Fatty acid metabolism is essential to maintain energetics and function in the normal heart. However, alterations in metabolism, energetics, and dysfunction have been documented in pathological hypertrophy and heart failure. These metabolic changes are consistent with an increased reliance on glucose and lactate at the expense of fatty acids, representing a reversion to a fetal metabolic profile. As the progression of heart failure continues, energy deprivation, as a result of declining ATP production from fatty acids, becomes a limiting factor in the ability of the failing heart to sustain normal function. Although the mechanisms are elusive, it appears that key metabolic enzymes that regulate fatty acid metabolism are downregulated. Therefore, it is conceivable that restoration of fatty acid oxidation may be beneficial for the failing heart. The function acetyI CoA carboxylase 2 (ACC2) is to catalyze the formation of malonyl CoA from acetyl CoA. As malonyl CoA levels rise, fatty acid transport through carnitine palmitoyl transferase I (CPTI) is inhibited. Therefore, ACC2 may be a potential target in which to modify fatty oxidation through its action on malonyl CoA. Previous studies established that the ACC2 total knockout mouse demonstrated increased fatty acid oxidation with a concurrent reduction in malonyl CoA in cardiac tissue. Therefore, the purpose of the present study is to enhance cardiac fatty acid oxidation by targeting ACC2 in a mouse model. The specific hypothesis of this study is that the increased fatty acid oxidation accompanied by ACC2 deletion will sustain mitochondrial function and myocardial energetics in hypertrophied hearts, thus protecting from the transition to heart failure. The results of this study will address a critical question in the field of cardiac metabolism and may provide insight to the pharmacological intervention with ACC2 inhibitors for heart failure patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HL096284-01
Application #
7675600
Study Section
Special Emphasis Panel (ZRG1-F10-H (21))
Program Officer
Meadows, Tawanna
Project Start
2009-07-20
Project End
2012-07-19
Budget Start
2009-07-20
Budget End
2010-07-19
Support Year
1
Fiscal Year
2009
Total Cost
$50,054
Indirect Cost
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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
Garcia-Menendez, Lorena; Karamanlidis, Georgios; Kolwicz, Stephen et al. (2013) Substrain specific response to cardiac pressure overload in C57BL/6 mice. Am J Physiol Heart Circ Physiol 305:H397-402
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
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 :