Over-expression of mitochondria-targeted calpain-1 induces dilated heart failure in transgenic mice: an important role of mitochondrial reactive oxygen species

Abstract

Ting Cao*, Dong Zheng, Lulu Zhang, Rui Ni, Tianqing Peng  Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province, China. Lawson Health Research Institute, Departments of Medicine and Pathology and Laboratory Medicine, Western University, London, Ontario, Canada Background: Calpain-1 has been shown to increase in mitochondria of the heart under certain pathological conditions. Increased calpain-1 in mitochondria is associated with myocardial dysfunction.  Aims: This study was to investigate forced up-regulation of calpain-1 in mitochondria induces myocardial injury and heart failure. Methods and Results: A novel line of transgenic mice over-expressing cardiomyocyte-specific and mitochondria-targeted calpain-1 was generated. Over-expression of mitochondria-targeted calpain-1 increased mitochondrial superoxide generation in hearts and induced cardiac hypertrophy, fibrosis and ventricular chamber dilation, leading to myocardial dysfunction and early death in transgenic mice. These effects of mitochondrial calpain-1 up-regulation were attenuated by administration of mitochondria-targeted antioxidant mito-TEMPO. Increased mitochondrial calpain-1 also correlated with mitochondrial dysfunction in transgenic mouse hearts.  Conclusions: Mitochondrial calpain-1 induces myocardial injury and dysfunction likely by promoting mitochondrial superoxide generation. Thus, mitochondrial calpain-1 may represent a novel mechanism underlying heart failure.