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Experimental Biology and Medicine 229:616-622 (2004)
© 2004 Society for Experimental Biology and Medicine

ORIGINAL RESEARCH ARTICLE

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

Laila Elsherif*, Youchun Jiang{dagger}, Jack T. Saari{ddagger} and Y. James Kang*,{dagger},1

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

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


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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-{kappa}B, and VEGF. The mRNA levels of ET-1, TGF-ß, TNF-{alpha}, and procollagen-I-{alpha}1 and III-{alpha}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-{alpha} 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


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Dietary copper deficiency (CuD) leads to cardiomyop-athy in experimental animal models (1–5). Copper depletion–induced cardiomyopathy is characterized by concentric cardiac hypertrophy such as occurs in the pressure overloaded heart (4, 6). Although CuD heart hypertrophy may be initially an adaptive response to a stress stimulus, which normalizes wall tension, further progression leads to impaired cardiac muscle function and heart failure (7).

The transition from cardiac hypertrophy to failure in CuD mice has been investigated in our laboratory on the level of cardiac function under stress and nonstress conditions and morphology of cardiac tissue including histopathological changes examined by light microscopy and ultrastructural alterations by electron microscopy (7). We also have shown that the deterioration in cardiac function and morphology is reversible upon Cu repletion (CuR; Ref. 8). In particular, CuR improved CuD-induced myocardial structural lesions, normalized CuD-depressed cardiac systolic and diastolic functions, and restored the response of cardiac muscle to ß-adrenergic stimulation (8).

Cardiac hypertrophy is often associated with poor prognosis and the onset of heart failure in patients (9). The transition from cardiac hypertrophy to failure is marked by a distinct alteration in gene expression profile, involving several major important cellular systems: loss of contractile proteins and the downregulation of Ca2+ handling proteins (10–16), both of which are implicated in the impaired cardiac function in heart failure patients, accumulation of extracellular matrix components that are involved in the increase in cardiac muscle stiffness (17), and changes in certain growth factors and cytokines such as VEGF and TNF-{alpha} (18–20), as well as the upregulation of the vasoconstrictor peptide ET-1 (21).

The changes in gene expression profile underlie the molecular mechanism of cardiac hypertrophy and its transition to heart failure. Depending on the initial hypertrophic stimuli such as hormones, cytokines, growth factors, vasoactive peptides, or catecholamines, the intracellular signaling pathways involved are different (22). However, the changes in gene expression with cardiac hypertrophy such as the upregulation of fetal genes including ß-myosin heavy chain (ß-MHC) and {alpha}-skeletal and {alpha}-smooth muscle actin, as well as atrial natriuretic peptide (ANF) and the downregulation of {alpha}-myosin heavy chain ({alpha}-MHC), are associated with several different etiologies including CuD-induced hypertrophy (23).

The purpose of this study was, thus, to extend the investigation of dietary CuD-induced cardiomyopathy to the molecular level to determine the changes in gene expression during the transition from heart hypertrophy to failure. Furthermore, the changes in gene expression patterns associated with the recovery from CuD-induced cardiomyopathy by CuR were also within the scope of this investigation. To this end, we have compared three groups of animals: CuD mice that were fed CuD diet until 4 weeks old, the stage at which functional and morphological deteriorations were marked (the transition phase from cardiac hypertrophy to failure); age-matched CuA controls; and CuD mice that were re-fed adequate Cu for an additional 2 weeks. We used cDNA microarray to determine changes in the expression of genes related to extracellular matrix components, cytoskeletal function, apoptosis, DNA damage, and acute-phase response. Real-time reverse transcription–polymerase chain reaction (RT-PCR) was used for assessment of genes involved in contractile function, Ca2+ cycling, and others.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and Treatment.
Friend Virus B-type (FVB) mice were bred and maintained at the University of Louisville animal facilities and housed in plastic cages at 22°C on a 12:12-hr light:dark cycle. Dams of the pups were fed copper-deficient (CuD) AIN-93 diet containing 0.33 ppm Cu or copper-adequate (CuA) diet containing 6.0 ppm Cu starting on the third day after delivery. The diet was prepared according to a previously published report (24). The primary ingredients are cornstarch (53%), casein (20%), sucrose (10%), and soybean oil (7%) with essential vitamins and minerals. After the pups were weaned on the 21st day after birth, they were fed the same diet until they were 4 weeks old, at which point some of the CuD animals were sacrificed and others were switched to CuA diet for an additional 2 weeks. Animals had free access to double distilled water. Cages, feeding jars, and water bottles were rinsed regularly with water containing EDTA first and then with distilled water. Body weight was monitored weekly starting from the third week after birth. All procedures were approved by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) certified University of Louisville Institutional Animal Care and Use Committee.

Microarray Analysis.
The procedure for the cDNA microarray was described previously (25). Briefly, the whole heart obtained from three mice in each treatment group was used and total RNA was isolated from the heart tissue using RNeasy columns (Qiagen, Valencia, CA). Aliquots from the purified RNA sample from each mouse were pooled, and the pooled RNA samples were used for microarray analysis in order to eliminate individual variability; however, individual RNA samples were used for real-time RT-PCR analysis. Total RNA was converted to [{alpha}-32P]-dATP-labeled cDNA probe by Moloney murine leukemia virus reverse transcriptase and the Atlas customer array-specific cDNA synthesis primer mix and purified with NucleoSpin columns (Clonetech). Membranes were prehybridized with Expresshyb from Clonetech for 60 mins at 68°C, followed by hybridization with probe overnight at 68°C. Membranes were washed 4 times in 2x standard saline citrate/1% sodium dodecyl sulfate, 30 mins each, and 2 times in 0.1x standard saline citrate/0.5% sodium dodecyl sulfate. Membranes were then wrapped and exposed to a Molecular Dynamics Phosphoimage Screen (Sunnyvale, CA). The hybridization procedure was repeated 3 times using the same pooled RNA sample for each treatment. The images were quantified densitometrically by using Atlas v2.01 software (Clonetech, Palo Alto, CA). Gene expression intensities were first corrected with background and then normalized with the sum of all nine housekeeping genes on the array. A total of 560 genes were analyzed. After acquiring imaging intensities of CuA, CuD and CuR groups, values that were less than 5000 or not significantly different from CuA control were eliminated (P < 0.05). The final data entry to Table 1Go includes only the genes whose alterations in expression by either CuD or CuA in comparison with the CuA controls reached 2-fold or more, either increased (with the value equal to or more than 2) or decreased (with the value equal to or less than 0.5).


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  		Table 1. Altered Myocardial Gene Expression in CuD and CuR Mice in Comparison to CuA Mice by Microarray Analysisa
 
Real-Time Reverse Transcription–Polymerase Chain Reaction (RT-PCR) Analysis.
Method for analysis of selected genes using real-time RT-PCR followed the published procedure (25, 26). In brief, total RNA was isolated from each mouse heart using RNeasy columns (Qiagen, Valencia, CA). RNA was reverse transcribed with Moloney murine leukemia virus reverse transcriptase and oligo-dT primers. Forward and reverse primers were designed using Primer Express software (Applied Biosystems, Foster City, CA; Table 2Go). The Sybr green DNA PCR kit (Applied Biosystems) was used for real-time RT-PCR analysis. Relative differences between groups were evaluated using cycle time values and expressed as relative increases or decreases setting the controls as 1.00. Assuming that the cycle time value is reflective of the initial starting copy and that there is 100% efficacy, a difference of one cycle is calculated from each gene’s standard curve.


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  		Table 2. Gene Name, Primer Sequence and Accession Number of Analysis Using Real-Time RT-PCR
 
Data Analysis.
A Student’s t test was used for all experimental data analysis. Differences were considered significant at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
CuD-induced myocardial pathological and functional changes and systemic alterations and the effect of CuR on these manifestations in the mouse model under the same condition have been reported previously (7, 8). The cDNA microarray analysis has revealed that the expression of many genes was altered by CuD and these alterations were corrected by CuA. The results presented in Table 1Go, however, only showed the genes whose expression changes induced by CuD or CuA in comparison to CuA reached 2-fold or more. By this 2-fold change criterion, only four genes were included in the table. In general, procollagen genes (I-{alpha}1 and III-{alpha}1) were upregulated by CuD. This upregulation was suppressed by CuR. A significant decrease in the mRNA level of the matricelluar protein thrombosponsin 1 was found in CuD (greater than 50% decrease), and CuR caused elevation of the mRNA level. Cyclin D1 mRNA levels were increased by CuD and decreased by CuR. Real-time RT-PCR analysis (Table 3Go) complemented the results obtained from the cDNA microarray with several cardiac specific genes. Specific changes in the myocardial gene expression in the CuD mice and their recovery in the CuR mice are described below.


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  		Table 3. Alterations in Gene Expression Analyzed by Real-Time RT-PCRa
 
ß-MHC mRNA was decreased in CuD heart compared to CuA controls by 35% (P < 0.05). Interestingly, CuR caused an increase of more than 3-fold of ß-MHC mRNA levels (P < 0.05). The difference in mRNA level of ß-MHC between CuD and CuR hearts is 5-fold (P < 0.05). Copper depletion led to a decrease to 85% of control in cardiac mRNA level of L-type Ca2+ channel and CuR not only reversed this alteration but also increased the mRNA levels for L-type Ca2+ channel more than 2-fold compared to CuA controls (P < 0.05). This elevation represents more than 3-fold increase compared to CuD cardiac tissue. Copper depletion caused a dramatic decrease in cardiac mRNA of K-dependent Na/Ca2+ exchanger and CuR caused an increase in the mRNA level.

CuD decreased matrix metalloproteins-2, -8, and -13 (MMPs) mRNA levels by 57%, 86%, and 73% compared to controls, respectively. Copper repletion normalized levels of both MMP-8 and MMP-13, however, did not recover the CuD-depressed expression of MMP-2. Cardiac TNF-{alpha} mRNA levels were increased in the CuD (by 30%, P < 0.05) and decreased significantly in the CuR cardiac tissue. ET-1 mRNA was increased more than 3-fold in CuD tissue and decreased to below 50% of control by CuR. A dramatic decrease in cardiac mRNA of VEGF was observed in CuD tissue (85% reduction compared to CuA control, P < 0.05); CuR corrected this decrease. The increase in VEGF mRNA by CuR represents greater than a 6-fold difference if compared to CuD mRNA levels. The levels of TGF-ß mRNA were approximately 2-fold higher in CuD cardiac tissue (P < 0.05) and reversed by CuR. Copper depletion significantly decreased the expression of NF-{kappa}B and CuR corrected this depression.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We have shown previously that CuD-induced cardiomyopathy leads to severe depression in cardiac contractility under stress and nonstress conditions (7). The effects on cardiac function and hemodynamics were all reversed upon reintroducing Cu into the diet of CuD animals, with a concomitant reversal of cardiac hypertrophy (8). In this study we present the results demonstrating the changes in myocardial gene expression that may account for the decreased cardiac function in CuD and the reversibility by CuR. We studied changes in several components essential for optimal cardiac function at the cardiomyocyte level (contractile apparatus and Ca2+ cycling proteins), as well as at the level of cardiac muscle as a whole (extracellular matrix components).

Given that contractility is governed by two cardiac cellular components, contractile proteins and those involved in Ca2+ cycling, alterations in the expression of these proteins lead to manifest changes in cardiomyocyte function as well as cardiac function as a whole. A differential expression of MHC occurs in pathological conditions depending on the type of stimulus. For example, an increase in thyroid hormone or exercise causes an elevation of {alpha}-MHC, whereas aging and pressure overload cause ß-MHC elevation (27). An increase in ß-MHC expression relative to {alpha}-MHC allows for more economy in force generation given its slow contractile velocity; an increase in ß-MHC is associated with cardiac hypertrophy in dietary CuD (23). Although ß-MHC mRNA is increased in the hypertrophied CuD heart, the mRNA level of ß-MHC decreased significantly when these hearts underwent transition to failure as shown in this study. In humans, the transition from hypertrophy to failure is marked by a decrease in myofibrillar and contractile protein content (28). It has been proposed that this loss of myofibrillar and contractile proteins constitutes a major reason for the systolic dysfunction observed in heart failure patients. Previous reports concerning myofibrillar protein content in CuD rat hearts also have shown a slight but significant shift in isomyosin types from V1 (composed of two {alpha} heavy chains) to V3 (composed of two ß heavy chains) and no changes in other myofibrillar proteins (29, 30). However, possible changes in the myofibrillar proteins during the transition to heart failure have not been reported in rats. Interestingly, CuA caused a significant shift from CuD-depressed ß-MHC mRNA levels to overexpression in the mouse model. This finding raises an important question: does the overexpression of a low velocity contractile protein benefit a dysfunctional heart, and what is the mechanism behind such a phenomenon?

Alterations in myocardial contractility in end-stage heart failure are linked to major changes in Ca2+ cycling (10, 11, 14). A major player in the regulation of Ca2+ homeostasis in cardiac excitation-contraction coupling is the sarcolemmal L-type Ca2+ channel. The L-type Ca2+ channel is a voltage gated channel that plays a role in the initiation of contraction by allowing the influx of Ca2+ through the sarcolemmal membrane into cardiac myocytes, which causes a release of Ca2+ from the sarcoplasmic reticulum (SR) through the SR ryanodine receptor (RyR). A decrease in L-type Ca2+ channel density in animal models of cardiac failure occurs, although reports are not consistent, and correlates with moderate to severe congestive heart failure (31). Results from failing human myocardium are controversial, with some showing a decrease in the abundance of specific L-type Ca2+ channel subunits and others showing no change in tissue from patients with end-stage failure (11). The present study showed a drastic decrease in L-type Ca2+ channel mRNA level in dietary CuD. This is consistent with some of the reports mentioned above and may account for altered channel function and disturbed excitation-contraction coupling. Conversely, the CuR-caused recovery of the expression of the mRNA for the L-type Ca2+ channel may contribute to the improved contractility observed in CuR animals.

The failing heart has a decreased frequency-dependent upregulation of force due to altered SR Ca2+ load (11). One of the major factors involved in SR Ca2+ load is the activity of the SRCA, Ca2+ availability to SRCA, and Ca2+ storage in and leak from the SR (11). Another contributor to SR Ca2+ loading is the NCX that exchanges Ca2+ for Na+ and constitutes the major Ca2+ efflux mechanism in cardiomyo-cytes (11). In the CuD-induced heart failure model, a drastic decrease in K-dependent NCX mRNA was observed, which might be involved in the myocardial contractile defects.

The accumulation of extracellular matrix (ECM) proteins in cardiac interstitium is one of the hallmarks of the hypertrophied (especially that associated with pressure overload) and failing heart and constitutes a major component in cardiac muscle dysfunction in addition to the adverse changes that occur in cardiac myocytes per se (17, 32). The increase in fibrillar collagen in pathological conditions is thought to be a result of fibroblast and/or myofibroblast increased synthesis and deposition of collagen (33). The accumulation of fibrillar collagen in the ECM accounts for the increased stiffness in cardiac muscle and impaired function (33). Previously we have shown an alteration in the time constant of relaxation Tau, as well as a prolonged relaxation time, both of which are indicative of increased myocardial stiffness in the CuD heart (7). These parameters identified increased muscle stiffness through direct measurement of heart muscle function. Previous reports have shown no change in the concentration of collagen in CuD but an increased proportion of collagen III protein in CuD hearts in rats and pigs (34, 35). Others have reported an increase in both collagen I and III, especially in areas where scar tissue and increased fibrosis occurred (37), and an increase in collagen deposition in the pericapillary areas in the CuD rat heart (37). We show here that mRNA levels of collagen I and III were indeed significantly increased in the CuD mouse hearts, agreeing well with our previous observations (7) and reports in the literature (34–37). Furthermore, TGF-ß expression was increased in CuD, suggesting activation of fibroblast and/or myofibroblast proliferation, leading to increases in collagen synthesis and deposition in myocardial tissue. The expression of TNF-{alpha} was also increased by CuD, and, interestingly, TNF-{alpha} expression was repressed by CuR. The decrease in TNF-{alpha} mRNA expression constitutes an interesting finding given the involvement of this cytokine not only in immune activation and coagulation but also in nitric oxide metabolism in vascular endothelial cells.

The accumulation of ECM collagen is governed by the rate of its synthesis by fibroblasts and myofibroblasts and its degradation by matrix metalloproteinases (MMPs; Ref. 34). MMP activity is under tight regulatory control at (i) the transcriptional level, (ii) the post-translation regulation level, and (iii) inhibition by endogenous (TIMP-1, -2, -3, and -4; Ref. 34). Under pathological conditions such as myocardial infarction and atherosclerosis, MMP activity is one of the major factors in myocardial matrix remodeling. The activation of MMP-1, -2, -3, and -9 during myocardial infarction occurs early in the pathological process and is thought to be involved in the tissue repair (38); however, a downregulation of MMP expression occurs in the prolonged pressure overload condition (39). In CuD-induced cardio-myopathy, a decrease in MMPs mRNA was observed, suggesting a similar mechanism to that observed in the prolonged pressure overload condition. The net result of increased ECM collagen and decreased MMP abundance favors the accumulation of ECM components in both CuD and prolonged pressure overload. Upon CuR, an increase in MMP-2, -8 and -13 were observed. In the case of MMP-13, mRNA levels were above those found in the control. The increase in MMP expression following CuR may contribute to the resolution of accumulated ECM collagens, leading to reduced fibrosis and improved cardiac function.

A drastic increase in the vasoconstrictor peptide ET-1 mRNA levels were found in CuD hearts. Cardiac ET-1 is an important endogenous vasoconstrictor that exerts its actions through specific receptors that are widely distributed in the cardiovascular system (21). The expression of ET-1 is found in various disease conditions such as hypertension, myocardial infarction, and heart failure (40). Furthermore functional deterioration of the left ventricle during the transition from cardiac hypertrophy to failure correlates well with ET-1 levels in the myocardium, suggesting an important role of ET-1 during the transition from compensatory hypertrophy to congestive heart failure in humans as well as experimental animal models (21). Interestingly, the reintroduction of Cu into the diet of CuD animals caused a drastic decrease in ET-1 mRNA levels to below those found in CuA controls. The mechanism by which this occurs warrants further investigation, especially given the beneficial effects of lowering ET-1 levels in heart failure.

Another important finding in this study is the decrease in VEGF mRNA level in the CuD myocardium. VEGF is a potent mitogen for endothelial cells, and if introduced to an ischemic limb induces angiogenesis and improves tissue perfusion (41). It was recently found that patients with congestive heart failure have reduced circulating VEGF concentrations (17). The mechanisms by which a decrease in circulating VEGF concentrations occurs are unknown; however, the decrease in myocardial VEGF mRNA in CuD suggests a change at least at the expression level.

In summary, CuD-induced cardiac failure is associated with gene expression changes in contractile proteins, Ca2+ cycling proteins, extracellular matrix collagens, and MMPs, as well as ET-1, VEGF, and TNF-{alpha}. Although these changes only reflect what would happen at the transcription level and do not necessarily demonstrate the changes in protein content and function, these findings provide important information for further studies regarding the molecular mechanism of CuD-induced cardiomyopathy and its recovery by Cu repletion.


   Footnotes
 
This work was supported by National Institutes of Health grants HL59225 and HL63760 and USDA grant 2002-35200-11573.

Received for publication January 6, 2004. Accepted for publication March 22, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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