Abstract 3562: Chronic Pressure Overload in Rats Reduces Mitochondrial Respiratory Capacity but not Coupling to ATP-Production
Two mitochondrial mechanisms have been suggested for the development of pressure overload contractile dysfunction: mitochondrial dysfunction through uncoupling or through reduced oxidative phosphorylation capacity due to PGC-1α downregulation. We assessed the respiratory capacity and coupling to ATP-production, PGC-1α and downstream target gene-expression, as well as fatty acid oxidation and UCP-expression in rat hearts subjected to chronic pressure overload developing heart failure. Transverse aortic constriction for 20 weeks resulted in heart failure with dyspnoea and pleural effusions, decreased ejection fraction (EF: 53±8% vs. 75±6% sham, p<0.05) and LV dilatation (LVEDD 9,9±0,6 vs. 7,6±0,3mm, p<0.05). Mitochondrial respiratory capacity and substrate oxidation rates were significantly affected in failing hearts. State 3 respiration of isolated mitochondria was significantly reduced with all substrates (natomsO/min/mg protein: glutamate 71±16 vs. 361±58, palmitoyl-carnitine 56±4 vs. 460±59, pyruvate 54±3 vs. 356±49, succinate 148±12 vs. 461±47, p<0.05). This decrease was associated with reduced PGC-1α expression, reduced fatty acid oxidation gene expression (MCAD, LCAD) and reduced rates of fatty acid (μmol/min/gdry: 0,28±0,04 vs. 1,02±0,04) and glucose oxidation (0,16±0,03 vs. 0,38±0,08) in the isolated working heart. The calculated rate of ATP production related to cardiac power in isolated working hearts was increased in failing hearts (μmol/mW: 8,96±1,20 vs. 2,23±0,44) suggesting decreased efficiency. However, coupling of mitochondrial oxygen consumption to ATP production was not affected by chronic pressure overload (ATP/O ratio: glutamate 2,49±0,09 vs. 2,18±0,24; palmitoyl-carnitine 2,56±0,04 vs. 2,51±0,31) suggesting that inefficiency is not due to uncoupling. The expression of mitochondrial uncoupling proteins was also not altered in failing hearts.
Conclusion: The results suggest that downregulation of the mitochondrial oxidative machinery, possibly through dysregulation of PGC-1α, and not uncoupling of the respiratory chain is involved in the development of pressure overload heart failure in rats.