Protection of the heart by treatment with a divalent-copper-selective chelator reveals a novel mechanism underlying cardiomyopathy in diabetic rats
- Equal contributors
1 School of Biological Sciences, Faculty of Science, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
2 Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
3 Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
4 National Isotope Centre, GNS Science, Gracefield, Wellington, New Zealand
5 Centre for Advanced Discovery and Experimental Therapeutics, Manchester Biomedical Research Centre, University of Manchester, Manchester, UK
6 Department of Pharmacology, Medical Sciences Division, University of Oxford, Oxford, UK
7 School of Physiology & Pharmacology, Medical Sciences Building, University of Bristol, Bristol, BS8 1TD, UK
Cardiovascular Diabetology 2013, 12:123 doi:10.1186/1475-2840-12-123Published: 28 August 2013
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.
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.
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.
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.