Abstract 170: Glucose Oxidation by Pyruvate Dehydrogenase Ameliorates Cradiomyocytes Contractility in Response to Hypoxic Stress

Abstract

Introduction: Pyruvate dehydrogenase (PDH) plays a key role in aerobic energy metabolism and occupies a central crossroad between glycolysis and the tricarboxylic acid cycle. Dichloroacetate (DCA), a PDH activator, has been revealed to increase glucose oxidation and reduce myocardial infarct size during ischemia and reperfusion. Hypothesis: Cardiac PDH activation plays a critical role in modulation of cardiomyocytes contractility and calcium signaling in response to hypoxia. Methods: Mechanical properties and intracellular Ca 2+ homeostasis were measured in isolated cardiomyocytes by IonOptix system. The stress signaling was evaluated using immunoblotting and immunoprecipitation analysis. Results: PDH activator DCA treatment significantly protects cardiomyocytes from hypoxia-induced contractile dysfunction as measured by maximal velocity of shortening (+dL/dt) and relengthening (–dL/dt), peak height and peak shortening (PS) amplitude, time-to-90% relengthening (TR90) in cardiomyocytes. However, DCA treatment did not show any protective effects on contractile functions of isolated cardiomyocytes from the cardiomyocyte specific PDH KO mouse hearts under hypoxic conditions. Intriguingly, the rise of intracellular Ca 2+ levels and intracellular ATP levels have no significant difference among wild type (WT) and PDH KO cardiomyocytes with and without DCA treatment. The results demonstrated that cardiomyocyte PDH KO does not affect cardiomyocyte contractility under normal physiological conditions, but significantly impaired the contractile functions of isolated cardiomyocytes under hypoxic conditions. Furthermore, the immunoblotting results showed that hypoxia triggered phosphorylation of AMP-activated protein kinase (AMPK) in isolated cardiomyocytes, but the AMPK phosphorylation was significantly impaired in PDH KO cardiomyocytes. DCA treatment clearly augmented ischemic AMPK phosphorylation in the isolated wild type (WT) but not in PDH KO cardiomyocytes. Conclusions: The glucose oxidation by pyruvate dehydrogenase (PDH) plays a critical role in cardiomyocyte contractility in response to hypoxic stress. PDH agonist DCA could be used for improve contractile function of cardiomyocytes under hypoxic insults.