Abstract
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.
Highlights
Intracellular calcium (Ca2+) coordinates the cardiac contraction cycle and is dysregulated in diabetic cardiomyopathy
Metabolic responses to drug treatment TETA had no effect on the elevated blood glucose levels in diabetic rats, it significantly increased the body-weight of diabetic rats in the latter stages of preventative treatment (Week 8; P = 0.02, Table 1); these findings could imply the occurrence of a systemic/metabolic improvement in TETA-treated animals without improved glycaemic regulation
TETA-treatment restored total copper content in LV myocardium of diabetic rats After 16 weeks, the total copper content of the LV myocardium was much lower in diabetic animals than in controls, whereas in TETA-treated diabetic animals, total copper was fully normalized (TETA-treated diabetic: 48 ± 6 μg/g, n = 7, P = 0.032 vs untreated diabetic)
Summary
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. Cardiovascular disease (CVD) is the main cause of mortality in diabetic patients, in whom it is frequently accompanied by heart failure [1]. Other significant contributors to risk include obesity, atherosclerosis, dyslipidaemia, endothelial dysfunction, defective platelet function, coagulation abnormalities, and diabetic cardiomyopathy [2]. The latter condition is considered to be a diabetes-specific cardiomyopathy, which is independent of macrovascular and microvascular disease and which contributes substantively to morbidity and mortality [2,3,4]. Elevated risk persists despite best available treatments with existing classes of medications, so new and improved therapeutic approaches for heart failure in diabetes are required
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