Volume 14 Issue 1, February 2004: 16-26
ORIGINAL ARTICLES
Mechanical stretch induces mitochondria-dependent apoptosis in neonatal rat cardiomyocytes and G2/M accumulation in cardiac fibroblasts
Xu Dong LIAO1,2, Xiao Hui WANG1, Hai Jing JIN1, Lan Ying CHEN2,*, Quan CHEN1,*
1Laboratory of Apoptosis and Cancer Biology, State Key Laboratory of Biomembrane and Membrane Biotechnology, Chinese Academy of Sciences, Beijing 100080, China.
2Cardiovascular Institute and Fu Wai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100037, China.
Correspondence: Quan CHEN Lan Ying CHEN(chenq@panda.ioz.ac.cn lanyingchen@hotmail.com)
Heart remodeling is
associated with the loss of cardiomyocytes and increase of fibrous tissue
owing to abnormal mechanical load in a number of heart disease conditions.
In present study, a well-described
in vitro sustained stretch model
was employed to study mechanical stretch-induced responses in both neonatal
cardiomyocytes and cardiac fibroblasts. Cardiomyocytes, but not cardiac
fibroblasts, underwent mitochondria-dependent apoptosis as evidenced by
cytochrome c (cyto c) and Smac/DIABLO release from mitochondria into cytosol
accompanied by mitochondrial membrane potential (Dy
m) reduction,
indicative of mitochondrial permeability transition pore (PTP) opening.
Cyclosporin A, an inhibitor of PTP, inhibited stretch-induced cyto c release,
Dy
m reduction and apoptosis, suggesting an important role of
mitochondrial PTP in stretch-induced apoptosis. The stretch also resulted
in increased expression of the pro-apoptotic Bcl-2 family proteins, including
Bax and Bad, in cardiomyocytes, but not in fibroblasts. Bax was accumulated
in mitochondria following stretch. Cell permeable Bid-BH3 peptide could
induce and facilitate stretch-induced apoptosis and Dy
m reduction
in cardiomyocytes. These results suggest that Bcl-2 family proteins play
an important role in coupling stretch signaling to mitochondrial death
machinery, probably by targeting to PTP. Interestingly, the levels of
p53 were increased at 12 h after stretch although we observed that Bax
upregulation and apoptosis occurred as early as 1 h. Adenovirus delivered
dominant negative p53 blocked Bax upregulation in cardiomyocytes but showed
partial effect on preventing stretch-induced apoptosis, suggesting that
p53 was only partially involved in mediating stretch-induced apoptosis.
Furthermore, we showed that p21 was upregulated and cyclin B1 was downregulated
only in cardiac fibroblasts, which may be associated with G
2/M
accumulation in response to mechanical stretch.
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