Myocardial energetics is impaired and fatty acid oxidation decreased in failing hearts of both animal models and patients. Although it is increasingly recognized that altered cardiac energy metabolism is integral of the development and progression of heart failure, optimizing metabolism of the failing heart has proven to be a challenge as the mechanisms linking abnormal metabolism to contractile dysfunction in heart failure remain poorly understood. Fatty acids are the primary fuel of adult heart, impaired fatty acid oxidation (FAO) can be maladaptive as it reduces the mitochondrial capacity for ATP synthesis. Furthermore, decreased FAO under conditions of increased fatty acid availability such as obesity, metabolic syndrome or high sympathetic activity can lead to accumulation of active lipid metabolites in myocardium causing lipotoxicity. As PPAR?, a master transcription factors for multiple FAO enzymes, was downregulated in cardiac hypertrophy and failure, previous studies aimed at normalizing fatty acid utilization in failing hearts have sought to reactivate PPAR?. These studies yielded very mixed results. Genetic and short-term pharmacological activation of PPAR? resulted in lipotoxic cardiomyopathy, contractile dysfunction and impaired response to myocardial ischemia while studies using chronic PPAR? activators showed no effect in cardiac remodeling. Since PPAR? regulates many aspects of fatty acid metabolism ranging from uptake, activation to 2-oxidation;it is likely that over-activation of fatty acid uptake that exceeds oxidation capacity can lead to lipotoxicity. To date, it has not been tested whether strategies that specifically enhance fatty acid oxidation in mitochondria or decrease active lipid intermediates in the cytosol improves the outcome of heart failure. Therefore, we propose to test two specific strategies that target single steps in fatty acid metabolism. First, we seek to enhance fatty acid entry into mitochondria via muscle carnitine palmitoyl transferease-1 (mCPT-1), the rate-limiting step of long chain fatty acid oxidation, by lowering malonyl-CoA level in the heart. This will be achieved by genetic deletion of the enzyme that catalyzes malonyl-CoA formation: acetyl-CoA carboxylase 2 (ACC2). Second, we will modulate endogenous lipid metabolism by increasing triglyceride synthesis and turnover so that active lipid intermediates will be reduced. This will be achieved by overexpressing the rate-limiting enzyme for triglyceride synthesis: diacylglyerol acyltransferase (DGAT1). These strategies will be tested in non-obese and obese mouse models subjected to pressure overload induced heart failure. Myocardial energy metabolism and mitochondrial function in these hearts will be assessed by multi-nuclear NMR spectroscopy and biochemical assays at baseline, compensated hypertrophy, and heart failure.

Public Health Relevance

This proposal will investigate the metabolic abnormalities of the heart that contribute to the development and progression of heart failure. Results from the study will provide a basis for optimizing cardiac metabolism as part of the treatment strategy for heart failure. This is particularly important for patients with metabolic disorders such as obesity or diabetes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL059246-10A1
Application #
7731887
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Liang, Isabella Y
Project Start
1998-05-01
Project End
2011-08-31
Budget Start
2009-09-30
Budget End
2010-08-31
Support Year
10
Fiscal Year
2009
Total Cost
$447,024
Indirect Cost
Name
University of Washington
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Roe, Nathan D; Standage, Stephen W; Tian, Rong (2016) The Relationship Between KLF5 and PPAR? in the Heart: It's Complicated. Circ Res 118:193-5
Yu, Qiujun; Lee, Chi Fung; Wang, Wang et al. (2014) Elimination of NADPH oxidase activity promotes reductive stress and sensitizes the heart to ischemic injury. J Am Heart Assoc 3:e000555
Kolwicz Jr, Stephen C; Purohit, Suneet; Tian, Rong (2013) Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes. Circ Res 113:603-16
Marney, Luke C; Kolwicz Jr, Stephen C; Tian, Rong et al. (2013) Sample preparation methodology for mouse heart metabolomics using comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry. Talanta 108:123-30
Kolwicz Jr, Stephen C; Olson, David P; Marney, Luke C et al. (2012) Cardiac-specific deletion of acetyl CoA carboxylase 2 prevents metabolic remodeling during pressure-overload hypertrophy. Circ Res 111:728-38
Karamanlidis, Georgios; Bautista-Hernandez, Victor; Fynn-Thompson, Francis et al. (2011) Impaired mitochondrial biogenesis precedes heart failure in right ventricular hypertrophy in congenital heart disease. Circ Heart Fail 4:707-13
Kolwicz Jr, Stephen C; Tian, Rong (2011) Glucose metabolism and cardiac hypertrophy. Cardiovasc Res 90:194-201
Kolwicz Jr, Stephen C; Tian, Rong (2010) Assessment of cardiac function and energetics in isolated mouse hearts using 31P NMR spectroscopy. J Vis Exp :
Karamanlidis, Georgios; Nascimben, Luigino; Couper, Gregory S et al. (2010) Defective DNA replication impairs mitochondrial biogenesis in human failing hearts. Circ Res 106:1541-8
Yan, Jie; Young, Martin E; Cui, Lei et al. (2009) Increased glucose uptake and oxidation in mouse hearts prevent high fatty acid oxidation but cause cardiac dysfunction in diet-induced obesity. Circulation 119:2818-28

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