NMR of Mitochondrial Transporters in Cardiac Hypertrophy

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DESCRIPTION (provided by applicant): This proposal exploits our recent findings, during the previously funded period, of compensatory activation of transporter mediated metabolic pathways in the hypertrophied myocardium that counter reduced rates of long chain free fatty acid (LCFA) oxidation and limited pyruvate dehydrogenase (PDH) activity. We have identified a mismatch between LCFA oxidation and TCA cycle flux rates in the pressure overloaded, hypertrophic rate heart that is not compensated by increased glucose oxidation via PDH. Rather, alternative means of glucose oxidation via increased anaplerotic flux into the second span of the TCA cycle are in evidence, as are accelerated exchange mechanisms for cytosolic intermediates to supplement the TCA cycle. We hypothesize that recruitment of alternative pathways to fuel the TCA cycle in the compensatory phase of pressure overload hypertrophy represent adaptive, yet less efficient mechanisms for supporting oxidative energy production. The overall goal is to intervene via pharmacologic and genomic manipulation of the metabolic adaptations that occur during compensated and later stage, decompensated hypertrophy in rat hearts. Our experimental aims will 1) explore the energetic implications of such adaptive changes in intermediary metabolism by pharmacologically augmenting pyruvate entry into the TCA cycle at PDH; 2) elucidate the link between increased OMC activity, a protein transferring cytosolic reducing equivalents into the mitochondria, and alleviation of the cytosolic redox load due to uncoupling of glycolytic rate from glucose oxidation in the hypertrophic heart; 3) exploit our newly developed advances in the efficiency of cardiac-specific in vivo gene transfer to elucidate the regulatory role of OMC in providing TCA cycle intermediates via induced OMC overexpression and OMC reductions in hypertrophic hearts; 4) combine 13C NMR and cardiac MRI microscopy to investigate the link between metabolic adaptations and wall strain by exploring potential distinctions between hypertrophic and dilated hearts. Novel experiments explore the metabolic distinctions between specific murine mouse models of concentric hypertrophy (protein kinase C beta overexpression) versus dilated cardiomyopathy (PKC epsilon overexpression) which we anticipate will display distinct strain profiles across the left ventricular wall. The research will define adaptive mechanisms that reduce energy production efficiency and may contribute to the progression toward heart failure.