The mammalian target of rapamycin modulates the immunoproteasome system in the heart

Hong Mei Zhang, Jianliang Fu, Ryan Hamilton, Vivian Diaz, Yiqiang Zhang

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

The mammalian target of rapamycin (mTOR) plays an important role in cardiac development and function. Inhibition of mTOR by rapamycin has been shown to attenuate pathological cardiac hypertrophy and improve the function of aging heart, accompanied by an inhibition of the cardiac proteasome activity. The current study aimed to determine the potential mechanism(s) by which mTOR inhibition modulates cardiac proteasome. Inhibition of mTOR by rapamycin was found to reduce primarily the immunoproteasome in both H9c2 cells in vitro and mouse heart in vivo, without significant effect on the constitutive proteasome and protein ubiquitination. Concurrent with the reduction of the immunoproteasome, rapamycin reduced two important inflammatory response pathways, the NF-κB and Stat3 signaling. In addition, rapamycin attenuated the induction of the immunoproteasome in H9c2 cells by inflammatory cytokines, including INFγ and TNFα, by suppressing NF-κB signaling. These data indicate that rapamycin indirectly modulated immunoproteasome through the suppression of inflammatory response pathways. Lastly, the role of the immunoproteasome during the development of cardiac hypertrophy was investigated. Administration of a specific inhibitor of the immunoproteasome ONX 0914 attenuated isoproterenol-induced cardiac hypertrophy, suggesting that the immunoproteasome may be involved in the development of cardiac hypertrophy and therefore could be a therapeutic target. In conclusion, rapamycin inhibits the immunoproteasome through its effect on the inflammatory signaling pathways and the immunoproteasome could be a potential therapeutic target for pathological cardiac hypertrophy.

Original languageEnglish (US)
Pages (from-to)158-167
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume86
DOIs
StatePublished - Sep 1 2015

Fingerprint

Sirolimus
Cardiomegaly
Proteasome Endopeptidase Complex
Ubiquitination
Isoproterenol
Cytokines

Keywords

  • Heart
  • Immunoproteasome
  • Inflammation
  • MTOR
  • Proteasome
  • Rapamycin

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

The mammalian target of rapamycin modulates the immunoproteasome system in the heart. / Zhang, Hong Mei; Fu, Jianliang; Hamilton, Ryan; Diaz, Vivian; Zhang, Yiqiang.

In: Journal of Molecular and Cellular Cardiology, Vol. 86, 01.09.2015, p. 158-167.

Research output: Contribution to journalArticle

Zhang, Hong Mei ; Fu, Jianliang ; Hamilton, Ryan ; Diaz, Vivian ; Zhang, Yiqiang. / The mammalian target of rapamycin modulates the immunoproteasome system in the heart. In: Journal of Molecular and Cellular Cardiology. 2015 ; Vol. 86. pp. 158-167.
@article{289e0610794f49639bbb3d95e4896a03,
title = "The mammalian target of rapamycin modulates the immunoproteasome system in the heart",
abstract = "The mammalian target of rapamycin (mTOR) plays an important role in cardiac development and function. Inhibition of mTOR by rapamycin has been shown to attenuate pathological cardiac hypertrophy and improve the function of aging heart, accompanied by an inhibition of the cardiac proteasome activity. The current study aimed to determine the potential mechanism(s) by which mTOR inhibition modulates cardiac proteasome. Inhibition of mTOR by rapamycin was found to reduce primarily the immunoproteasome in both H9c2 cells in vitro and mouse heart in vivo, without significant effect on the constitutive proteasome and protein ubiquitination. Concurrent with the reduction of the immunoproteasome, rapamycin reduced two important inflammatory response pathways, the NF-κB and Stat3 signaling. In addition, rapamycin attenuated the induction of the immunoproteasome in H9c2 cells by inflammatory cytokines, including INFγ and TNFα, by suppressing NF-κB signaling. These data indicate that rapamycin indirectly modulated immunoproteasome through the suppression of inflammatory response pathways. Lastly, the role of the immunoproteasome during the development of cardiac hypertrophy was investigated. Administration of a specific inhibitor of the immunoproteasome ONX 0914 attenuated isoproterenol-induced cardiac hypertrophy, suggesting that the immunoproteasome may be involved in the development of cardiac hypertrophy and therefore could be a therapeutic target. In conclusion, rapamycin inhibits the immunoproteasome through its effect on the inflammatory signaling pathways and the immunoproteasome could be a potential therapeutic target for pathological cardiac hypertrophy.",
keywords = "Heart, Immunoproteasome, Inflammation, MTOR, Proteasome, Rapamycin",
author = "Zhang, {Hong Mei} and Jianliang Fu and Ryan Hamilton and Vivian Diaz and Yiqiang Zhang",
year = "2015",
month = "9",
day = "1",
doi = "10.1016/j.yjmcc.2015.07.027",
language = "English (US)",
volume = "86",
pages = "158--167",
journal = "Journal of Molecular and Cellular Cardiology",
issn = "0022-2828",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - The mammalian target of rapamycin modulates the immunoproteasome system in the heart

AU - Zhang, Hong Mei

AU - Fu, Jianliang

AU - Hamilton, Ryan

AU - Diaz, Vivian

AU - Zhang, Yiqiang

PY - 2015/9/1

Y1 - 2015/9/1

N2 - The mammalian target of rapamycin (mTOR) plays an important role in cardiac development and function. Inhibition of mTOR by rapamycin has been shown to attenuate pathological cardiac hypertrophy and improve the function of aging heart, accompanied by an inhibition of the cardiac proteasome activity. The current study aimed to determine the potential mechanism(s) by which mTOR inhibition modulates cardiac proteasome. Inhibition of mTOR by rapamycin was found to reduce primarily the immunoproteasome in both H9c2 cells in vitro and mouse heart in vivo, without significant effect on the constitutive proteasome and protein ubiquitination. Concurrent with the reduction of the immunoproteasome, rapamycin reduced two important inflammatory response pathways, the NF-κB and Stat3 signaling. In addition, rapamycin attenuated the induction of the immunoproteasome in H9c2 cells by inflammatory cytokines, including INFγ and TNFα, by suppressing NF-κB signaling. These data indicate that rapamycin indirectly modulated immunoproteasome through the suppression of inflammatory response pathways. Lastly, the role of the immunoproteasome during the development of cardiac hypertrophy was investigated. Administration of a specific inhibitor of the immunoproteasome ONX 0914 attenuated isoproterenol-induced cardiac hypertrophy, suggesting that the immunoproteasome may be involved in the development of cardiac hypertrophy and therefore could be a therapeutic target. In conclusion, rapamycin inhibits the immunoproteasome through its effect on the inflammatory signaling pathways and the immunoproteasome could be a potential therapeutic target for pathological cardiac hypertrophy.

AB - The mammalian target of rapamycin (mTOR) plays an important role in cardiac development and function. Inhibition of mTOR by rapamycin has been shown to attenuate pathological cardiac hypertrophy and improve the function of aging heart, accompanied by an inhibition of the cardiac proteasome activity. The current study aimed to determine the potential mechanism(s) by which mTOR inhibition modulates cardiac proteasome. Inhibition of mTOR by rapamycin was found to reduce primarily the immunoproteasome in both H9c2 cells in vitro and mouse heart in vivo, without significant effect on the constitutive proteasome and protein ubiquitination. Concurrent with the reduction of the immunoproteasome, rapamycin reduced two important inflammatory response pathways, the NF-κB and Stat3 signaling. In addition, rapamycin attenuated the induction of the immunoproteasome in H9c2 cells by inflammatory cytokines, including INFγ and TNFα, by suppressing NF-κB signaling. These data indicate that rapamycin indirectly modulated immunoproteasome through the suppression of inflammatory response pathways. Lastly, the role of the immunoproteasome during the development of cardiac hypertrophy was investigated. Administration of a specific inhibitor of the immunoproteasome ONX 0914 attenuated isoproterenol-induced cardiac hypertrophy, suggesting that the immunoproteasome may be involved in the development of cardiac hypertrophy and therefore could be a therapeutic target. In conclusion, rapamycin inhibits the immunoproteasome through its effect on the inflammatory signaling pathways and the immunoproteasome could be a potential therapeutic target for pathological cardiac hypertrophy.

KW - Heart

KW - Immunoproteasome

KW - Inflammation

KW - MTOR

KW - Proteasome

KW - Rapamycin

UR - http://www.scopus.com/inward/record.url?scp=84938678109&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84938678109&partnerID=8YFLogxK

U2 - 10.1016/j.yjmcc.2015.07.027

DO - 10.1016/j.yjmcc.2015.07.027

M3 - Article

C2 - 26239133

AN - SCOPUS:84938678109

VL - 86

SP - 158

EP - 167

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

SN - 0022-2828

ER -