Ar N-hexanoic-Try-Ile-(6)-amino hexanoic amide supplier copper concentrations by transporting copper into secretory vesicles from the trans-Golgi network, which shuttle to the plasma membrane for copper excretion [76]. Here we found that, in diabetic LV, protein levels of both ATOX1 and ATP7B were decreased, consistent with possible impairment of copper supply for activation of cuproenzymes. The decreased localization of ATP7B to the sarcolemmal membrane and intercalated disc regions in diabetes could limit intercellular transport of copper. Cumulatively these mechanisms could contribute to the pattern of copper deficiency and impaired cardiac function [9,10]. We also found that the ATP7A copper transporter, which is thought to function mainly in intestinal copper acquisition [39], is expressed in the myocardium. TETA enhanced the expression of ATP7A mRNA and protein, which could compensate and help to rectify impaired copper delivery to the secretory pathway/intercellular transport PubMed ID: by defective ATP7B action. These effects could contribute to the restoration of physiological copper homeostasis and biosynthesis of active copper-dependent enzymes in the myocardium, in parallel to the TETA-mediated restoration of the CCS-SOD1 pathway. The observed up-regulation of ATP7A with enhanced peri-nuclear localization following TETA treatment is consistent with enhanced delivery of copper to the trans-Golgi network,presumably aiding copper supply for newly-synthesized copper proteins. Some of the observed abnormalities, for example lowered levels of CTR1, CCS and SOD1, probably contribute to the causation of the localized copper-deficiency state in diabetic myocardium or to its adverse consequences, and thus to the functional impairment observed in the hearts of diabetic animals [8,45,48]; other effects, such as elevated CTR2 and lowered MT1/2 and ATP7B, may reflect endogenous responses directed towards ameliorating copper deficiency or its impacts. How might TETA exert its intracellular effects? We have previously shown that TETA selectively binds excess Cu (II) in diabetic individuals and elicits its removal from the body via urinary excretion, through studies where the following methods were applied: electron paramagnetic resonance spectroscopy; X-ray crystallography; potentiometric, spectrophotometric and mass-spectrometric analysis of complex formation between Cu (II), and TETA and its metabolites; and clinical studies [8,45,55,64]. Thus TETA can remove excess Cu (II) from the ECM, probably by binding and removing it from pathogenic binding sites such as those in AGE-modified collagen [77,78]. AGEcoordinated Cu (II) almost certainly remains catalytically active, and could therefore bind to the external, highaffinity Cu (II)-binding site present near the NH2-terminus of CTR1 [79]. Thus, elevated Cu (II) bound to AGEmodified collagen in diabetic individuals could participate in the modulation of cell copper metabolism through binding to CTR1, perhaps resulting in its translocation away from the cell membrane as shown herein. However, TETA is also known to cross cell membranes, probably via mechanisms employed by its physiological homologues, spermine and spermidine [80]. For example, there is substantive evidence that TETA can traverse cell membranes in the gut and kidney via a Na+/spermineantiporter-mediated mechanism [81]. It thus has the potential to exert direct effects in the intracellular compartment. TETA forms two main metabolites in the body, monoacetyl-TETA and diacetyl-TETA [54,82-85].