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ARS Home » Plains Area » Grand Forks, North Dakota » Grand Forks Human Nutrition Research Center » Healthy Body Weight Research » Research » Publications at this Location » Publication #164116
Title: DIETARY COPPER RESTRICTION-INDUCED CHANGES IN MYOCARDIAL GENE EXPRESSION AND THE EFFECT OF COPPER REPLETION

Author
item ELSHERIF, LAILA - UNIV OF LOUISVILLE
item JIANG, YOUCHUN - UNIV OF LOUISVILLE
item Saari, Jack
item KANG, Y - UNIV OF LOUISVILLE

Submitted to: Experimental Biology and Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/22/2004
Publication Date: 7/1/2004
Citation: Elsherif, L., Jiang, Y., Saari, J.T., Kang, Y.J. 2004. Dietary copper restriction-induced changes in myocardial gene expression and the effect of copper repletion. Experimental Biology and Medicine. 229:616-662.

Interpretive Summary: Dietary copper deficiency leads to a variety of detrimental changes in the heart, including structural molecular and functional changes that are suggestive of heart failure. We have previously shown that certain genes normally only expressed in hearts of the embryo are re-expressed in copper-deficient adult hearts and that hearts from copper-deficient rats were not able to develop as high a maximum pressure, had an elevated pressure during relaxation, were not able to contract and relax as fast, and exhibited a blunted response to an adrenalin-like compound, as compared to copper-adequate hearts. All are characteristics associated with heart failure. Further, the functional changes were largely restored on repletion of dietary copper. The purpose of this study was to broaden the examination of genetic changes that occur with dietary copper deficiency and subsequent copper repletion. Mice were fed adequate or copper-deficient diet for 5 weeks; some copper-deficient mice were then fed copper adequate diet for 2 weeks. We found that copper deficiency altered genetic expression of proteins in the heart that affect heart contraction, calcium movement, structural support, inflammation and repair following injury. Copper repletion reduced these changes and, in some cases, eliminated them or overcorrected them. These findings further illustrate the need for adequate copper nutrition in proper heart function.

Technical Abstract: Dietary copper (Cu) restriction leads to cardiac hypertrophy and failure in mice and Cu repletion (CuR) reverses the hypertrophy and prevents the transition to heart failure. The present study was undertaken to determine changes in myocardial gene expression involved in Cu deficient (CuD) cardiomyopathy and its reversal by CuR. Analysis was performed on 4 wks old CuD mice that exhibited signs of cardiac failure, their age matched CuA controls, and the CuD mice refed adequate Cu for 2 wks. Total RNA was isolated from hearts and subjected to cDNA microarray and real time RT-PCR analysis. Dietary CuD caused a decrease in cardiac mRNA of beta-MHC, L-type Ca**2+ -channel, K-dependent NCX, MMP-2, -8, and -13, NF-kappa B, and VEGF. The mRNA levels of ET-1, TGF-beta, TNF-alpha, and procollagen-I-alpha 1 and III-alpha 1 were increased in the CuD cardiac tissue. CuR resulted in cardiac mRNA levels of most of the genes examined returning to control levels, although the K-dependent NCX and MMP-2 values did not reach to the CuA control. In addition, CuR caused an increase in beta-MHC, L-type Ca**2+ channel, MMP-13 to levels surpassing those of CuA control, and a decrease in ET-1, and TNF-alpha mRNA levels. In summary, changes in gene expression of elements involved in contractility, Ca**2+ cycling, and inflammation and fibrosis may account for the altered cardiac function found in CuD mice. The return to normal cardiac function by CuR may be a result of the favorable regression in gene expression of these critical components in myocardial tissue.