FATTY ACID METABOLISM IN CARDIAC ISCHEMIA

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The long term objective of the proposed research is to define factors which play a role in control of the subcellular and metabolic fate of long chain fatty acids (FA) in the normal and ischemic heart. Coincident with physiological observations of depressed contractility in reversibly injured, reoxygenated myocardium is the accumulation of cellular lipid, as demonstrated by electron microscopy of excised tissue, and noninvasively by nuclear magnetic resonance and positron emission tomography. Therefore, decreased FA oxidation occurs in cells which are structurally normal, and which oxidize glucose as a preferred fuel. FA ester accumulation in these cells may then play a role in contractile dysfunction and electrophysiological changes via membrane perturbant effects. In the first specific aim, interaction of FA esters with isolated cardiac membranes, and their affinity for specific membrane sites will be related to the presence or absence of cardiac fatty acid binding protein. Also, the influence of decreased protein recognition sites for FA esters on cardiac membranes (e.g., mitochondrial carnitine acylcarnitine translocase, CAT) on FA ester residence times will be investigated. The mechanisms responsible for changes in the numbers of these recognition sites will be studied in the second specific aim. Alterations in mitochondrial matrix glutathione and membrane protein sulfhydryls in ischemia will be related to changes in sulfhydryl-dependent processes involved in FA metabolism. Specifically, these include (1) potential rate limitation of acylcarnitine transport by CAT when excess transport sites are inactivated by ischemia/reperfusion (2) coupling of CAT with carnitine palmitoyl CoA transferase (CPT) which funnels acyl units to B-oxidation (3) CoA-SH oxidation (4) CPT kinetics and sensitivity to malonyl-CoA and (5) membrane lipid changes via lysophospholipid acyl transferase. Results from these experiments will provide information necessary to explain ultrastructural, contractile and noninvasive observations of abnormal lipid metabolism during reversible ischemic injury in the heart.