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.
[1]Soochow Univ, Inst Biol, Suzhou 215123, Peoples R China;
[2]Soochow Univ, Inst Med Sci, Suzhou 215123, Peoples R China;
[3]London Hlth Sci Ctr, Lawson Hlth Res Inst, Crit Illness Res, VRL 6th Floor,A6-140,800 Commissioners Rd, London, ON N6A 4S2, Canada;
[4]Univ Western Ontario, Dept Med, London, ON N6A 4S2, Canada;
[5]Univ Toronto, Fac Med, Toronto, ON M5S 1A8, Canada;
[6]Fudan Univ, Shanghai Zhongshan Hosp, Shanghai Inst Cardiovasc Dis, Shanghai 200032, Peoples R China;
[7]Univ Iowa, Coll Med, Francois M Abboud Cardiovasc Res Ctr, Div Cardiovasc Med,Dept Internal Med, Iowa City, IA 52242 USA;
[8]Univ Cincinnati, Dept Pharmacol & Syst Physiol, Coll Med, Cincinnati, OH 45267 USA;
[9]Univ Western Ontario, Dept Pathol & Lab Med, London, ON N6A 4S2, Canada
(8.0+极速模式)