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Show SCHOOL OF MEDICINE AND HEALTH SCIENCES UNDERGRADUATE RESEARCH ABSTRACTS Douglas Hunter Renata Pereira 120 THE ROLE OF CARDIAC PGC-1a OVEREXPRESSION ON MITOCHONDRIAL MORPHOLOGY AND DYNAMICS IN PRESSURE OVERLOAD HYPERTROPHY Douglas Hunter (Renata Pereira) Molecular Medicine Program University of Utah Cardiac muscle must have a continuous energy supply because of its permanent contractile activity.Thus, mitochondria play a central role in the regulation of cardiac contractility. Peroxisome proliferator-activated receptor coactivator-1 a (PGC-1 a) is an inducible integrator that regulates mitochondrial biogenesis and function. During pathological hypertrophy the decline in cardiac muscle oxidative capacity is associated with the down regulation of PGC-1 a. Our goal was to determine whether cardiac overexpression of PGC-1 a would be sufficient to preserve mitochondrial number and morphology due to pressure overload hypertrophy (POH), as well as to test the hypothesis that mitochondrial dynamics (fusion and fission) are altered in P O H and that PGC-1 a overexpression would be able to prevent these changes. There were four groups of mice, Control Sham and TAC (Cont) and Transgenic Sham and TAC (TG). Transgenic mice contained the entire human PGC-1 a locus. Both Cont and TG TAC mice underwent minimally invasive transverse aortic constriction (TAC) to induce POH. Mitochondrial number, morphology, and volume density of cardiac cells were assessed by electron microscopy. Protein expression of fusion and fission proteins in cardiac mitochondria were assessed using western blotting. We observed that, 4 weeks after TAC, mitochondrial morphology was unchanged in Cont and TG mice. However, mitochondrial number was significantly reduced in Cont TAC mice when compared with shams. In contrast,TG mice had preserved mitochondrial number 4 weeks afterTAC. Mitochondrial volume density was unaltered in response to TAC in both Cont and TG mice. W e observed that P O H affected the expression of proteins involved in mitochondrial dynamics in the heart. There was a significant decrease in both mitochondrial fission and fusion proteins in Cont TAC mice, which were preserved inTG mice following TAC. Overexpression of PGC-1 a was successful in reversing the pathology of POH in mitochondrial biogenesis and function in TG TAC mouse models. N e w models involving an inducible form of PGC-1 a should be tested to determine if possible gene therapies could be developed to reverse pathological hypertrophy and heart failure in humans. |
