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ORIGINAL RESEARCH ARTICLE

Dietary Copper Restriction-Induced Changes in Myocardial Gene Expression and the Effect of Copper Repletion

Laila Elsherif^*, Youchun Jiang, Jack T. Saari and Y. James Kang^*,,1

Departments of ^* Pharmacology and Toxicology and Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40202; and U.S. Department of Agriculture, Human Nutrition Research Center, Grand Forks, North Dakota 58202

To whom requests for reprints should be addressed at ¹ Department of Medicine, University of Louisville School of Medicine, 511 South Floyd Street, MDR 530, Louisville, KY 40292. E-mail: jkang01{at}louisville.edu

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 three groups of mice: 4-week-old CuD mice that exhibited signs of cardiac failure, their age-matched copper-adequate (CuA) controls, and the CuD mice that were re-fed adequate Cu for 2 weeks. Total RNA was isolated from hearts and subjected to cDNA micro-array and real-time reverse transcription–polymerase chain reaction analysis. Dietary CuD caused a decrease in cardiac mRNA of ß-MHC, L-type Ca²⁺ channel, K-dependent NCX, MMP-2, -8, and -13, NF-B, and VEGF. The mRNA levels of ET-1, TGF-ß, TNF-, and procollagen-I-1 and III-1 were increased in the CuD cardiac tissue. Copper repletion 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 those of the CuA control. In addition, CuR caused an increase in ß-MHC, L-type Ca²⁺channel, MMP-13 to levels surpassing those of CuA control, and a decrease in ET-1, and TNF- mRNA levels. In summary, changes in gene expression of elements involved in contractility, Ca²⁺ 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.

Key Words: cardiomyopathy • copper deficiency • copper repletion • cDNA microarray • real-time RT-PCR

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