The long term objectives of this research are: 1) elucidate intracellular mechanisms linking cardiac dysfunction to protein-mediated, cellular uptake, accumulation and turnover of lipid, in the form of triacylglyceride (TAG), and the altered fatty acid oxidation in diabetic cardiomyopathy;2)advance nondestructive, metabolic profiling of the heart using novel applications of carbon-13 (13C) NMR, to monitor distinct contributions of lipid transport processesinto the cardiac muscle cell during the altered TAG turnover that occurs in diseased and stressed hearts. Based on data acquired during the currently funded period, new experiments will test a 3-fold hypothesis: 1)The balance between long chain fatty acid uptakeand oxidation that determines TAG turnover is heavily influenced by the activity of fatty acid transport proteins on the cell membrane and that disruption of this balance in the diabetic heart contributes to the development of cardiac dysfunction; 2) dynamic NMR of 13C enrichment rates of TAG in the intact, beating heart provide precise kinetic information on the activity of fatty acid transporters on the cell membrane that determine the extent of lipid deposition in both normal and diseased hearts; and 3) intramyocardial lipid content affects regional strain in the left venctricle (LV) wall by either intracellular mechanisms leading to contractile dysfunction and/or mechanical influences on LV wall dynamics. The hypotheses will betested on rats and mice using a unique multidisciplinary approach that combines 13C NMR of metabolic flux and lipid uptake dynamics in intact hearts with genetic manipulation of fatty acid uptake and oxidation for comparisonto diabetic animals, as well as in vivo cardiac tagged MRI of wall strain with in vivo chemical shift imaging and localized NMR spectroscopy of TAG content in hearts of transgenic mouse models mimicing the diabetic phenotype for TAG accumulation.
Specific aims are: 1) Define changes in fatty acid uptake and TAG turnover due to different affinities of long chain fatty acids (palmitate vs. oleate) for incorporation into the TAG pool; 2) use 13CNMR of intact hearts to nondestructive^ detect perturbations of fatty acid transport/uptake into cardiomyocytesof transgenic mouse hearts and rat hearts receiving metabolic gene transfer; 3) measureregional 2D strain and intra/extracellular TAG content in the LVwall of mice with altered lipid metabolism.Anticipated results will provide a mechanistic link between cardiac lipid accumulation and contractile dysfunction in diseased hearts.
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