Altered Ca2+ homeostasis and impaired mitochondrial function in cardiomyopathy

TH Kuo, L Zhu, K Golden, JD Marsh… - Molecular and cellular …, 2002 - Springer
TH Kuo, L Zhu, K Golden, JD Marsh, SK Bhattacharya, BF Liu
Molecular and cellular biochemistry, 2002Springer
Altered Ca 2+ homeostasis and myocyte death is a major characteristic of the hereditary
cardiomyopathy in the dystrophic hamster. Despite numerous studies, the mechanisms that
link calcium dysregulation and cell death in this animal model remain unclear. We have
shown previously that the maintenance of mitochondrial Ca 2+ homeostasis is essential for
cell survival, and that loss of mitochondrial Ca 2+ is closely correlated with cell death in
cultured cells. Here, we have further investigated the role of mitochondrial Na+-Ca 2+ …
Abstract
Altered Ca2+ homeostasis and myocyte death is a major characteristic of the hereditary cardiomyopathy in the dystrophic hamster. Despite numerous studies, the mechanisms that link calcium dysregulation and cell death in this animal model remain unclear. We have shown previously that the maintenance of mitochondrial Ca2+ homeostasis is essential for cell survival, and that loss of mitochondrial Ca2+ is closely correlated with cell death in cultured cells. Here, we have further investigated the role of mitochondrial Na+-Ca2+ exchange (NCE) in the development of cardiomyopathy in the dystrophic hamster. We found that the myocyte death was associated with elevated NCE activity together with a reduced level of matrix Ca2+, and impaired mitochondrial energetics. The upregulation of NCE activity in myopathic heart was also accompanied by enhanced expression of the sarcolemmal Na+-Ca2+ exchange (NCX) without alterations in the L-type Ca2+ channel expression. Treatment of dystrophic hamsters with diltiazem (a potent inhibitor of NCE and Ca2+ channels) prevented the occurrence of cell death and restored the normal expression of NCX. Our findings implicate the dysregulation of both sarcolemmal and mitochondrial Na+-Ca2+ exchange in cell death in the myopathic heart.
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