Exosomes from Suxiao Jiuxin pill-treated cardiac mesenchymal stem cells decrease H3K27 demethylase UTX expression in mouse cardiomyocytes in vitro

Authors: Xiao-fen RUAN1,2,3,4,5, Yong-jun LI2,3, Cheng-wei JU2,3, Yan SHEN3, Wei LEI4, Can CHEN4, Yang LI3, Hong YU5, Yu-tao LIU3, Ilman KIM3, Xiao-long WANG1, Neal L WEINTRAUB3, Yaoliang TANG3
1 Cardiovascular Department, Cardiovascular Research Institute of Traditional Chinese Medicine, Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
2 Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China
3 Medical College of Georgia, Augusta University, Augusta, GA, USA
4 Laboratory of Cardiovascular Diseases, Guangdong Medical University, Zhanjiang 524023, China
5 Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China
Corresponding to: Xiao-long WANG:, Yaoliang TANG:,
DOI: 10.1038/aps.2018.18
Received: 15 March 2018
Accepted: 23 August 2017
Advance online: 11 January 2018


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 (SJPExos) to cause epigenetic chromatic remodeling in recipient CMs. C-MSC isolated from mouse hearts were pretreated with SJP (SJPExos), 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.
Keywords: traditional Chinese medicine; Suxiao Jiuxin pill; tetramethylpyrazine; borneol; cardiac mesenchymal stem cells; exosomes; epigenetic regulation; H3K27 methylases; H3K27 demethylases; UTX