Cardiomyocyte apoptosis is associated with increased wall stress in chronic failing left ventricle.
OBJECTIVE
We examined cardiomyocyte apoptosis in chronic heart failure (HF) and its possible link to elevated wall stress.


RESULTS
Moderate HF was produced in sheep by sequential coronary microembolization. Six months later, the animals remained in a stable compensated haemodynamic state of HF. Apoptosis of cardiomyocytes in left ventricles was verified using Western blotting based on increased expression of: the apoptosis-associated death receptor Fas (1.5-fold); its ligand (FasL, 2.0-fold); and an upstream protease caspase-8 (2.7-fold) as well as its active cleavage peptide, p20 (5.6-fold). Previously we have reported the elevated expression of caspase-3 in the same animal model. The occurrence of apoptotic cardiomyocytes (0.3%) was quantified by TUNEL assays. Haemodynamic analysis indicated that ventricular dilatation, without wall thickening, caused a 2-fold increase in LV wall stress which, together with LV end-diastolic pressure, was linearly correlated with expression of Fas/FasL. Immunohistochemical studies localized FasL and caspase-8 to intercalated discs, suggesting that wall stress may play a role in initiating cardiomyocyte apoptosis.


CONCLUSIONS
Apoptosis of cardiomyocytes in chronic HF is associated with increased wall stress, which may be responsible for the activation of a Fas/FasL and caspase-8 interaction in the region of intercalated discs.
Jiang
L
L
Department of Cardiology, Cardiac Technology Centre, Royal North Shore Hospital, St. Leonards, NSW, Australia. lelej@physiol.usyd.edu.au
Huang
Y
Y
Hunyor
S
S
dos Remedios
C G
CG
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002303:Cardiac Output, Low / Q000473:pathology; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002908:Chronic Disease; D053222:Fas Ligand Protein; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008562:Membrane Glycoproteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000473:pathology*; D012756:Sheep; D013312:Stress, Physiological / Q000473:pathology*; D018487:Ventricular Dysfunction, Left / Q000473:pathology*; D019014:fas Receptor / Q000378:metabolism
D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases