Journal article
Increased calpain-1 in mitochondria induces dilated heart failure in mice: role of mitochondrial superoxide anion
Basic research in cardiology, Vol.114(3), pp.17-15
05/01/2019
DOI: 10.1007/s00395-019-0726-1
PMCID: PMC9444798
PMID: 30874894
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 1month starting from age 2months 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.
Details
- Title: Subtitle
- Increased calpain-1 in mitochondria induces dilated heart failure in mice: role of mitochondrial superoxide anion
- Creators
- Ting Cao - Soochow UniversityShuai Fan - Soochow UniversityDong Zheng - Soochow UniversityGrace Wang - University of TorontoYong Yu - Fudan UniversityRuizhen Chen - Fudan UniversityLong-Sheng Song - Roy J. and Lucille A. Carver College of MedicineGuo-Chang Fan - University of Cincinnati Medical CenterZhuxu Zhang - Western UniversityTianqing Peng - Soochow University
- Resource Type
- Journal article
- Publication Details
- Basic research in cardiology, Vol.114(3), pp.17-15
- DOI
- 10.1007/s00395-019-0726-1
- PMID
- 30874894
- PMCID
- PMC9444798
- NLM abbreviation
- Basic Res Cardiol
- ISSN
- 0300-8428
- eISSN
- 1435-1803
- Publisher
- Springer Nature
- Number of pages
- 15
- Grant note
- 81,470,499; 81521001; 31570904 / National Natural Science Foundation of China; National Natural Science Foundation of China (NSFC) BK20171216 / Natural Science Foundation of Jiangsu Province MOP-133657 / Canadian Institutes of Health Research; Canadian Institutes of Health Research (CIHR)
- Language
- English
- Date published
- 05/01/2019
- Academic Unit
- Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984293075302771
Metrics
19 Record Views