Diabetic cardiomyopathy is associated with defective myocellular copper regulation and both defects are rectified by divalent copper chelation

Cardiovascular Diabetology

Garth J S Cooper⁴  Anthony R J Phillips⁵  Yee Soon Choong³  Bernard Barry¹  John Kennedy¹  Deming Gong³  Jingshu Xu⁵  Selina McHarg²  Lin Zhang³  Umayal Narayanan³  Sebastian Hogl³  Carlos C H Cheung³  Greeshma V Amarsingh³  Hong Liu³  Shaoping Zhang⁵ 

[1] National Isotope Centre, GNS Science, Gracefield, Wellington, New Zealand;Centre for Advanced Discovery and Experimental Therapeutics, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, and the Centre for Diabetes and Endocrinology, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, UK;The School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand;Department of Pharmacology, Medical Sciences Division, University of Oxford, Oxford, UK;The Maurice Wilkins Centre for Molecular Biodiscovery, Faculty of Science, University of Auckland, Auckland, New Zealand

关键词: Heart failure;    Copper metalation;    Cu (II)-chelation;    Copper chaperones;    Superoxide dismutase 1;    Copper transporters;    Myocellular copper;    Left-ventricular dysfunction;    Copper-deficiency cardiomyopathy;    Diabetic cardiomyopathy;   

Others  :  791720
DOI  :  10.1186/1475-2840-13-100

 received in 2014-04-10, accepted in 2014-05-27,  发布年份 2014

【 摘 要 】

Background

Heart disease is the leading cause of death in diabetic patients, and defective copper metabolism may play important roles in the pathogenesis of diabetic cardiomyopathy (DCM). The present study sought to determine how myocardial copper status and key copper-proteins might become impaired by diabetes, and how they respond to treatment with the Cu (II)-selective chelator triethylenetetramine (TETA) in DCM.

Methods

Experiments were performed in Wistar rats with streptozotocin (STZ)-induced diabetes with or without TETA treatment. Cardiac function was analyzed in isolated-perfused working hearts, and myocardial total copper content measured by particle-induced x-ray emission spectroscopy (PIXE) coupled with Rutherford backscattering spectrometry (RBS). Quantitative expression (mRNA and protein) and/or activity of key proteins that mediate LV-tissue-copper binding and transport, were analyzed by combined RT-qPCR, western blotting, immunofluorescence microscopy, and enzyme activity assays. Statistical analysis was performed using Student’s t-tests or ANOVA and p-values of < 0.05 have been considered significant.

Results

Left-ventricular (LV) copper levels and function were severely depressed in rats following 16-weeks’ diabetes, but both were unexpectedly normalized 8-weeks after treatment with TETA was instituted. Localized myocardial copper deficiency was accompanied by decreased expression and increased polymerization of the copper-responsive transition-metal-binding metallothionein proteins (MT1/MT2), consistent with impaired anti-oxidant defences and elevated susceptibility to pro-oxidant stress. Levels of the high-affinity copper transporter-1 (CTR1) were depressed in diabetes, consistent with impaired membrane copper uptake, and were not modified by TETA which, contrastingly, renormalized myocardial copper and increased levels and cell-membrane localization of the low-affinity copper transporter-2 (CTR2). Diabetes also lowered indexes of intracellular (IC) copper delivery via the copper chaperone for superoxide dismutase (CCS) to its target cuproenzyme, superoxide dismutase-1 (SOD1): this pathway was rectified by TETA treatment, which normalized SOD1 activity with consequent bolstering of anti-oxidant defenses. Furthermore, diabetes depressed levels of additional intracellular copper-transporting proteins, including antioxidant-protein-1 (ATOX1) and copper-transporting-ATPase-2 (ATP7B), whereas TETA elevated copper-transporting-ATPase-1 (ATP7A).

Conclusions

Myocardial copper deficiency and defective cellular copper transport/trafficking are revealed as key molecular defects underlying LV impairment in diabetes, and TETA-mediated restoration of copper regulation provides a potential new class of therapeutic molecules for DCM.

【 授权许可】

   
2014 Zhang et al.; licensee BioMed Central Ltd.

【 图 表 】

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