Open AccessCalpain-2 promotes MKP-1 expression protecting cardiomyocytes in both in vitro and in vivo mouse models of doxorubicin-induced cardiotoxicity
Author(s) -
Dong Zheng,
Zhaoliang Su,
Yi Zhang,
Rui Ni,
Guo-Chang Fan,
Jeffrey Robbins,
LongSheng Song,
Jianmin Li,
Tianqing Peng
Publication year - 2019
Publication title -
archives of toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.264
H-Index - 111
eISSN - 1432-0738
pISSN - 0340-5761
DOI - 10.1007/s00204-019-02405-w
Subject(s) - calpain , doxorubicin , tensin , gene knockdown , cardiotoxicity , phosphatase , apoptosis , cancer research , pharmacology , biology , microbiology and biotechnology , chemistry , medicine , phosphorylation , pten , signal transduction , pi3k/akt/mtor pathway , biochemistry , toxicity , chemotherapy , enzyme
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.