This proposal exploits the opportunity for a comprehensive 13C NMR evaluation of fatty acid handling within the intact, functioning heart. The overall goal is to further develop and apply our kinetic 13C NMR methods to study the reciprocal relationship between the activity of the key regulator of fatty acid oxidation, carnitine palmitoyl transferase I (CPTI) and turnover of the myocardial triglyceride pool in normal and diabetic animal models. New and exciting findings from the previously funded period enable 13C NMR to distinguish between oxidative rates in the mitochondria and the rate of long chain fatty acid transport, via CPT1, as well as detect the incorporation rate of 13C-enriched palmitate into the myocardial triglyceride pool, all in the intact, beating heart. Therefore, this study explores the hypotheses that: 1) changes in the regulation of long chain fatty acid oxidation, via CPT1 activity, mediate the turnover rate of myocardial triglycerides and can be evaluated in whole hearts by a comprehensive examination of 13C enrichment kinetics; 2) Alterations in triglyceride content and turnover in the diabetic myocardium occur due to a combination of hyperlipidemia and changes in the expression of genes encoding enzymes for fatty acid uptake and oxidation pathways and that these can be distinguished via 13C NMR as independent mediators in the pathogenesis of diabetic cardiomyopathy. This hypothesis will be tested in both in both rat and mouse models of normal, diabetic, and genetically altered cardiac phenotypes.
Specific aims are: 1) Determine reciprocal effects of fatty acid oxidation rates on triglyceride turnover via cardiac 13C NMR during partial inhibition of CPT1; 2) Examine long chain fatty acid oxidation rates, CPT1 activity, and triglyceride pool turnover in the hearts of rats with type-I (insulin deficient) diabetes and test for a potential link between triglyceride accumulation and turnover and the activation of protein kinase C; 3) Investigate effects of triglyceride pool size on the reciprocal nature of CPT1 activity and triglyceride turnover in a transgenic mouse model, overexpressing peroxisome proliferator-activated receptor alpha (PPAR-alpha), that mimics the diabetic phenotype for fatty acid and glucose metabolism and allows for dietary control of myocardial triglyceride pool size; 4) Examine long chain fatty acid oxidation rates, CPT1 activity, and triglyceride turnover in a more clinically relevant animal model of type II (insulin resistant) diabetes, the db/db mouse model, versus non-diabetic, wild-type mice.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37HL049244-10
Application #
6683274
Study Section
Diagnostic Radiology Study Section (RNM)
Program Officer
Dunn, Rosalie
Project Start
1993-08-01
Project End
2008-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
10
Fiscal Year
2003
Total Cost
$516,039
Indirect Cost
Name
University of Illinois at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Banke, Natasha H; Lewandowski, E Douglas (2015) Impaired cytosolic NADH shuttling and elevated UCP3 contribute to inefficient citric acid cycle flux support of postischemic cardiac work in diabetic hearts. J Mol Cell Cardiol 79:13-20
O'Donnell, J Michael; Fasano, Matthew J; Lewandowski, E Douglas (2015) Resolving confounding enrichment kinetics due to overlapping resonance signals from 13C-enriched long chain fatty acid oxidation and uptake within intact hearts. Magn Reson Med 74:330-5
Lahey, Ryan; Wang, Xuerong; Carley, Andrew N et al. (2014) Dietary fat supply to failing hearts determines dynamic lipid signaling for nuclear receptor activation and oxidation of stored triglyceride. Circulation 130:1790-9
Carley, Andrew N; Bi, Jian; Wang, Xuerong et al. (2013) Multiphasic triacylglycerol dynamics in the intact heart during acute in vivo overexpression of CD36. J Lipid Res 54:97-106
Lewandowski, E Douglas; Fischer, Susan K; Fasano, Matthew et al. (2013) Acute liver carnitine palmitoyltransferase I overexpression recapitulates reduced palmitate oxidation of cardiac hypertrophy. Circ Res 112:57-65
Banke, Natasha H; Yan, Lin; Pound, Kayla M et al. (2012) Sexual dimorphism in cardiac triacylglyceride dynamics in mice on long term caloric restriction. J Mol Cell Cardiol 52:733-40
O'Donnell, J Michael; Kalichira, Asha; Bi, Jian et al. (2012) In vivo, cardiac-specific knockdown of a target protein, malic enzyme-1, in rat via adenoviral delivery of DNA for non-native miRNA. Curr Gene Ther 12:454-62
Kudej, Raymond K; Fasano, Mathew; Zhao, Xin et al. (2011) Second window of preconditioning normalizes palmitate use for oxidation and improves function during low-flow ischaemia. Cardiovasc Res 92:394-400
Banke, Natasha H; Wende, Adam R; Leone, Teresa C et al. (2010) Preferential oxidation of triacylglyceride-derived fatty acids in heart is augmented by the nuclear receptor PPARalpha. Circ Res 107:233-41
Hankiewicz, Janusz H; Banke, Natasha H; Farjah, Mariam et al. (2010) Early impairment of transmural principal strains in the left ventricular wall after short-term, high-fat feeding of mice predisposed to cardiac steatosis. Circ Cardiovasc Imaging 3:710-7

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