After two decades of study, we have come to realize that for prevention and treatment of heart failure, it is essential to understand the mechanisms underlying the development of cardiac hypertrophy which proceed to heart failure, and to identify factors which contribute to the transition to heart failure. The glycolytic pathway is an essential component of the molecular machinery of the cell. Alterations in the enzyme activity and substrate contents for enzymes in glycolysis have been observed in numerous animal models of cardiac hypertrophy and heart failure, as well as in failing human myocardium. Their functional significance and importantly, their roles in the development of heart failure have yet to be defined. The goal of this research project is to fill in this significant gap and to define the role of altered glucose utilization in the pathogenesis of cardiac hypertrophy and transition to heart failure. Taking advantage of an established model of pressure overload hypertrophy, namely rats with banded ascending aorta, we will perform a longitudinal study to cover the full spectrum of cardiac pathology from hypertrophy to failure. Using a combination of the tools of physiology, biochemistry, biophysics, and molecular biology, we will determine the time course of and the mechanisms which determine the alterations in glucose entry and in vivo regulation of phosphofructokinase (PFK) activity, as well as their significance for contractile function in hearts with hypertrophy and failure. Knowledge gained from this study will not only enhance our understanding of this metabolic pathway in cardiac hypertrophy but could also shape future strategies for the prevention and treatment of heart failure.
The specific aims are: To test the hypothesis that the balance between basal and insulin-regulated glucose entry shifts in cardiac hypertrophy and failure, specifically, that there is a progressive increase in basal glucose entry during the evolution of heart failure. To test the hypothesis that glycolysis is activated in the hypertrophied heart via the activation of PFK and cannot be activated further in the failing heart. To test the hypothesis that increase glucose utilization in hypertrophied heart, as a compensatory mechanism, has reached its maximum and is not able to increase further to support ATP synthesis and the recruitment of contractile reserve in the failing heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059246-04
Application #
6389776
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Liang, Isabella Y
Project Start
1998-05-01
Project End
2003-04-30
Budget Start
2001-05-01
Budget End
2003-04-30
Support Year
4
Fiscal Year
2001
Total Cost
$55,730
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
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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