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

Abstract

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.

Elevation of brain glucose and polyol-pathway intermediates with accompanying brain-copper deficiency in patients with Alzheimer’s disease: metabolic basis for dementia

“…Instead, we measured levels of metabolites and trace metals in whole brains from male rats with streptozotocin-induced diabetes (a model of severe T1D)21 and whole mouse brains from a model of AD (13–14-month-old male triple-transgenic mice)26, by applying the same methods we used for analysis of human brain. Diabetic-rat brain displayed marked elevations in glucose, sorbitol, and fructose, similar to those in human AD brain (Suppl.…”

Behind the Link between Copper and Angiogenesis: Established Mechanisms and an Overview on the Role of Vascular Copper Transport Systems

“…Defective myocardial copper homeostasis has been shown to be rectified by trientine chelation, shown to restore copper uptake through the up-regulation of low-affinity CTR2 and an enhanced localization of such transporter to the sarcolemmal membrane [126]. Exiguous evidence has revealed a substantial role for CTR2 in tumour angiogenesis, but the underlying mechanisms are not completely defined.…”

“…Interestingly, a down-regulation of CTR1, but not CTR2, has been detected in the left ventricular myocardium of rats with diabetic cardiomyopathy, a disorder characterized by endothelial dysfunction and altered cardiomyocyte expression levels of VEGF and VEGF receptors [126]. Defective myocardial copper homeostasis has been shown to be rectified by trientine chelation, shown to restore copper uptake through the up-regulation of low-affinity CTR2 and an enhanced localization of such transporter to the sarcolemmal membrane [126].…”

Complex formation equilibria of Cu2+ and Zn2+ with Irbesartan and Losartan

“…[1] Defective copper regulation is widespread in diabetes, where it is likely one of the causes of cardiovascular disease, [2] and is now serving as a target for experimental therapeutic intervention by treatment with a Cu 2+ -selective chelator. [3] In diabetes, impaired copper regulation manifests as enhanced urinary Cu 2+ excretion, elevated systemic copper balance and defective myo-cellular copper regulation, [2,4,5] and it has been involved in increased pro-oxidant stress, defective antioxidant defenses, [6] and progressive damage to the blood vessels, heart, kidneys and nerves (the 'diabetic complications'). [7] Cardiovascular disease in diabetic patients tends to be more aggressive and disabling than in matched non-diabetic patients.…”