Gene expression profiling identifies the novel role of immunoproteasome in doxorubicin-induced cardiotoxicity

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Wen-Jie Zhao1, Sheng-Nan Wei1, Xiang-Jun Zeng2

  • 1Department of Physiology and Pathophysiology, Beijing Anzhen Hospital the Key Laboratory of Remodeling-Related Cardiovascular Diseases, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; Department of Cardiology, Chaoyang Hospital, Capital Medical University, Beijing 100069, China; Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing 100029, China.

Toxicology
|April 22, 2015
PubMed

Insights

Doxorubicin (DOX) chemotherapy damages the heart by affecting the ubiquitin-proteasome system (UPS). This study reveals immunoproteasome down-regulation contributes to DOX cardiotoxicity, suggesting it as a potential therapeutic target.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Biochemistry

Background:

  • Doxorubicin (DOX) is a common chemotherapy drug known to cause cardiotoxicity.
  • The ubiquitin-proteasome system (UPS) is crucial for protein degradation, but its role in DOX-induced cardiotoxicity is not fully understood.

Purpose of the Study:

  • To investigate the expression and function of the UPS, particularly the immunoproteasome, in the context of DOX-induced cardiotoxicity.
  • To explore the potential of the immunoproteasome as a therapeutic target for preventing DOX cardiotoxicity.

Main Methods:

  • C57BL/6 mice were treated with DOX, followed by assessments of cardiac function (echocardiography) and cardiomyocyte apoptosis (TUNEL assay).
  • Gene expression was analyzed using microarray and qPCR. Proteasome activity and protein ubiquitination levels were measured.
  • The effects of manipulating immunoproteasome subunit expression on DOX-induced apoptosis were examined.

Main Results:

  • DOX treatment significantly impaired cardiac function and increased cardiomyocyte apoptosis.
  • Microarray analysis showed significant alterations in genes related to apoptosis and the UPS, with down-regulation of immunoproteasome catalytic subunits (β1i, β2i, β5i).
  • DOX decreased proteasome activity and increased polyubiquitinated proteins. Overexpression of immunoproteasome subunits attenuated DOX-induced apoptosis, while knockdown exacerbated it.

Conclusions:

  • The immunoproteasome plays a critical role in regulating cardiomyocyte apoptosis during DOX treatment.
  • Down-regulation of the immunoproteasome contributes to DOX-induced cardiotoxicity.
  • Targeting the immunoproteasome may offer a novel strategy for preventing chemotherapy-induced heart damage.
Keywords:
ApoptosisCardiotoxicityDoxorubicinImmunoproteasomeMicroarrayUbiquitin-proteasome system

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