BackgroundHeart 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.MethodsExperiments 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.ResultsLeft-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).ConclusionsMyocardial 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.

Dysregulation of renal Cu homeostasis may be a key event eliciting development of diabetic nephropathy. Selective Cu(II) chelation can protect against pathogenic mechanisms that lead to or cause diabetic nephropathy and might be clinically useful in the treatment of early-stage diabetic kidney disease.

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Otolith chemical analyses (proton-induced X-ray emission and laser ablation inductively coupled plasma mass spectrometry) were used to examine patterns of diadromy in Australian grayling Prototroctes maraena collected from three rivers in south-eastern Australia. Concentrations of Sr:Ca and Ba:Ca were measured in the sagittal otoliths of 25 fish and in water samples collected on two occasions from multiple sites within freshwater, estuarine and marine reaches of the rivers. The results provide evidence of marine residency during the juvenile phase, with high Sr:Ca and low Ba:Ca in the inner region of the otoliths that were consistent across all three rivers. This general pattern was apparent for all individuals examined, suggesting that diadromous migration may be an obligate aspect of the life history. The chemical signatures of the outer regions of the otoliths were distinct between the three rivers, whilst there was no difference in the inner regions of the otoliths. This suggests that juveniles from different rivers may reside in a relatively homogenous chemical environment, such as the sea, and populations in coastal Victorian rivers may share a common marine recruitment source. #