Apoptosis of ventricular and atrial myocytes from pacing-induced canine heart failure.
OBJECTIVE
Rapid ventricular pacing in dogs results in a low output cardiomyopathic state similar to idiopathic dilated cardiomyopathy in man. Cell death by apoptosis may play an important role in the loss of cardiac function. This study investigates the molecular pathways involved in the regulation of apoptosis in dogs with pacing-induced heart failure.


METHODS
Apoptosis was identified by terminal transferase nick end-labelling (TUNEL) in the ventricles and atria of dog hearts affected by rapid-ventricular pacing. Western blots were used to determine expression of the components involved in the initiation (Fas, Fas-Ligand, FADD), regulation (Bcl-2, Bax) and execution (caspase-2 and caspase-3) of apoptosis.


RESULTS
Pacing-induced heart failure resulted in a significant increase in the number of ventricular and atrial myocyte nuclei undergoing apoptosis as measured by TUNEL. Compared to the samples from control hearts (n=6) the expression of Bcl-2, an inhibitor of apoptosis, was significantly reduced in ventricles from five dogs with pacing-induced heart failure. No change in the expression of the apoptotic inducer Bax was detected. Fas and FADD were significantly elevated in all paced ventricles, and Fas-L was only detected in the paced hearts. Both caspase-2 and caspase-3 were elevated following ventricular pacing.


CONCLUSIONS
We have identified components of the signalling pathways along which apoptosis proceeds following the induction of heart failure in dogs. Apoptosis was also detected in the atria raising the possibility that, like human dilated cardiomyopathy, the molecular changes are global.
Heinke
M Y
MY
Muscle Research Unit, Institute for Biomedical Research, Department of Anatomy and Histology, The University of Sydney, NSW 2006, Sydney, Australia.
Yao
M
M
Chang
D
D
Einstein
R
R
dos Remedios
C G
CG
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002304:Cardiac Pacing, Artificial; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D004285:Dogs; D005260:Female; D006325:Heart Atria / Q000473:pathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D020287:In Situ Nick-End Labeling; D008297:Male; D009206:Myocardium / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D020169:Caspases