Abstract 13053: Uncoupling of Glycolysis and Pyruvate Oxidation Plays a Key Role in the Maintenance of LV Function Under Chronic Pressure Overload
Background Cardiac hypertrophy, induced by chronic pressure overload, is associated with increased rates of glycolysis and overall glucose utilization, but the rates of pyruvate oxidation do not rise in accordance with rates of pyruvate generation. This study was designed to elucidate the the pathophysiological significance of the uncoupling of glycolysis and pyruvate oxidation under chronic pressure overload.
Methods and Results (1) C57/B6 mice were subjected to transverse aortic constriction (TAC) to induce pressure overload. The activities of pyruvate dehydrogenase (PDH), a gate-keeping enzyme for the entry of pyruvate into the mitochondrial tricarboxylic cycle, are negatively regulated by phosphorylation. PDH was slightly phosphorylated under the unstressed condition, and highly phosphorylated in hypertrophied hearts with preserved ejection fraction (3 days and 14 days after TAC), but completely dephosphorylated in the dilated failing hearts (56 days after TAC). (2) Dichloroacetate (DCA), an inhibitor of PDH kinases, significantly inhibited the phosphorylation levels of PDH after TAC and accelerated LV dysfunction. (3) Heart-specific expression of aldehyde dehydrogenase 2 (Aldh2) gene with a single nucleotide polymorphism (Aldh2*2) caused impaired mitochondrial ALDH activity against a broad range of aldehydes. (4) Mitochondrial function was declined, and the redox state in the mitochondrial matrices shifted towards oxidative in Aldh2*2-expressing cells. (5) The Aldh2*2-TG mice had enhanced glucose uptake and increased rates of glycolysis under the unstressed condition. (6) Furthermore, glucose biotransformation was shifted from glycolysis towards the pentose phosphate pathway to generate NADPH, and amino acid metabolism that ultimately provides precursor amino acids for glutathione biosynthesis. (7) Notably, the Aldh2*2-TG mice exhibited enhanced tolerance to pressure overload.
Conclusion Uncoupling of glycolysis and pyruvate oxidation plays a key role in the maintenance of LV function in chronic pressure overload, at least partially via the reduction of mitochondrial ROS production and activation of the cytosolic glutathione redox cycle.
- © 2011 by American Heart Association, Inc.