Paradoxical downregulation of the glucose oxidation pathway despite enhanced flux in severe heart failure

Academic Article

Abstract

  • Free fatty acid (FFA) oxidation is depressed in severe heart failure due to reduced activity of mitochondrial fatty acid oxidation enzymes. It is unknown whether the concomitant enhancement in cardiac glucose use is a consequence of reduced FFA oxidation, or also due to potentiation of the carbohydrate oxidative pathway. FFA and glucose oxidation rates were measured in vivo in 9 normal dogs and 9 dogs with pacing-induced heart failure by infusing 3H-oleate and 14C-glucose. FFA oxidation was lower (39 ± 9 vs. 73 ± 5 nmol min-1 g-1), while glucose oxidation was higher (42 ± 8 vs. 17 ± 6 nmol min-1 g-1) in failing compared to normal hearts (P < 0.05). At the end of the in vivo experiment, clamp-frozen biopsies were harvested from the left ventricle. Messenger RNAs encoding for proteins involved in both glucose and fatty acid metabolism, and for citrate synthase, were significantly reduced. Protein expression of GLUT-1 and GLUT-4, and GLUT-4 translocation to the sarcolemma showed no significant differences between the two groups despite a significant reduction in mRNAs with heart failure. GAPDH mRNA, protein expression, and activity were all reduced. The E2 subunit of pyruvate dehydrogenase was decreased both at the mRNA and protein level, with no effect on either fractional or maximal activity. In conclusion, we found either no changes or moderate downregulation of key enzymes of the carbohydrate metabolism in failing hearts, which suggests that the increase in glucose oxidation in vivo was principally due to impaired FFA oxidation and that the maximal myocardial capacity to obtain energy from substrate is globally depressed. © 2004 Elsevier Ltd. All rights reserved.
  • Authors

    Digital Object Identifier (doi)

    Author List

  • Lei B; Lionetti V; Young ME; Chandler MP; D'Agostino C; Kang E; Altarejos M; Matsuo K; Hintze TH; Stanley WC
  • Start Page

  • 567
  • End Page

  • 576
  • Volume

  • 36
  • Issue

  • 4