ISO 处理和 BMSC 共培养后的信使 RNA 表达。通路富集分析显示，差异基因的表达与5'-单磷酸腺苷激活蛋白激酶（AMPK）信号通路密切相关，且叉头盒O 1（FoxO1）的表达在BMSCs存在下显着增加。此外，我们通过蛋白质印迹分析测定了 p-AMPK/AMPK 和 p-FoxO1/FoxO1 的表达水平。与BMSCs共培养后，p-AMPK/AMPK的表达上调，而p-FoxO1/FoxO1的表达下调。 AMPK 特异性拮抗剂化合物 C 抑制 BMSC 共培养诱导的 p-FoxO1/FoxO1 下调。此外，用特异性 FoxO1 拮抗剂 AS1842856 治疗可降低体内和体外 BMSC 对心肌细胞肥大的抑制作用。我们目前的研究表明 BMSC 对心肌细胞肥大的抑制部分是通过 AMPK-FoxO1 信号通路发生的。