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

  • Ting Cao
  • Shuai Fan
  • Dong Zheng
  • Grace Wang
  • Yong Yu
  • Ruizhen Chen
  • Long-Sheng Song
  • Guo-Chang Fan
  • Zhuxu Zhang
  • Tianqing PengEmail author
Original Contribution

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.

Keywords

Calpain Heart failure Mitochondria Superoxide onion ATP synthase 

Notes

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.).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

395_2019_726_MOESM1_ESM.pptx (282 kb)
Supplementary material 1 (PPTX 282 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Ting Cao
    • 1
  • Shuai Fan
    • 1
  • Dong Zheng
    • 1
    • 2
    • 3
    • 8
  • Grace Wang
    • 4
  • Yong Yu
    • 5
  • Ruizhen Chen
    • 5
  • Long-Sheng Song
    • 6
  • Guo-Chang Fan
    • 7
  • Zhuxu Zhang
    • 3
    • 8
  • Tianqing Peng
    • 1
    • 2
    • 3
    • 8
    Email author
  1. 1.Institutes of Biology and Medical SciencesSoochow UniversitySuzhouChina
  2. 2.Critical Illness ResearchLawson Health Research Institute, London Health Sciences CentreLondonCanada
  3. 3.Department of MedicineUniversity of Western OntarioLondonCanada
  4. 4.Faculty of MedicineUniversity of TorontoTorontoCanada
  5. 5.Shanghai Institute of Cardiovascular Diseases, Shanghai Zhongshan HospitalFudan UniversityShanghaiChina
  6. 6.Division of Cardiovascular Medicine, Department of Internal Medicine, François M. Abboud Cardiovascular Research CenterUniversity of Iowa Carver College of MedicineIowa CityUSA
  7. 7.Department of Pharmacology and Systems PhysiologyUniversity of Cincinnati College of MedicineCincinnatiUSA
  8. 8.Department of Pathology and Laboratory MedicineUniversity of Western OntarioLondonCanada

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