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

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.

• Authors: Dong Zheng, Zhaoliang Su, Yi Zhang, Rui Ni, Guo-Chang Fan, Jeffrey Robbins, Long-Sheng Song, Jianmin Li, Tianqing Peng
• Journal: Archives of toxicology (Arch Toxicol) Vol. 93 Issue 4 Pg. 1051-1065 (04 2019) ISSN: 1432-0738 [Electronic] Germany
• PMID: 30810770 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Doxorubicin
• Dual Specificity Phosphatase 1
• Dusp1 protein, mouse
• Calpain
• Capn2 protein, mouse

Topics

• Animals
• Apoptosis (drug effects, genetics)
• Calpain (genetics, metabolism)
• Cardiotoxicity
• Cells, Cultured
• Doxorubicin (toxicity)
• Dual Specificity Phosphatase 1 (genetics)
• Gene Expression (drug effects)
• Heart (drug effects)
• Mice, Transgenic
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• Up-Regulation