期刊
INTERNATIONAL JOURNAL OF CARDIOLOGY
卷 197, 期 -, 页码 26-32出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.ijcard.2015.06.010
关键词
Calpain; Mitochondria; Mitochondrial permeability transition pore; Calcium; Ischemia-reperfusion injury
资金
- JSPS KAKENHI Grant [24659334, 25293162]
- Grants-in-Aid for Scientific Research [25293162, 24659334] Funding Source: KAKEN
Background/objectives: : Opening of the mitochondrial permeability transition pore (mPTP) is involved in ischemia-reperfusion injury. Isoforms of Ca2+-activated cysteine proteases, calpains, are implicated in the development of myocardial infarction in ischemia-reperfusion. Growing evidence has revealed the presence of calpains in the mitochondria. We aimed to characterize mitochondrial calpains in the rat heart and to investigate the roles of calpains in mPTP opening after ischemia-reperfusion. Methods and results: : Western blotting analysis showed the expression of mu-calpain, m-calpain and calpain 10 in mitochondria isolated from male Sprague-Dawley rats, but casein zymography detected only m-calpain activity. Subcellular fractionation of mitochondria demonstrated the distribution of m-calpain to the matrix fraction. Addition of >500 mu M of Ca2+ to isolated mitochondria induced mitochondrial swelling, reflecting mPTP opening, and calpain activation. Ca(2+-)induced mitochondrial swelling was inhibited partially by the calpain inhibitor calpeptin. These results support a partial contribution of calpain in the opening of the mPTP. The addition of Ca2+ to the mitochondria induced inactivation of complex I of the electron transport chain, and cleavage of the ND6 complex I subunit, which were inhibited by calpeptin. Mitochondria isolated from rat hearts that underwent 30 min of coronary occlusion followed by 30 min of reperfusion showed activation of mitochondrial calpains, ND6 cleavage, complex I inactivation, and mPTP opening, which were inhibited by pretreatment with calpain inhibitor 1. Conclusions: : We demonstrated for the first time the presence of mitochondrialmatrixm-calpain, and its contribution to complex I inactivation and mPTP opening after postischemic reperfusion in the rat heart. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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