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Toxicology. 2015 Jul 3;333:76-88. doi: 10.1016/j.tox.2015.04.009. Epub 2015 Apr 17.

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

Author information

1
Department 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.
2
Department 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. Electronic address: megan_zeng@163.com.
3
Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
4
Department 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. Electronic address: hhli1995@yahoo.com.

Abstract

The most well-known cause of chemotherapy-induced cardiotoxicity is doxorubicin (DOX). The ubiquitin-proteasome system (UPS) is the main cellular machinery for protein degradation in eukaryotic cells. However, the expression pattern of the UPS in DOX-induced cardiotoxicity remains unclear. C57BL/6 mice were intraperitoneally injected with a single dose of DOX (15mg/kg). After 1, 3 and 5 days, cardiac function and apoptosis were detected with echocardiography and TUNEL assay. Microarray assay and qPCR analysis were also performed at day 5. We found that DOX caused a significant decrease in cardiac function at day 5 and increase in cardiomyocyte apoptosis at days 3 and 5. Microarray data revealed that totally 1185 genes were significantly regulated in DOX-treated heart, and genes involved in apoptosis and the UPS were mostly altered. Among them, the expression of 3 immunoproteasome catalytic subunits (β1i, β2i and β5i) was markedly down-regulated. Moreover, DOX significantly decreased proteasome activities and enhanced polyubiquitinated proteins in the heart. Importantly, overexpression of immunoproteasome catalytic subunits (β1i, β2i or β5i) significantly attenuated DOX-induced cardiomyocyte apoptosis and other UPS gene expression while knockdown of them significantly increased DOX-induced cardiomyocyte apoptosis. These effects were partially associated with increased degradation of multiple pro-apoptotic proteins. In conclusion, our studies suggest that immunoproteasome plays an important role in DOX-induced cardiomyocyte apoptosis, and may be a novel therapeutic target for prevention of DOX-induced cardiotoxicity.

KEYWORDS:

Apoptosis; Cardiotoxicity; Doxorubicin; Immunoproteasome; Microarray; Ubiquitin-proteasome system

PMID:
25896364
DOI:
10.1016/j.tox.2015.04.009
[Indexed for MEDLINE]

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