Sustained pressure overload causes cardiac hypertrophy and the transition to heart failure. The aortic banding mouse model leads to hypertrophic cardiomyopathy and heart failure through the mechanism of sustained pressure overload but we have evidence that mineral imbalance may be involved. We have observed that increasing dietary copper (Cu) intake from 6 mg Cu/kg diet to 20 mg/kg diet can reverse the established hypertrophic cardiomyopathy in the aortic banding mouse model even in the presence of sustained pressure overload. Decreased cytochrome c oxidase (CCO) activity and mitochondriopathy are associated with heart failure in humans. The same CCO defect and mitochondriopathy are also found in the mouse model of pressure overload-induced cardiomyopathy and increasing dietary Cu intake recovered CCO activity and reversed mitochondriopathy. We propose this study to carry out the following aims:
Aim 1 is to explore molecular mechanism by which sustained pressure overload causes Cu restriction to CCO in the heart. We will test the hypothesis that Cu mobilization and redistribution or efflux in response to oxidative stress generated by sustained pressure overload leads to Cu restriction to CCO, resulting in altered CCO assembly and suppressed CCO activity.
Aim 2 is to determine the essential role of recovery of suppressed CCO activity in Cu supplementation-induced regression of cardiomyopathy by sustained pressure overload. A cardiac COX10 conditional knockout mouse model in which cardiac CCO activity can be reduced by 50- 70% under the treatment with tamoxifen will be used. We hypothesize that Cu supplementation would not rescue the failing heart in the cardiac COX10-knockout or CCO-deficient mice if the recovery of CCO activity is essential, even Cu supplementation can reverse alterations in other events including calcineurin/NFAT, PI3K/Akt, and ERK1/2 pathways or can activate other cardiomyopathy regression mechanisms.
Aim 3 is to define potential application of Cu therapy to appropriate populations of heart failure patients by testing the hypothesis that Cu supplementation should be limited to pressure overload cardiomyopathy, not applied to diabetic cardiomyopathy because diabetes causes liver dysfunction, which in turn causes Cu retention in the system, increasing the risk of Cu toxicity to the heart and other organs. Therefore, Cu supplementation is not an appropriate approach to rescue diabetic cardiomyopathy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063760-08
Application #
7893175
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Ershow, Abby
Project Start
1999-12-01
Project End
2013-06-30
Budget Start
2010-07-01
Budget End
2013-06-30
Support Year
8
Fiscal Year
2010
Total Cost
$185,000
Indirect Cost
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
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