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

Cardiovascular Diabetology

Original Investigation

Marie-Louise Ward¹  Mark B Cannell²  Bernard Barry³  John Kennedy³  Shaoping Zhang⁴  Garth JS Cooper⁵  Lin Zhang⁶  Anthony RJ Phillips⁷ 

[1] Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand;Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand;School of Physiology & Pharmacology, Medical Sciences Building, University of Bristol, BS8 1TD, Bristol, UK;National Isotope Centre, GNS Science, Gracefield, Wellington, New Zealand;School of Biological Sciences, Faculty of Science, University of Auckland, Private Bag 92019, 1142, Auckland, New Zealand;School of Biological Sciences, Faculty of Science, University of Auckland, Private Bag 92019, 1142, Auckland, New Zealand;Centre for Advanced Discovery and Experimental Therapeutics, Manchester Biomedical Research Centre, University of Manchester, Manchester, UK;Department of Pharmacology, Medical Sciences Divisionv, University of Oxford, Oxford, UK;School of Biological Sciences, Faculty of Science, University of Auckland, Private Bag 92019, 1142, Auckland, New Zealand;Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand;School of Biological Sciences, Faculty of Science, University of Auckland, Private Bag 92019, 1142, Auckland, New Zealand;Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand;

关键词: 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;   

DOI  :  10.1186/1475-2840-12-123

 received in 2013-06-20, accepted in 2013-08-25,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundIntracellular 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.MethodsWe 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.ResultsTotal 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.ConclusionsDiabetes 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.

【 授权许可】

Unknown   
© Zhang et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.