TY - JOUR T1 - THE EFFECTS OF ACUTE AND CHRONIC UP-REGULATION OF PYRUVATE DEHYDROGENASE IN THE HEART JF - Heart JO - Heart SP - A11 LP - A12 DO - 10.1136/heartjnl-2014-306916.34 VL - 100 IS - Suppl 4 AU - L Giles AU - V Ball AU - DJ Tyler Y1 - 2014/12/01 UR - http://heart.bmj.com/content/100/Suppl_4/A11.3.abstract N2 - 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. ER -