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Show 215 THE UNIVERSITY OF UTAH It is generally accepted that mitochondrial dysfunction develops in the failing heart. Patho-logical hypertrophy, which increases the risk for developing heart failure, is associated with reduced fatty acid (FA) metabolism and increased dependence on glucose utilization. In a previous study performed by O'Neill et al, it was shown that PI3K had a role of critical modula-tor of mitochondrial FA metabolism in the heart. In this study, constitutive activation of PI3K in the heart was sufficient to increase FA utilization and selectively upregulate mitochondrial oxidative capacity for FA substrates. Inhibition of PI3K prevented the increase in FA oxidation capacity that occurred in response to physiological cardiac hypertrophy, despite increased PGC-1α mRNA and protein levels. Thus, this study identified a necessary role for PI3K in coor-dinating myocardial FA oxidation capacity with physiological cardiac hypertrophy. Based on these previous studies, we hypothesized that PI3K signaling may modulate mito-chondrial function not only in physiological cardiac hypertrophy but also in pathological hypertrophy. To prove this, we examined mitochondrial and contractile function in the hearts of mice with transgenic overexpression of a constitutively active (caPI3K) or dominant nega-tive (dnPI3K) PI3K transgene following transverse aortic constriction (TAC). We found that although PI3K activity is partly responsible for the modulation of mitochondri-al function in response to physiological hypertrophy in normal hearts, this is not the case for hearts with pathological hypertrophy induced through transverse aortic constriction. Further research will explore the function of PI3K activity in exercise induced hypertrophy. Noh, Jung H. "Constitutive Activation of PI3K Does Not Prevent Mitochondrial or Contractile Dysfunction in Pressure Overload Cardiac Hypertrophy." Circulation A11982 124 (2011). Print. O'Neill, BT. Et al. "A Conserved Role for Phosphatidylinositol 3-kinase but Not Akt Signal-ing in Mitochondrial Adaptations That Accompany Physiological Cardiac Hypertrophy." Cell Metabolism 6.4 (2007): 296-306. Web. 09 Dec. 2011. <http://www.ncbi.nlm.nih.gov/ pubmed/17908558>. PI3K SIGNALING AND ITS EFFECTS ON MITOCHONDRIAL FUNCTION IN PATHOLOGICAL CARDIAC HYPERTROPHY Evangeleena Manzanares, Jueng H. Noh, (E. Dale Abel) Division of Endocrinology, Metabolism and Diabetes University of Utah health sciences leap program Evangeleena Manzanares Jueng H. Noh E. Dale Abel |
