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J Am Coll Cardiol, 2000; 35:1769-1777 © 2000 by the American College of Cardiology Foundation |
a Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College School of Science, Technology and Medicine, Heart Science Center, Harefield Hospital, Harefield, United Kingdom
Manuscript received September 8, 1999; revised manuscript received December 30, 1999, accepted February 21, 2000.
Reprint requests and correspondence: Dr. N. Latif, Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College School of Science, Technology and Medicine, Heart Science Center, Harefield Hospital, Harefield, England. UB9 6JH. UK
najma.latif{at}harefield.nthames.nhs.uk
OBJECTIVES
To elucidate the pattern of expression of four members of the Bcl-2 family of proteins and to correlate this with terminal deoxynucleotidyl transferase [TdT]-mediated dUTP nick end labelling (TUNEL) and DNA fragmentation.
BACKGROUND
Apoptosis has been implicated as a possible mechanism in the development of heart failure. However, the mechanisms involved remain unclear.
METHODS
We have studied the expression of four members of the Bcl-2 family that are involved in the regulation of apoptosis and analyzed DNA fragmentation as a marker of apoptosis and as a biochemical criterion to distinguish between apoptosis and necrosis in dilated cardiomyopathy (DCM), ischemic heart disease (IHD) and normal donors.
RESULTS
Western blot analysis and immunocytochemistry of the proapoptotic and antiapoptotic Bcl-2 proteins demonstrated significantly higher levels of all these proteins in the diseased groups compared with normal donors. Additionally, Bax was significantly higher in the IHD group compared with DCM. Terminal deoxynucleotidyl transferase [TdT]-mediated dUTP nick end labelling analysis demonstrated a significantly higher percentage of TUNEL-positive cells in the diseased groups compared with the control. Genomic DNA extraction of ventricular myocardial tissue showed no demonstrable DNA laddering for any of the groups.
CONCLUSIONS
The significant increases in the levels of the proapoptotic proteins Bak and Bax and the higher percentage of TUNEL-positive cells in both diseased groups suggests the presence of ongoing apoptosis. However, increases in the antiapoptotic proteins, Bcl-2 and Bcl-xL, suggest a possible concommitant, compensatory antiapoptotic mechanism in patients with heart failure.
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