Exosomes from Suxiao Jiuxin pill-treated cardiac mesenchymal stem cells decrease H3K27 demethylase UTX expression in mouse cardiomyocytes in vitro
Exosomes from Suxiao Jiuxin pill-treated cardiac mesenchymal stem cells decrease H3K27 demethylase UTX expression in mouse cardiomyocytes in vitro
复制标题
速效救心丸处理的心脏间充质干细胞的外泌体在体外降低小鼠心肌细胞中H3K27去甲基化酶UTX的表达
DOI：
10.1038/aps.2018.18
复制
发表时间：
2018-04-01
影响因子：
8.2
通讯作者：
Tang, Yaoliang
中科院分区：
文献类型：
--
作者：
Ruan, Xiao-fen;Li, Yong-jun;Tang, Yaoliang
速消救心丸是治疗中国急性冠脉综合征的传统中药，其主要成分为川芎嗪和冰片。然而，到目前为止，SJP对心脏微环境的有益影响的分子机制尚不清楚。心脏间充质干细胞(C-MSCs)通过释放微囊(外体)与心肌细胞(CMS)进行通讯，部分通过表观遗传调节机制恢复心脏内稳态和诱导修复。在这项研究中，我们研究了生姜多糖治疗是否改变了C-MSC来源的外切体(SJP-Exos)，从而导致受体CMS的表观遗传学染色质重构。从小鼠心脏分离的c-MSC用生姜多糖(SJP-Exos)、川芎嗪(TMP-Exos)或Bor(Bor-Exos)处理。然后，用对照C-MSCs的外切体(Ctrl-Exos)、SJP-Exos、TMP-Exos或Bor-Exos处理小鼠心肌细胞株HL-1细胞。SJP-Exos显著增加HL-1细胞组蛋白3赖氨酸27三甲基化(H3K27me3)的蛋白水平，H3K27me3是心脏转录抑制的关键表观遗传染色质标志物。为了进一步探讨SJP-Exo介导的H3K27me3上调的机制，我们检测了外切体处理的HL-1细胞中关键的组蛋白甲基酶(EZH1、EZH2和EED)和去甲基酶(JMJD3和UTX)的mRNA表达水平。SJP-Exo可选择性抑制受体HL-1细胞中UTX的表达。此外，SJP-Exo处理的HL-1细胞中细胞复制的内源性标志物--增殖细胞核抗原显著高于Ctrl-Exo处理的HL-1细胞。这些结果表明，SJP-Exos可促进心肌细胞增殖，并能调节C-MSC来源的外切体，引起受体心肌细胞染色质的表观重构，因此，SJP-Exos可能用于促进心肌细胞的增殖。
Suxiao Jiuxin pill (SJP) is a traditional Chinese medicine for the treatment of acute coronary syndrome in China, which contains two principal components, tetramethylpyrazine (TMP) and borneol (BOR). Thus far, however, the molecular mechanisms underlying the beneficial effects of SJP on the cardiac microenvironment are unknown. Cardiac mesenchymal stem cells (C-MSCs) communicate with cardiomyocytes (CMs) through the release of microvesicles (exosomes) to restore cardiac homeostasis and elicit repair, in part through epigenetic regulatory mechanisms. In this study, we examined whether SJP treatment altered C-MSC-derived exosomes (SJP-Exos) to cause epigenetic chromatic remodeling in recipient CMs. C-MSC isolated from mouse hearts were pretreated with SJP (SJP-Exos), TMP (TMP-Exos) or BOR (BOR-Exos). Then, HL-1 cells, a mouse cardiomyocyte line, were treated with exosomes from control C-MSCs (Ctrl-Exos), SJP-Exos, TMP-Exos or BOR-Exos. Treatment with SJP-Exos significantly increased the protein levels of histone 3 lysine 27 trimethylation (H3K27me3), a key epigenetic chromatin marker for cardiac transcriptional suppression, in the HL-1 cells. To further explore the mechanisms of SJP-Exo-mediated H3K27me3 upregulation, we assessed the mRNA expression levels of key histone methylases (EZH1, EZH2 and EED) and demethylases (JMJD3 and UTX) in the exosome-treated HL-1 cells. Treatment with SJP-Exo selectively suppressed UTX expression in the recipient HL-1 cells. Furthermore, PCNA, an endogenous marker of cell replication, was significantly higher in SJP-Exo-treated HL-1 cells than in Ctrl-Exo-treated HL-1 cells. These results show that SJP-Exos increase cardiomyocyte proliferation and demonstrate that SJP can modulate C-MSC-derived exosomes to cause epigenetic chromatin remodeling in recipient cardiomyocytes; consequently, SJP-Exos might be used to promote cardiomyocyte proliferation.