title: Electron transport chain dysfunction in neonatal pressure-overload hypertrophy precedes cardiomyocyte apoptosis independent of oxidative stress.
abstract: OBJECTIVE
  We have previously shown in a model of pressure-overload hypertrophy that there is increased cardiomyocyte apoptosis during the transition from peak hypertrophy to ventricular decompensation. Electron transport chain dysfunction is believed to play a role in this process through the production of excessive reactive oxygen species. In this study we sought to determine electron transport chain function in pressure-overload hypertrophy and the role of oxidative stress in myocyte apoptosis.
  
  
  RESULTS
  Neonatal rabbits underwent thoracic aortic banding at 10 days of age. Compensated hypertrophy (4 weeks of age), decompensated hypertrophy (6 weeks of age), and age-matched controls (n = 4-8 per group) as identified by serial echocardiography were studied. Electron transport chain complex activities were determined by spectophotometry in isolated mitochondria. Complex I was significantly decreased (P = .005) at 4 weeks and further decreased at 6 weeks (P = .001). Complex II was significantly decreased at both time points (4 weeks, P = .003; 6 weeks, P = .009). However, hyddrogen peroxide production, measured in isolated mitochondria by fluorescence spectroscopy, was significantly decreased at 4 weeks of age in banded animals compared with controls (P = .038), and mitochondrial DNA oxidative damage (measurement of 8- hydroxydeoxyguanosine by enzyme-linked immunosorbent assay) was also significantly decreased at 4 weeks of age (P = .031). Mitochondrial activated apoptosis was determined by Bax/Bcl-2 ratios (immunoblotting). Bax/Bcl-2 levels were significantly increased in banded animals at 6 weeks.
  
  
  CONCLUSIONS
  In pressure-overload hypertrophy, the transition from compensated left ventricular hypertrophy to failure and cardiomyocyte apoptosis is preceded by mitochondrial complex I and II dysfunction followed by an increase in Bax/Bcl-2 ratios. The mechanism of apoptosis initiation is independent of increased oxidative stress.
authors.affiliation: Department of Cardiac Surgery, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Griffiths
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Friehs
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Scherr
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Poutias
authors.forename: Francis X
authors.initials: FX
authors.lastname: McGowan
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Del Nido
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D006332:Cardiomegaly / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D028361:Mitochondrial Diseases / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D011817:Rabbits