Abstract

Pyruvate dehydrogenase (PDH) is a key enzyme in the regulation of substrate utilisation in the heart. Alterations in PDH activity have been observed in many cardiovascular-related diseases, such as diabetes and left ventricular hypertrophy, suggesting that metabolism plays a role in disease onset and progression. Dichloroacetate (DCA) is a potent activator of PDH and can be used to provide mechanistic information about the role that PDH plays in cardiac substrate selection.

The effect of acute and chronic PDH up-regulation was assessed in vivo and in the perfused rat heart. PDH flux was assessed in control and DCA-treated rats at baseline, 1 and 5 weeks following chronic DCA (0.75 gl-1) treatment using hyperpolarized [1–13C]pyruvate. DCA rats also received a bolus infusion of DCA (30 mg.ml-1) at baseline to acutely up-regulate PDH activity. Control and DCA treated hearts were rapidly excised and Langendorff perfused with [3H]glucose following the 5 weeks of chronic DCA treatment to assess glycolytic flux. Control hearts were also assessed in the presence of 1 mM DCA to assess the effects of acute up-regulation of PDH on glycolysis.

In vivo PDH flux was significantly enhanced following both an acute infusion and chronic treatment with DCA for 1 and 5 weeks. However, DCA treatment resulted in significant reductions in glycolytic flux and lactate production in the perfused heart following both acute and chronic PDH up-regulation. This suggests that despite increasing glucose oxidation, up-regulation of PDH activity appears to lead to a reduction in glycolytic flux promoting increased coupling between glycolysis and glucose oxidation.