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Increased calpain-1 in mitochondria induces dilated heart failure in mice: role of mitochondrial superoxide anion

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Abstract

We and others have reported that calpain-1 was increased in myocardial mitochondria from various animal models of heart disease. This study investigated whether constitutive up-regulation of calpain-1 restricted to mitochondria induced myocardial injury and heart failure and, if so, whether these phenotypes could be rescued by selective inhibition of mitochondrial superoxide production. Transgenic mice with human CAPN1 up-regulation restricted to mitochondria in cardiomyocytes (Tg-mtCapn1/tTA) were generated and characterized with low and high over-expression of transgenic human CAPN1 restricted to mitochondria, respectively. Transgenic up-regulation of mitochondria-targeted CAPN1 dose-dependently induced cardiac cell death, adverse myocardial remodeling, heart failure, and early death in mice, the changes of which were associated with mitochondrial dysfunction and mitochondrial superoxide generation. Importantly, a daily injection of mitochondria-targeted superoxide dismutase mimetics mito-TEMPO for 1 month starting from age 2 months attenuated cardiac cell death, adverse myocardial remodeling and heart failure, and reduced mortality in Tg-mtCapn1/tTA mice. In contrast, administration of TEMPO did not achieve similar cardiac protection in transgenic mice. Furthermore, transgenic up-regulation of mitochondria-targeted CAPN1 induced a reduction of ATP5A1 protein and ATP synthase activity in hearts. In cultured cardiomyocytes, increased calpain-1 in mitochondria promoted mitochondrial permeability transition pore (mPTP) opening and induced cell death, which were prevented by over-expression of ATP5A1, mito-TEMPO or cyclosporin A, an inhibitor of mPTP opening. In conclusion, this study has provided direct evidence demonstrating that increased mitochondrial calpain-1 is an important mechanism contributing to myocardial injury and heart failure by disrupting ATP synthase, and promoting mitochondrial superoxide generation and mPTP opening.

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Acknowledgements

This study was supported by operating grants from the National Natural Science Foundation of China (81,470,499 to T.P., 81521001 and 31570904 to R.C.), Natural Science Foundation of Jiangsu Province (BK20171216 to T.P.), and the Canadian Institutes of Health Research (MOP-133657 to T.P.).

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Authors and Affiliations

  1. Institutes of Biology and Medical Sciences, Soochow University, Suzhou, 215123, China

    Ting Cao, Shuai Fan, Dong Zheng & Tianqing Peng

  2. Critical Illness Research, Lawson Health Research Institute, London Health Sciences Centre, VRL 6th Floor, A6-140, 800 Commissioners Road, London, ON, N6A 4S2, Canada

    Dong Zheng & Tianqing Peng

  3. Department of Medicine, University of Western Ontario, London, ON, N6A 4S2, Canada

    Dong Zheng, Zhuxu Zhang & Tianqing Peng

  4. Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada

    Grace Wang

  5. Shanghai Institute of Cardiovascular Diseases, Shanghai Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Yong Yu & Ruizhen Chen

  6. Division of Cardiovascular Medicine, Department of Internal Medicine, François M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA

    Long-Sheng Song

  7. Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA

    Guo-Chang Fan

  8. Department of Pathology and Laboratory Medicine, University of Western Ontario, London, ON, N6A 4S2, Canada

    Dong Zheng, Zhuxu Zhang & Tianqing Peng

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  1. Ting Cao
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  2. Shuai Fan
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Cao, T., Fan, S., Zheng, D. et al. Increased calpain-1 in mitochondria induces dilated heart failure in mice: role of mitochondrial superoxide anion. Basic Res Cardiol 114, 17 (2019). https://doi.org/10.1007/s00395-019-0726-1

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