The failing heart displays an altered metabolic phenotype, characterized by downregulation of free fatty acid oxidation, enhanced glycolysis and glucose oxidation and impaired mitochondrial capacity for oxygen consumption and ATP generation. Whether these metabolic alterations are adaptive or maladaptive mechanisms and contribute to the progression from compensated to decompensated heart failure (HF) remain open questions. We have recently identified a potential link between increased carbohydrate metabolism and a major mechanism of cellular damage in the failing heart, namely oxidative stress. In decompensated HF, myocardial glucose-6-phosphate dehydrogenase (G6PDH) is upregulated and, consequently, more glucose is channeled into the oxidative pentose phosphate pathway. This leads to an increased synthesis of cytosolic NADPH, an electron donor normally utilized by cells to regenerate antioxidant systems, but that in the failing myocardium can fuel superoxide-producing enzymes such as NADPH oxidase and uncoupled NO synthase. We therefore provided the first evidence to suggest a cause- effect relationship linking enhanced glucose utilization, increased NADPH supply by upregulation of the pentose phosphate pathway and higher superoxide production in the failing heart. The overall goal of the present project is to test the hypothesis that HF increases myocardial flux of glucose into the oxidative pentose phosphate pathway, enhances NADPH supply to superoxide-generating enzymes, and accelerates oxidative stress and functional damage. Studies will be performed on chronically instrumented dogs with pacing-induced HF.
Specific Aim #1 is to determine whether the altered substrate metabolism increases myocardial oxidative stress in HF. Circulating free fatty acids and glucose will be altered in healthy and HF dogs to simulate physiological conditions such as fasting and post-prandial state and to assess their effects on cardiac oxidative stress at baseline and during catecholamine stress.
Specific Aim #2 : is to determine whether the oxidative pentose phosphate pathway plays a critical role in fueling superoxide-generating enzymes in the failing heart. During development of HF, myocardial G6PDH will be knocked down by delivering DNA encoding for short interfering RNA and carried by viral vectors. Alternatively, G6PDH gene will be delivered via viral vectors to induce its overexpression.
Specific Aim #3 : is to determine whether the

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
7P01HL074237-10
Application #
8532020
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
10
Fiscal Year
2013
Total Cost
$265,462
Indirect Cost
$28,833
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
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