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.
authors.affiliation: Department of Clinical Oncology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China. Electronic address: zhm@fmmu.edu.cn.
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Fu
authors.affiliation: Barshop Institute, The University of Texas Health Science Center at San Antonio, TX 78249, United States.
authors.forename: Ryan
authors.initials: R
authors.lastname: Hamilton
authors.affiliation: Barshop Institute, The University of Texas Health Science Center at San Antonio, TX 78249, United States.
authors.forename: Vivian
authors.initials: V
authors.lastname: Diaz
authors.affiliation: Barshop Institute, The University of Texas Health Science Center at San Antonio, TX 78249, United States; Department of Physiology, The University of Texas Health Science Center at San Antonio, TX 78249, United States.
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D051379:Mice; D016328:NF-kappa B / Q000235:genetics; D009842:Oligopeptides / Q000008:administration & dosage; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D054875:Ubiquitination / Q000235:genetics
chemical_list: D016328:NF-kappa B; D009842:Oligopeptides; C542291:PR-957; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex; D020123:Sirolimus
keywords: Heart; Immunoproteasome; Inflammation; Proteasome; Rapamycin; mTOR