title: Upregulation of Bcl-2 proteins during the transition to pressure overload-induced heart failure.
abstract: BACKGROUND
  Cardiomyocyte apoptosis is implicated in the pathogenesis of heart failure and mitochondria play an important role in this mode of cell death. In this study, activity of the Bcl-2 family of mitochondrial apoptotic proteins and their regulator (p53) were assessed during the transition to heart failure.
  
  
  METHODS
  Ten adult male sheep were banded with a variable aortic constriction device. This was progressively inflated to increase left ventricular (LV) afterload. The sheep were monitored echocardiographically, measuring LV Mass Index (LVMI), diastolic LV Internal Diameter (LVIDd) and Fractional Shortening (FS). Serial LV endomyocardial biopsies were obtained, to measure expression of p53 and Bcl-2 family proteins by Western blotting.
  
  
  RESULTS
  Over the first 3-4 weeks, the sheep developed hypertrophy (LVMI 79.5+/-4.6 vs. 44.0+/-3.0 g/m2, p<0.01), followed by gradual LV dilatation (LVIDd 4.23+/-0.08 vs. 3.39+/-0.07 cm, p<0.01). Ventricular function remained stable until 7-8 weeks post banding, when there was significant deterioration (FS 18.3+/-2.4 vs. 46.9+/-2.6%, p<0.01), associated with clinical heart failure. Upregulation of the Bax/Bcl-2 ratio, associated with increased levels of p53, was demonstrated in each of the echocardiographically defined stages (LV hypertrophy, LV dilatation and LV failure). In parallel, significantly higher levels of anti-apoptotic protein (Bcl-xL) was associated with LV dilatation and failure.
  
  
  CONCLUSIONS
  Upregulation of Bax/Bcl-2 ratio occurs during the transition to heart failure and in particular with the initial hypertrophic response. Increase in expression of the anti-apoptotic protein Bcl-xL suggests possible concomitant compensatory mechanisms being activated during the transition to heart failure.
authors.affiliation: Department of Cardiothoracic Surgery, Oxford Heart Centre, John Radcliffe Hospital, Oxford OX3 9DY, United Kingdom. narain.moorjani@doctors.org.uk
authors.forename: Narain
authors.initials: N
authors.lastname: Moorjani
authors.forename: Pedro
authors.initials: P
authors.lastname: Catarino
authors.forename: Danyah
authors.initials: D
authors.lastname: Trabzuni
authors.forename: Soad
authors.initials: S
authors.lastname: Saleh
authors.forename: Azad
authors.initials: A
authors.lastname: Moorji
authors.forename: Nduna
authors.initials: N
authors.lastname: Dzimiri
authors.forename: Futwan
authors.initials: F
authors.lastname: Al-Mohanna
authors.forename: Stephen
authors.initials: S
authors.lastname: Westaby
authors.forename: Manzoor
authors.initials: M
authors.lastname: Ahmad
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006333:Heart Failure / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D006352:Heart Ventricles / Q000000981:diagnostic imaging; D008297:Male; D009206:Myocardium / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012016:Reference Values; D012756:Sheep; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000378:metabolism; D017725:Ventricular Pressure
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53