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

Acta Pharmacologica Sinica volume 39, pages 579586 (2018) | Download Citation

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Abstract

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.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (No 81403352, 81573647 to Xiao-long WANG and Xiao-fen RUAN, and 81528002 to Yaoliang TANG), the Shanghai Key Laboratory of Traditional Chinese Clinical Medicine (No 14DZ2273200); this study was also partially supported by the Tianjin Zhongxin Pharmaceutical Group Co, Ltd, Tianjin, China.

Il-man KIM, Neal L WEINTRAUB, and Yaoliang TANG were partially supported by the American Heart Association GRNT31430008, NIH-AR070029, NIH-HL086555, NIH-HL134354, and NIH-HL12425.

Author information

Author notes

    • Xiao-fen Ruan
    •  & Yong-jun Li

    These authors contributed equally to this work.

Affiliations

  1. Cardiovascular Department, Cardiovascular Research Institute of Traditional Chinese Medicine, Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

    • Xiao-fen Ruan
    •  & Xiao-long Wang
  2. Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China

    • Yong-jun Li
    •  & Cheng-wei Ju
  3. Medical College of Georgia, Augusta University, Augusta, GA, USA

    • Xiao-fen Ruan
    • , Yong-jun Li
    • , Cheng-wei Ju
    • , Yan Shen
    • , Yang Li
    • , Yu-tao Liu
    • , Il-man Kim
    • , Neal L Weintraub
    •  & Yaoliang Tang
  4. Laboratory of Cardiovascular Diseases, Guangdong Medical University, Zhanjiang 524023, China

    • Wei Lei
    •  & Can Chen
  5. Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China

    • Hong Yu

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Corresponding authors

Correspondence to Xiao-long Wang or Yaoliang Tang.

Supplementary information

Image files

  1. 1.

    Supplementary Figure S1

    Trimethylation of H3K27 in HL-1 cells following application of Ctrl, SJP, TMP and BOR.

  2. 2.

    Supplementary Figure S2

    Dose and time effect of SJP-Exo on UTX expression in HL-1.

  3. 3.

    Supplementary Figure S3

    Fingerprint chromatograms of SJP.

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DOI

https://doi.org/10.1038/aps.2018.18

Supplementary information is available at the website of Acta Pharmacologica Sinica.

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