1. Calpain-2 promotes MKP-1 expression protecting cardiomyocytes in both in vitro and in vivo mouse models of doxorubicin-induced cardiotoxicity
- Author
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Dong Zheng, Zhaoliang Su, Jeffrey Robbins, Tianqing Peng, Long-Sheng Song, Jianmin Li, Rui Ni, Yi Zhang, and Guo-Chang Fan
- Subjects
0301 basic medicine ,Genetically modified mouse ,Health, Toxicology and Mutagenesis ,Phosphatase ,Gene Expression ,Apoptosis ,Mice, Transgenic ,010501 environmental sciences ,Pharmacology ,Toxicology ,01 natural sciences ,Article ,03 medical and health sciences ,medicine ,Tensin ,PTEN ,Animals ,Doxorubicin ,Myocytes, Cardiac ,Protein kinase B ,Cells, Cultured ,0105 earth and related environmental sciences ,Gene knockdown ,Cardiotoxicity ,biology ,Chemistry ,Calpain ,Myocardium ,Dual Specificity Phosphatase 1 ,Heart ,General Medicine ,Up-Regulation ,030104 developmental biology ,biology.protein ,medicine.drug - 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 signalling. This study also suggests that calpain-2/MKP-1 signaling may represent new therapeutic targets for doxorubicin-induced cardiac injury.
- Published
- 2019