Calpain-2 promotes MKP-1 expression protecting cardiomyocytes in both in vitro and in vivo mouse models of doxorubicin-induced cardiotoxicity

Dong Zheng; Zhaoliang Su; Yi Zhang; Rui Ni; Guo-Chang Fan; Jeffrey Robbins; Long-Sheng Song; Jianmin Li; Tianqing Peng

doi:10.1007/s00204-019-02405-w

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Calpain-2 promotes MKP-1 expression protecting cardiomyocytes in both in vitro and in vivo mouse models of doxorubicin-induced cardiotoxicity

Journal article

Peer reviewed

Calpain-2 promotes MKP-1 expression protecting cardiomyocytes in both in vitro and in vivo mouse models of doxorubicin-induced cardiotoxicity

Dong Zheng, Zhaoliang Su, Yi Zhang, Rui Ni, Guo-Chang Fan, Jeffrey Robbins, Long-Sheng Song, Jianmin Li and Tianqing Peng

Archives of toxicology, Vol.93(4), pp.1051-1065

04/2019

DOI: 10.1007/s00204-019-02405-w

PMCID: PMC9441256

PMID: 30810770

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https://www.ncbi.nlm.nih.gov/pmc/articles/9441256View

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Abstract

We recently reported that doxorubicin decreased the expression of calpain-1/2, while inhibition of calpain activity promoted doxorubicin-induced cardiac injury in mice. In this study, we investigated whether and how elevation of calpain-2 could affect doxorubicin-triggered cardiac injury. Transgenic mice with inducible cardiomyocyte-specific expression of calpain-2 were generated. An acute cardiotoxicity was induced in both transgenic mice and their relevant wild-type littermates by injection of a single dose of doxorubicin (20 mg/kg) and cardiac injury was analyzed 5 days after doxorubicin injection. Cardiomyocyte-specific up-regulation of calpain-2 did not induce any adverse cardiac phenotypes under physiological conditions by age 3 months, but significantly reduced myocardial injury and improved myocardial function in doxorubicin-treated mice. Cardiac protection of calpain-2 up-regulation was also observed in a mouse model of chronic doxorubicin cardiotoxicity. Up-regulation of calpain-2 increased the protein levels of mitogen activated protein kinase phosphatase-1 (MKP-1) in cultured mouse cardiomyocytes and heart tissues. Over-expression of MKP-1 prevented, whereas knockdown of MKP-1 augmented doxorubicin-induced apoptosis in cultured cardiomyocytes. Moreover, knockdown of MKP-1 offset calpain-2-elicited protective effects against doxorubicin-induced injury in cultured cardiomyocytes. Mechanistically, up-regulation of calpain-2 reduced the protein levels of phosphatase and tensin homolog and consequently promoted Akt activation, leading to increased MKP-1 protein steady-state levels by inhibiting its degradation. Collectively, this study reveals a new role of calpain-2 in promoting MKP-1 expression via phosphatase and tensin homolog/Akt signaling. This study also suggests that calpain-2/MKP-1 signaling may represent new therapeutic targets for doxorubicin-induced cardiac injury.

Animals

Apoptosis - drug effects

Apoptosis - genetics

Calpain - genetics

Calpain - metabolism

Cardiotoxicity

Cells, Cultured

Doxorubicin - toxicity

Dual Specificity Phosphatase 1 - genetics

Gene Expression - drug effects

Heart - drug effects

Mice, Transgenic

Myocardium - metabolism

Myocardium - pathology

Myocytes, Cardiac - drug effects

Myocytes, Cardiac - metabolism

Myocytes, Cardiac - pathology

Up-Regulation

Details

Title: Subtitle: Calpain-2 promotes MKP-1 expression protecting cardiomyocytes in both in vitro and in vivo mouse models of doxorubicin-induced cardiotoxicity
Creators: Dong Zheng - Soochow University
Zhaoliang Su - Jiangsu University
Yi Zhang - Soochow University
Rui Ni - Lawson Health Research Institute
Guo-Chang Fan - University of Cincinnati Medical Center
Jeffrey Robbins - University of Cincinnati Medical Center
Long-Sheng Song - University of Iowa
Jianmin Li - First Affiliated Hospital of Wenzhou Medical University
Tianqing Peng - Western University
Resource Type: Journal article
Publication Details: Archives of toxicology, Vol.93(4), pp.1051-1065
DOI: 10.1007/s00204-019-02405-w
PMID: 30810770
PMCID: PMC9441256
NLM abbreviation: Arch Toxicol
ISSN: 0340-5761
eISSN: 1432-0738
Grant note: LY14H020005 / Natural Science Foundation of Zhejiang Province G-17-0018361 / Heart and Stroke Foundation of Canada BK20171216 / Basic Research Program of Jiangsu Province
Language: English
Date published: 04/2019
Academic Unit: Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984288726802771

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