Cardiovascular Toxicology

, Volume 8, Issue 3, pp 137–144 | Cite as

Role of Copper and Homocysteine in Pressure Overload Heart Failure

  • William M. HughesJr.
  • Walter E. Rodriguez
  • Dorothea Rosenberger
  • Jing Chen
  • Utpal Sen
  • Neetu Tyagi
  • Karni S. Moshal
  • Thomas Vacek
  • Y. James Kang
  • Suresh C. TyagiEmail author


Elevated levels of homocysteine (Hcy) (known as hyperhomocysteinemia HHcy) are involved in dilated cardiomyopathy. Hcy chelates copper and impairs copper-dependent enzymes. Copper deficiency has been linked to cardiovascular disease. We tested the hypothesis that copper supplement regresses left ventricular hypertrophy (LVH), fibrosis and endothelial dysfunction in pressure overload DCM mice hearts. The mice were grouped as sham, sham + Cu, aortic constriction (AC), and AC + Cu. Aortic constriction was performed by transverse aortic constriction. The mice were treated with or without 20 mg/kg copper supplement in the diet for 12 weeks. The cardiac function was assessed by echocardiography and electrocardiography. The matrix remodeling was assessed by measuring matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinases (TIMPs), and lysyl oxidase (LOX) by Western blot analyses. The results suggest that in AC mice, cardiac function was improved with copper supplement. TIMP-1 levels decreased in AC and were normalized in AC + Cu. Although MMP-9, TIMP-3, and LOX activity increased in AC and returned to baseline value in AC + Cu, copper supplement showed no significant effect on TIMP-4 activity after pressure overload. In conclusion, our data suggest that copper supplement helps improve cardiac function in a pressure overload dilated cardiomyopathic heart.


Homocysteine Copper Pressure overload Heart failure Matrix remodeling 



Ascending aortic constriction






Effective dose, 50 percent


Ethylenediaminetetraacetic acid






High pressure liquid chromatography


Left ventricular hypertrophy


Left ventricular inner diameter during diastole


Lysyl oxidase


Matrix metalloproteinase

NADPH oxidase

Nicotinamide adenine dinucleotide phosphate oxidase


Parts per million


Electric QRS complex


Reactive oxygen species


Sodium dodecyl sulfate-polyacrylamide gel electrophoresis


Tissue inhibitor of matrix metalloproteinase



This study was supported in part by the NIH grants HL-74185 and HL-88012 to SCT.


  1. 1.
    Macreadie, I. G. (2007). Copper transport and Alzheimer’s disease. European Biophysics Journal, 37(3), 295–300. doi: 10.1007/s00249-007-0235-2.PubMedCrossRefGoogle Scholar
  2. 2.
    Trumbo, P., Yates, A. A., Schlikcer, S., & Poos, M. (2001). Dietary reference intakes: Vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Journal of the American Dietetic Association, 101, 294–301. doi: 10.1016/S0002-8223(01)00078-5.PubMedCrossRefGoogle Scholar
  3. 3.
    Linnebank, M., Lutz, H., Jarre, E., Vielhaber, S., Noelker, C., Struys, E., et al. (2006). Binding of copper is a mechanism of homocysteine toxicity leading to COX deficiency and apoptosis in primary neurons, PC12 and SHSY-5Y cells. Neurobiology of Disease, 23(3), 725–730. doi: 10.1016/j.nbd.2006.06.010.PubMedCrossRefGoogle Scholar
  4. 4.
    Reiser, S., Smith, J. C., Jr., Mertz, W., Holbrook, J. T., Scholfield, D. J., Powell, A. S., et al. (1985). Indices of copper status in humans consuming a typical American diet containing either fructose or starch. The American Journal of Clinical Nutrition, 42, 242–251.PubMedGoogle Scholar
  5. 5.
    Jiang, Y., Reynolds, C., Xiao, C., Feng, W., Zhou, Z., Rodriguez, W., et al. (2007). Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in mice. The Journal of Experimental Medicine, 204, 657–666. doi: 10.1084/jem.20061943.PubMedCrossRefGoogle Scholar
  6. 6.
    Kopp, S. J., Klevay, L. M., & Feliksik, J. M. (1983). Physiological and metabolic characterization of a cardiomyopathy by chronic copper deficiency. Heart and Circulatory Physiology, 14, H855–H866.Google Scholar
  7. 7.
    Oikarinen, L., Nieminen, M. S., Viitasalo, M., Toivonen, L., Jern, S., Dahlof, B., et al. (2004). QRS duration and QT interval predict mortality in hypertensive patients with left ventricular hypertrophy. The Losartan Intervention for Endpoint Reduction in Hypertension Study. Hypertension, 43(5), 1029–1034. doi: 10.1161/01.HYP.0000125230.46080.c6.PubMedCrossRefGoogle Scholar
  8. 8.
    Castelli, W. P. (1996). Lipids, risk factors and ischemic heart disease. Atherosclerosis, 124, S1–S9. doi: 10.1016/0021-9150(96)05851-0.PubMedCrossRefGoogle Scholar
  9. 9.
    Reeves, P. G., Nielsen, F. H., & Fahey, G. C. (1993). Ain-93 purified diets for laboratory rodents—final report of the American Institute of Nutrition Ad Hoc Writing Committee on the reformulation of the Ain-76A rodent diet. The Journal of Nutrition, 123, 1939–1951.PubMedGoogle Scholar
  10. 10.
    Tarnavski, O., McMullen, J. R., Schinke, M., Nie, Q., Kong, S., & Izumo, S. (2004). Mouse cardiac surgery: Comprehensive techniques for the generation of mouse models of human diseases and their application for genomic studies. Physiological Genomics, 16(3), 349–360. doi: 10.1152/physiolgenomics.00041.2003.PubMedCrossRefGoogle Scholar
  11. 11.
    Rodriguez, W., Tyagi, N., Joshua, I., Passmore, J., Fleming, J., Falcone, J., et al. (2006). Pioglitazone mitigates renal glomerular vascular changes in high-fat, high-calorie-induced type 2 diabetes mellitus. American Journal of Physiology. Renal Physiology, 291, F694–F701. doi: 10.1152/ajprenal.00398.2005.PubMedCrossRefGoogle Scholar
  12. 12.
    Tyagi, N., Moshal, K. S., Tyagi, S. C., & Lominadze, D. (2007). gamma-Aminbuturic acid A receptor mitigates homocysteine-induced endothelial cell permeability. Endothelium, 14(6), 315–323. doi: 10.1080/10623320701746164.PubMedCrossRefGoogle Scholar
  13. 13.
    Tyagi, N., Moshal, K. S., Sen, U., Lominadze, D., Ovechkin, A. V., & Tyagi, S. C. (2006). Ciglitazone ameliorates homocysteine-mediated mitochondrial translocation and matrix metalloproteinase-9 activation in endothelial cells by inducing peroxisome proliferators activated receptor-gamma activity. Cellular and Molecular Biology, 52, 21–27.PubMedGoogle Scholar
  14. 14.
    Moshal, K. S., Zeldin, D. C., Sithu, S. D., Sen, U., Tyagi, N., Kumar, M., et al. (2008). Cytochrome P450 (CYP) 2J2 gene transfection attenuates MMP-9 via inhibition of NF-kappabeta in hyperhomocysteinemia. Journal of Cellular Physiology, 215(3), 771–781. doi: 10.1002/jcp.21356.PubMedCrossRefGoogle Scholar
  15. 15.
    Sen, U., Tyagi, N., Kumar, M., Rodriguez, W., & Tyagi, S. (2007). Cystathionine-beta synthase gene transfer and 3-deazaadenosine ameliorate inflammatory response in endothelial cells. American Journal of Physiology. Cell Physiology, 293(6), C1779–C1787. doi: 10.1152/ajpcell.00207.2007.PubMedCrossRefGoogle Scholar
  16. 16.
    Malinow, M. R., Kang, S. S., Taylor, L. M., Wong, P. W., Coull, B., Inahara, T., et al. (1989). Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease. Circulation, 79, 1180–1188.PubMedGoogle Scholar
  17. 17.
    Hultberg, B., Andersson, A., & Isaksson, A. (1997). Copper ions differ from other thiol reactive metal ions in their effects on the concentration and redox status of thiols in HeLa cell cultures. Toxicology, 117, 89–97. doi: 10.1016/S0300-483X(96)03554-8.PubMedCrossRefGoogle Scholar
  18. 18.
    Tamura, T., & Turnlund, J. R. (2004). Effect of long-term, high-copper intake on the concentrations of plasma homocysteine and B vitamins in young men. Nutrition (Burbank, Los Angeles County, Calif.), 20(9), 757–759. doi: 10.1016/j.nut.2004.05.011.Google Scholar
  19. 19.
    Elsherif, L., Ortines, R. V., Saari, J. T., & Kang, Y. J. (2003). Congestive heart failure in copper-deficient mice. Experimental Biology and Medicine, 228(7), 811–817.PubMedGoogle Scholar
  20. 20.
    Emsley, A., Jeremy, J. Y., Gomes, G., Angelini, G. D., & Plane, F. (1999). Copper interacts with homocysteine to inhibit nitric oxide formation in the rat isolated aorta. British Journal of Pharmacology, 126, 1034–1040. doi: 10.1038/sj.bjp. 0702374.PubMedCrossRefGoogle Scholar
  21. 21.
    Shukla, N., Koupparis, A., Jones, R. A., Angelini, G. D., Persad, R., & Jeremy, J. Y. (2006). Penicillamine administration reverses the inhibitory effect of hyperhomocysteinemia on endothelium-dependent relaxation and superoxide formation in the aorta of the rabbit. European Journal of Pharmacology, 531, 201–208. doi: 10.1016/j.ejphar.2005.12.003.PubMedCrossRefGoogle Scholar
  22. 22.
    Mansoor, M. A., Bergmark, C., Haswell, S. J., Savage, I. F., Evans, P. H., Berge, R. K., et al. (2000). Correlation between plasma total homocysteine and copper in patients with peripheral vascular disease. Clinical Chemistry, 46, 385–391.PubMedGoogle Scholar
  23. 23.
    Rucker, R. B., Kosonen, T., Clegg, M. S., Mitchell, A. E., Rucker, B. R., Uriu-Hare, J. Y., et al. (1998). Copper, lysyl oxidase and extracellular matrix protein cross-linking. The American Journal of Clinical Nutrition, 67, 996S–1002S.PubMedGoogle Scholar
  24. 24.
    Xia, B., Llanos, R. M., & Mercer, J. F. B. (2008). ATP7A transgenic and nontransgenic mice are resistant to high copper exposure. The Journal of Nutrition, 138(4), 693–697.Google Scholar

Copyright information

© Humana Press 2008

Authors and Affiliations

  • William M. HughesJr.
    • 1
  • Walter E. Rodriguez
    • 1
  • Dorothea Rosenberger
    • 1
  • Jing Chen
    • 2
  • Utpal Sen
    • 1
  • Neetu Tyagi
    • 1
  • Karni S. Moshal
    • 1
  • Thomas Vacek
    • 1
  • Y. James Kang
    • 3
  • Suresh C. Tyagi
    • 1
    Email author
  1. 1.Department of Physiology and Biophysics, School of MedicineUniversity of LouisvilleLouisvilleUSA
  2. 2.Department of Environmental and Occupational Health Sciences, School of MedicineUniversity of LouisvilleLouisvilleUSA
  3. 3.Department of Pharmacology and Toxicology, School of MedicineUniversity of LouisvilleLouisvilleUSA

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