Alterations in Hypertrophic Gene Expression by Dietary Copper Restriction in Mouse Heart

Abstract

Abstract. Dietary copper (Cu) restriction causes a hypertrophic cardiomyopathy similar to that induced by work overload in rodent models. However, a possible change in the program of hypertrophic gene expression has not been studied in the Cu‐deficient heart. This study was undertaken to fill that gap. Dams of mouse pups were fed a Cu‐deficient diet (0.35 mg/kg diet) or a Cu‐adequate control diet (6.10 mg/kg) on the fourth day after birth, and weanling mice continued on the dams′ diet until they were sacrificed. After 5 weeks of feeding, Cu concentrations were dramatically decreased in the heart and the liver of the mice fed the Cu‐deficient diet. Corresponding to these changes, serum ceruloplasmin concentrations and hepatic Cu,Zn‐superoxide dismutase activities were significantly (P < 0.05) depressed. The size of the Cu‐deficient hearts was greatly enlarged as estimated from the absolute heart weight and the ratio of heart weight to body weight. The abundances of mRNAs for atrial natriuretic factor, β‐myosin heavy chain, and α‐skeletal actin in left ventricles were all significantly increased in the Cu‐ deficient hearts. Furthermore, Cu deficiency activated the expression of the c‐myc oncogene in the left ventricle. This study thus demonstrated that a molecular program of alterations in embryonic genes, similar to that shown in the work‐overloaded heart, was activated in the hypertrophied heart induced by Cu deficiency.

Influence of copper on early development: Prenatal and postnatal considerations

“…Postnatal Cu deficient hearts show increased apoptosis [101], excessive lipid deposits, mitochondrial necrosis and hypertrophy, disorganized basal laminae ECM [94, 102, 103], and reexpression of fetal genes [104]. Interestingly, when Cu deficiency is initiated at postnatal day 3 (not during pregnancy) and Cu repletion begun at 4 weeks of age, many of the ultrastructural, contractile, and hemodynamic functional abnormalities in the heart, as well as the expression of genes involved in contractility, calcium metabolism, inflammation and fibrosis, are reversed during the myocardial regeneration [105, 106].…”

Cardiac nitric oxide synthases are elevated in dietary copper deficiency

“…Cu-deficient hearts have also been shown to undergo events specifically associated with cardiac failure, including reexpression of fetal genes, inability to respond to an adrenergic stimulus and apoptosis [7][8][9][10][11].…”

Role of copper in regression of cardiac hypertrophy

“…The most obvious changes along with the cardiac hypertrophy include the cardiomyocyte enlargement and the mitochondrial swelling (Goodman et al, 1970;Kopp et al, 1983;Medeiros et al, 1991a), as well as the associated depression in electrical (Viestenz & Klevay, 1982), contractile (Prohaska & Heller, 1982), and respiratory functions (Bode et al, 1992) in rats. In a mouse model, similar Cu-deficient cardiac defects were observed (Kang et al, 2000;Elsherif et al, 2003). In general, dietary Cu deficiency induces concentric cardiac hypertrophy with characteristic alterations in myocardial structural, functional and biochemical pathways resembling heart hypertrophy induced by pressure overload (Medeiros et al, 1993).…”