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Show 113 school of medicine and health sciences Constant energy supply is required to maintain cardiac contractility. As such the heart relies on a number of fuel substrates to meet this demand. Loss of the heart's flexibility in substrate utilization is proposed to be a contributing factor in the development of cardiac dysfunction. In times of cardiac stress, as with hypertension, there is an increased reliance on glucose utilization. In the cell, glucose is enzymatically converted to generate pyruvate. Upon entry into the mitochondria, pyruvate is then converted to acetyl-CoA by the pyruvate dehydrogenase complex (PDC). In part, PDC is regulated by an inhibitory phosphorylation mediated by a family of four protein kinases (PDK's) and two phospha-tases. Inhibition of PDC effectively separates glycolysis in the cytosol and glucose oxidation in the mitochondria thereby decreasing ATP production from glucose oxidation and therefore energy supply. In the failing human heart expression of PDK is decreased. To better understand the role PDK-mediat-ed regulation plays in the failing heart, mice with individual genetic ablation of PDK isoforms 2 and 4 (P2KO and P4KO) and together (DKO) have been examined using thoracic aortic constriction (TAC), a model of hypertension. In vivo assessment of contractile function by echocardiography revealed that function was maintained in P2KO knockout mice compared to equivalently treated P4KO, DKO and wild-type controls (WT). A recent publication examining skeletal muscle revealed that in the absence of PDK2 there was in increase in isoform 1 (PDK1). Our studies discovered that PDK1 actually decreases in the heart of DKO mice. These tissue-specific differences identify novel roles whereby PDK isoforms exhibit unique but overlapping roles in response to cardiac stress. Future studies will examine the levels of PDK1 in the heart of P2KO, P4KO, DKO, and WT models. These existing data suggest that PDK isoform-specific inhibition could potentially be useful in treating hypertension-induced heart failure. PYRUVATE DEHYRDOGENASE KINASE DEFICIENCY ATTENUATES CONTRACTILE DYSFUNCTION IN RESPONSE TO PRESSURE OVERLOAD-INDUCED HEART FAILURE Chase A Andrizzi (E. Dale Abel) Division of Endocrinology, Metabolism & Diabetes University of Utah UNDERGRADUATE RESEARCH ABSTRACTS Chase A. Andrizzi Dale Abel |
