Protection of the heart by treatment with a divalent-copper-selective chelator reveals a novel mechanism underlying cardiomyopathy in diabetic rats

Lin Zhang, Marie-Louise Ward, Anthony RJ Phillips, Shaoping Zhang, John Kennedy, Bernard Barry, Mark B Cannell, Garth JS Cooper

Research output: Contribution to journalArticle (Academic Journal)

21 Citations (Scopus)
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Abstract

Background

Intracellular calcium (Ca2+) coordinates the cardiac contraction cycle and is dysregulated in diabetic cardiomyopathy. Treatment with triethylenetetramine (TETA), a divalent-copper-selective chelator, improves cardiac structure and function in patients and rats with diabetic cardiomyopathy, but the molecular basis of this action is uncertain. Here, we used TETA to probe potential linkages between left-ventricular (LV) copper and Ca2+ homeostasis, and cardiac function and structure in diabetic cardiomyopathy.

Methods

We treated streptozotocin-diabetic rats with a TETA-dosage known to ameliorate LV hypertrophy in patients with diabetic cardiomyopathy. Drug treatment was begun either one (preventative protocol) or eight (restorative protocol) weeks after diabetes induction and continued thereafter for seven or eight weeks, respectively. Total copper content of the LV wall was determined, and simultaneous measurements of intracellular calcium concentrations and isometric contraction were made in LV trabeculae isolated from control, diabetic and TETA-treated diabetic rats.

Results

Total myocardial copper levels became deficient in untreated diabetes but were normalized by TETA-treatment. Cardiac contractility was markedly depressed by diabetes but TETA prevented this effect. Neither diabetes nor TETA exerted significant effects on peak or resting [Ca2+]i. However, diabetic rats showed extensive cardiac remodelling and decreased myofibrillar calcium sensitivity, consistent with observed increases in phosphorylation of troponin I, whereas these changes were all prevented by TETA.

Conclusions

Diabetes causes cardiomyopathy through a copper-mediated mechanism that incorporates myocardial copper deficiency, whereas TETA treatment prevents this response and maintains the integrity of cardiac structure and myofibrillar calcium sensitivity. Altered calcium homeostasis may not be the primary defect in diabetic cardiomyopathy. Rather, a newly-described copper-mediated mechanism may cause this disease.

Original languageEnglish
Article number123
Number of pages17
JournalCardiovascular Diabetology
Volume12
Issue number1
DOIs
Publication statusPublished - 28 Aug 2013

Keywords

  • Copper homeostasis
  • Calcium homeostasis
  • Anti-oxidant defence
  • Cardiac contraction
  • Cardiovascular disease
  • Copper deficiency
  • Copper excess
  • Cardiomyopathy
  • Diabetes mellitus
  • Essential trace nutrient
  • Experimental therapeutics
  • Left-ventricular dysfunction
  • Left-ventricular remodelling
  • Calcium responsiveness
  • Myocardium
  • Myocardial calcium sensitivity
  • QT interval
  • Triethylenetetramine
  • Troponin

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