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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
Article

Abstract

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.

Keywords

Homocysteine Copper Pressure overload Heart failure Matrix remodeling 

Abbreviations

AC

Ascending aortic constriction

Cu

Copper

DTT

Dithiothreitol

ED50

Effective dose, 50 percent

EDTA

Ethylenediaminetetraacetic acid

Hcy

Homocysteine

HHcy

Hyperhomocysteinemia

HPLC

High pressure liquid chromatography

LVH

Left ventricular hypertrophy

LVIDd

Left ventricular inner diameter during diastole

LOX

Lysyl oxidase

MMP

Matrix metalloproteinase

NADPH oxidase

Nicotinamide adenine dinucleotide phosphate oxidase

ppm

Parts per million

QRS

Electric QRS complex

ROS

Reactive oxygen species

SDS-PAGE

Sodium dodecyl sulfate-polyacrylamide gel electrophoresis

TIMP

Tissue inhibitor of matrix metalloproteinase

Notes

Acknowledgments

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

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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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