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Calpain inhibitor MDL 28170 protects against the Ca 2+ paradox in rat hearts
Author(s) -
Bi ShengHui,
Jin ZhenXiao,
Zhang JianYing,
Chen Tao,
Zhang ShengLi,
Yang Yang,
Duan WeiXun,
Yi DingHua,
Zhou JingJun,
Ren Jun
Publication year - 2012
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2012.05683.x
Subject(s) - calpain , calcium , chemistry , apoptosis , proteolysis , cardiac function curve , calcium in biology , intracellular , lactate dehydrogenase , cytosol , medicine , endocrinology , microbiology and biotechnology , biochemistry , biology , heart failure , enzyme
Summary The calcium paradox represents an important model in which to study myocardial injuries due to intracellular Ca 2+ overload. In a previous study, calpain was transiently activated in Ca 2+ ‐paradoxic hearts. The aim of the present study was to determine the role of calpain in myocardial dysfunction in hearts subjected to the Ca 2+ paradox and to elucidate the underlying mechanisms. Rat hearts were isolated, Langendorff perfused and subjected to the Ca 2+ paradox, which was induced by 3 min Ca 2+ depletion followed by 30 min Ca 2+ repletion, in the presence or absence of the calpain inhibitor 10 umol/L MDL 28170. Cardiac function was evaluated. Furthermore, cell death and the degradation of troponin I ( T n I ) were assessed and calpain activity was determined by measurement of the α‐fodrin fragment and confocal image analysis. Upon Ca 2+ repletion, the hearts immediately deteriorated, exhibiting a marked depression in cardiac function and an enlarged myocardial injury area. This was accompanied by significant increases in lactate dehydrogenase, mitochondrial release of cytochrome c , the apoptotic index and degraded T n I . These changes were significantly inhibited by MDL 28170, with the exception of T n I degradation. Compared with the control group, Ca 2+ ‐paradoxic hearts showed a marked increase in cleaved 150 kDa fragments resulting from specific calpain‐mediated proteolysis of α‐fodrin. This effect was attenuated by MDL 28170. Confocal image analysis revealed the translocation of both μ‐ and m‐calpain to the sarcolemmal membrane in Ca 2+ ‐paradoxic hearts, indicating increased activity of both isoforms. The results suggest that the Ca 2+ paradox promotes calpain activity, leading to necrosis, apoptosis and myocardial dysfunction.