Abstract 15553: PPAR-gamma Receptor Stimulation with Chronic Administration of Pioglitazone Reduces State 3 Respiration of Isolated Mitochondria and Lowers Tissue ATP Levels in Hibernating Swine Myocardium
Background. Although clinical studies suggest that chronic administration of glitazones may exacerbate heart failure, the reasons are unclear. Using a swine model of hibernating myocardium, we tested whether chronic stimulation of the PPAR-gamma receptor with pioglitazone (PIO) would alter energetics, by reducing mitochondrial respiration and tissue levels of ATP within the chronically ischemic myocardium.
Methods. Eighteen pigs underwent thoracotomy with placement of a constrictor around the LAD artery. At 8-weeks post-recovery, they received daily PIO (3 mg/kg) or placebo in the chow for 4 additional weeks. Prior to sacrifice, regional function was done by ECHO and regional blood flows were obtained by µspheres at baseline and during high-dose dobutamine (40 µg/kg/min). Post-sacrifice, tissue was harvested for ATP levels (enzymatically) and isolated mitochondria were studied with a Clark electrode.
Results: In all pigs, baseline function (% wall thickening) was lower in the hibernating LAD versus Remote region (42±5% vs 58±5%; P<0.05). LAD blood flow when normalized to remote region was 83±5% at baseline and 64±7% during dobutamine, with no intergroup differences noted. Compared with the placebo group, the PIO group demonstrated a reduced energetic state, including lower ATP levels in the tissue (1.61±0.22 versus 2.35±0.25 µmol/g; P<0.05) and depressed mitochondrial state 3 respiration (102±13 versus 161±22 nmol O2/min/mg; P<0.05). As shown in the Figure, the lower levels of state 3 respiration in isolated mitochondria correlated with depressed ATP levels within the same regions.
Conclusions. Chronic administration of the PPAR-gamma agonist pioglitazone altered bioenergetics in hibernating hearts, including a reduction in mitochondrial state 3 respiration and tissue ATP levels. Future studies should address whether PPAR-gamma stimulation promotes an energetic cause of heart failure by altering expression of electron transport chain proteins.
- Energy metabolism
- Cardiac metabolism
- Ischemic heart disease
- Mitochondrial energetics, heart failure, arrhythmias
- © 2012 by American Heart Association, Inc.