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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL038863-03
Application #
3355301
Study Section
Cardiovascular Study Section (CVA)
Project Start
1989-08-15
Project End
1991-07-31
Budget Start
1989-08-15
Budget End
1990-07-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Moore, Meredith L; Park, Edwards A; McMillin, Jeanie B (2003) Upstream stimulatory factor represses the induction of carnitine palmitoyltransferase-Ibeta expression by PGC-1. J Biol Chem 278:17263-8
Wang, Guo-Li; Moore, Meredith L; McMillin, Jeanie B (2002) A region in the first exon/intron of rat carnitine palmitoyltransferase Ibeta is involved in enhancement of basal transcription. Biochem J 362:609-18
Moore, M L; Wang, G L; Belaguli, N S et al. (2001) GATA-4 and serum response factor regulate transcription of the muscle-specific carnitine palmitoyltransferase I beta in rat heart. J Biol Chem 276:1026-33
Xia, Y; McMillin, J B; Lewis, A et al. (2000) Electrical stimulation of neonatal cardiac myocytes activates the NFAT3 and GATA4 pathways and up-regulates the adenylosuccinate synthetase 1 gene. J Biol Chem 275:1855-63
Hickson-Bick, D L; Buja, L M; McMillin, J B (2000) Palmitate-mediated alterations in the fatty acid metabolism of rat neonatal cardiac myocytes. J Mol Cell Cardiol 32:511-9
Wang, D; Xia, Y; Buja, L M et al. (1998) The liver isoform of carnitine palmitoyltransferase I is activated in neonatal rat cardiac myocytes by hypoxia. Mol Cell Biochem 180:163-70
Xia, Y; Buja, L M; McMillin, J B (1998) Activation of the cytochrome c gene by electrical stimulation in neonatal rat cardiac myocytes. Role of NRF-1 and c-Jun. J Biol Chem 273:12593-8
Wang, D; Harrison, W; Buja, L M et al. (1998) Genomic DNA sequence, promoter expression, and chromosomal mapping of rat muscle carnitine palmitoyltransferase I. Genomics 48:314-23
Xia, Y; Buja, L M; Scarpulla, R C et al. (1997) Electrical stimulation of neonatal cardiomyocytes results in the sequential activation of nuclear genes governing mitochondrial proliferation and differentiation. Proc Natl Acad Sci U S A 94:11399-404
Wang, D; Buja, L M; McMillin, J B (1996) Acetyl coenzyme A carboxylase activity in neonatal rat cardiac myocytes in culture: citrate dependence and effects of hypoxia. Arch Biochem Biophys 325:249-55

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