(Circulation. 1997;96:1580-1585.)
© 1997 American Heart Association, Inc.
Articles |
The bcl-2 Gene Product Prevents Programmed Cell Death of Ventricular Myocytes
From the Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre, Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada R2H 2A6.
Correspondence to Dr Lorrie A. Kirshenbaum, Institute of Cardiovascular Sciences, St Boniface Hospital Research Centre, Room 3042, 351 Taché Ave, Winnipeg, Manitoba, Canada R2H 2A6. E-mail Lorrie{at}SBRC.umanitoba.ca
Background To formally test whether the antiapoptotic protein bcl-2 would prevent programmed cell death in cardiac muscle cells provoked by p53, a known trigger of apoptosis in a variety of different cell types, we used replication defective adenovirus encoding either the bcl-2 and p53 genes to deliver bcl-2 and p53 to ventricular myocytes with high efficiency and uniformity.
Methods and Results Vital staining of ventricular myocytes revealed a significant (7-fold, P<.05) increase in myocyte cell death in the presence of p53 in contrast to uninfected cells or those infected with a control virus. In addition, in the presence of p53, nucleosomal DNA fragmentation observed by Hoescht 33258 staining and terminal transferase deoxynucleotide end labeling indicated a significant increase in apoptotic cardiac nuclei compared with control cells, confirming the hypothesis that p53 alone is sufficient to trigger apoptosis of ventricular myocytes. Moreover, a significant increase in transcription of the bax promoter was seen in the presence but not in the absence of p53 compared with control cells. Expression of the antiapoptotic gene bcl-2 in ventricular myocytes was sufficient to prevent ventricular myocyte death and apoptosis provoked by p53. Importantly, the antiapoptotic effects of bcl-2 were independent of altered p53 expression or localization of p53 to cardiac nuclei. However, p53 dependent transcription of bax was repressed 4-fold (P<.05) by bcl-2, suggesting a tentative link between p53-mediated apoptosis and the protective properties conferred by bcl-2 in ventricular myocytes.
Conclusions To our knowledge, the data provide the first indication for the operation of bcl-2 in ventricular myocytes as an antiapoptotic factor.
Key Words: apoptosis • adenovirus • cells • genes • molecular biology
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