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Cell research (2004); 14(1):16-26

Mechanical stretch induces mitochondria-dependent apoptosis in neonatal rat cardiomyocytes and G₂/M accumulation in cardiac fibroblasts

Xu Dong LIAO^1,2, Xiao Hui WANG¹, Hai Jing JIN¹, Lan Ying CHEN^2,*, Quan CHEN^1,*

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.

Received, Sep 8, 2003; Revised, Nov 6, 2003; Accepted, Nov 25, 2003.

Correspondence: Quan CHEN 86-10-6253-7763(Phn) 86-10-6256-5689(Fax) chenq@panda.ioz.ac.cn Lan Ying CHEN 86-10-6831-4466-ext-8068(Phn) 86-10-6831-3012(Fax) lanyingchen@hotmail.com

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Abstract

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 G₂/M accumulation in response to mechanical stretch.

Keywords: apoptosis, mechanical stretch, Bcl-2 and its family proteins, mitochondria, cardiomyocyte.