Dietary copper restriction causes cardiac hypertrophy, ultimately leading to heart failure. A proposed mechanism for this cardiomyopathy is the accumulation of reactive oxygen species. Using a cardiac-specific metallothionein (MT)- overexpressing transgenic mouse model, we have observed that elevation of this potent antioxidant in the heart suppresses the progression of heart hypertrophy and likely results in the retarded development of heart failure induced by dietary copper restriction. This observation suggests that oxidative stress may play a crucial role in the pathogenesis of heart failure. We therefore propose to test the hypothesis that oxidative stress triggers the transition from heart hypertrophy to failure induced by copper deficiency. We will use the cardiac-specific MT- overexpressing transgenic mouse model to carry out the following specific aims: (1) To define the role of oxidative stress in the transition from heart hypertrophy to failure, a detailed time- course study of the development of heart failure by dietary copper restriction will be performed. In particular, this study will focus on defining the cause-and-effect relationship between oxidative stress and dynamic changes in cardiomyopathy, cardiac dysfunction and heart failure. (2) To determine cellular events involved in the transition from heart hypertrophy to failure, the significance of cell death in the pathogenesis will be defined by immuno-gold TUNEL and electron microscopy in combination with a novel procedure using cardiac alpha-sarcomeric actin antibody to label necrotic cells. The relative contributions of apoptosis and necrosis to the total cell loss will be analyzed. (3) To investigate signaling pathways leading to myocardial cell death during the transition from heart hypertrophy to failure, oxidative stress-induced mitochondrial cytochrome c release and activation of caspase-9 and -3 will be examined by immunohistochemical method, enzymatic assay and Western blot analysis. The consequence of caspase inhibition will be analyzed in order to dissect major pathways leading to cell death. (4) To examine the role of atrial natriuretic peptide (ANP) and tumor necrosis factor-alpha (TNF-alpha) in the late phase transition from heart hypertrophy to failure, dynamic changes in ANP and TNF-alpha production will be studied. Molecular mechanisms of up-regulation of these cytokines will be analyzed through examining the activation of transcription factors NF-kappaB and AP-1. (5) To explore possible mechanisms by which MT inhibits oxidative stress-mediated myocardial cell death induced by dietary copper deficiency, the effect of MT on oxidative stress- mediated mitochondrial membrane changes that lead to cytochrome c release will be examined. The overall goal of this study is to define the role of oxidative stress in copper deficiency-induced pathogenesis of heart failure. This study will give critical insights into the signaling pathways and molecular mechanisms of failure induced by copper deficiency. Importantly, the data obtained will provide valuable information for novel experimental as well as clinical approaches for possible interventions of the transition from heart hypertrophy to heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063760-04
Application #
6747570
Study Section
Nutrition Study Section (NTN)
Program Officer
Evans, Frank
Project Start
2001-06-15
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2006-05-31
Support Year
4
Fiscal Year
2004
Total Cost
$321,750
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
Hou, Jianglong; Kang, Y James (2012) Regression of pathological cardiac hypertrophy: signaling pathways and therapeutic targets. Pharmacol Ther 135:337-54
Xie, Yuping; Chen, Jianmin; Han, Pengfei et al. (2012) Immunohistochemical detection of differentially localized up-regulation of lysyl oxidase and down-regulation of matrix metalloproteinase-1 in rhesus monkey model of chronic myocardial infarction. Exp Biol Med (Maywood) 237:853-9
Dai, Dao-Fu; Johnson, Simon C; Villarin, Jason J et al. (2011) Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Galphaq overexpression-induced heart failure. Circ Res 108:837-46
Kang, Y James (2011) Copper and homocysteine in cardiovascular diseases. Pharmacol Ther 129:321-31
Zuo, Xiao; Xie, Huiqi; Dong, Daoyin et al. (2010) Cytochrome c oxidase is essential for copper-induced regression of cardiomyocyte hypertrophy. Cardiovasc Toxicol 10:208-15
Xue, Wanli; Cai, Lu; Tan, Yi et al. (2010) Cardiac-specific overexpression of HIF-1{alpha} prevents deterioration of glycolytic pathway and cardiac remodeling in streptozotocin-induced diabetic mice. Am J Pathol 177:97-105
Zhou, Yang; Bourcy, Katherine; Kang, Y James (2009) Copper-induced regression of cardiomyocyte hypertrophy is associated with enhanced vascular endothelial growth factor receptor-1 signalling pathway. Cardiovasc Res 84:54-63
Xie, Huiqi; Kang, Y James (2009) Role of copper in angiogenesis and its medicinal implications. Curr Med Chem 16:1304-14
Feng, Wenke; Ye, Fei; Xue, Wanli et al. (2009) Copper regulation of hypoxia-inducible factor-1 activity. Mol Pharmacol 75:174-82
Zhou, Zhanxiang; Johnson, W Thomas; Kang, Y James (2009) Regression of copper-deficient heart hypertrophy: reduction in the size of hypertrophic cardiomyocytes. J Nutr Biochem 20:621-8

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