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

Xiao Fen Ruan, Yong Jun Li, Cheng Wei Ju, Yan Shen, Wei Lei, Can Chen, Yang Li, Hong Yu, Yu Tao Liu, Il Man Kim, Xiao Long Wang, Neal L. Weintraub, Yaoliang Tang

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)579-586
Number of pages8
JournalActa Pharmacologica Sinica
Volume39
Issue number4
DOIs
StatePublished - Apr 1 2018
Externally publishedYes

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Exosomes
Mesenchymal Stromal Cells
Cardiac Myocytes
Epigenomics
Chromatin Assembly and Disassembly
Chinese Traditional Medicine
Proliferating Cell Nuclear Antigen
Therapeutics
Acute Coronary Syndrome
In Vitro Techniques
Histones
Lysine
Chromatin
China
Homeostasis
Up-Regulation
Color
Messenger RNA
isoborneol
tetramethylpyrazine

Keywords

  • borneol
  • cardiac mesenchymal stem cells
  • epigenetic regulation
  • exosomes
  • H3K27 demethylases
  • H3K27 methylases
  • Suxiao Jiuxin pill
  • tetramethylpyrazine
  • traditional Chinese medicine
  • UTX

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Exosomes from Suxiao Jiuxin pill-treated cardiac mesenchymal stem cells decrease H3K27 demethylase UTX expression in mouse cardiomyocytes in vitro. / Ruan, Xiao Fen; Li, Yong Jun; Ju, Cheng Wei; Shen, Yan; Lei, Wei; Chen, Can; Li, Yang; Yu, Hong; Liu, Yu Tao; Kim, Il Man; Wang, Xiao Long; Weintraub, Neal L.; Tang, Yaoliang.

In: Acta Pharmacologica Sinica, Vol. 39, No. 4, 01.04.2018, p. 579-586.

Research output: Contribution to journalArticle

Ruan, XF, Li, YJ, Ju, CW, Shen, Y, Lei, W, Chen, C, Li, Y, Yu, H, Liu, YT, Kim, IM, Wang, XL, Weintraub, NL & Tang, Y 2018, 'Exosomes from Suxiao Jiuxin pill-treated cardiac mesenchymal stem cells decrease H3K27 demethylase UTX expression in mouse cardiomyocytes in vitro', Acta Pharmacologica Sinica, vol. 39, no. 4, pp. 579-586. https://doi.org/10.1038/aps.2018.18
Ruan, Xiao Fen ; Li, Yong Jun ; Ju, Cheng Wei ; Shen, Yan ; Lei, Wei ; Chen, Can ; Li, Yang ; Yu, Hong ; Liu, Yu Tao ; Kim, Il Man ; Wang, Xiao Long ; Weintraub, Neal L. ; Tang, Yaoliang. / Exosomes from Suxiao Jiuxin pill-treated cardiac mesenchymal stem cells decrease H3K27 demethylase UTX expression in mouse cardiomyocytes in vitro. In: Acta Pharmacologica Sinica. 2018 ; Vol. 39, No. 4. pp. 579-586.
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T1 - Exosomes from Suxiao Jiuxin pill-treated cardiac mesenchymal stem cells decrease H3K27 demethylase UTX expression in mouse cardiomyocytes in vitro

AU - Ruan, Xiao Fen

AU - Li, Yong Jun

AU - Ju, Cheng Wei

AU - Shen, Yan

AU - Lei, Wei

AU - Chen, Can

AU - Li, Yang

AU - Yu, Hong

AU - Liu, Yu Tao

AU - Kim, Il Man

AU - Wang, Xiao Long

AU - Weintraub, Neal L.

AU - Tang, Yaoliang

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N2 - 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.

AB - 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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KW - tetramethylpyrazine

KW - traditional Chinese medicine

KW - UTX

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