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Copper(II)-selective chelation improves function and antioxidant defences in cardiovascular tissues of rats as a model of diabetes: comparisons between triethylenetetramine and three less copper-selective transition-metal-targeted treatments |
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| Authors: | J Lu D Gong S Y Choong H Xu Y-K Chan X Chen S Fitzpatrick S Glyn-Jones S Zhang T Nakamura K Ruggiero V Obolonkin S D Poppitt A R J Phillips G J S Cooper |
| Institution: | 1. School of Biological Sciences, Faculty of Science, University of Auckland, Private Bag, 92019, Auckland, New Zealand 6. National Centre for Interprofessional Education and Collaborative Practice, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland, New Zealand 7. College of Chemistry and Chemical Engineering, ShenZhen University, ShenZhen, People’s Republic of China 5. Human Nutrition Unit, University of Auckland, Auckland, New Zealand 2. The Maurice Wilkins Centre for Molecular Biodiscovery, Faculty of Science, University of Auckland, Auckland, New Zealand 8. Department of Pharmacology, Kansai Medical University, Osaka, Japan 4. Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand 3. Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand 9. Department of Pharmacology, Medical Sciences Division, University of Oxford, Oxford, UK |
| Abstract: | Aims/hypothesisTreatment with the Cu(II)-selective chelator triethylenetetramine (TETA) improves cardiovascular disease in human patients, and cardiac and vascular/renal disease in rats used as a model of diabetes. Here we tested two hypotheses: first, that TETA elicits greater improvement in organ function than less Cu-selective transition-metal-targeted treatments; second, that the therapeutic actions of TETA are consistent with mediation through suppression of oxidative stress.MethodsRats were made diabetic with streptozotocin (55 mg/kg, i. v.) and treated from 8 weeks after disease induction for the following 8 weeks with effective dosages of oral TETA, or one of three less Cu-selective transition-metal-targeted treatments: d-penicillamine, deferiprone or Zn acetate. Treatment effects were measured in ex vivo cardiac and aortic tissues, plasma and urine.ResultsDiabetes damaged both cardiac and renal/vascular function by impairing the ability of cardiac output to respond physiologically to rising afterload, and by significantly elevating the urinary albumin/creatinine ratio. Diabetes also lowered total antioxidant potential and heparan sulphate levels in cardiac and arterial tissues, and serum ferroxidase activity, whereas it elevated urinary heparan sulphate excretion. TETA treatment rectified or partially rectified all these defects, whereas the other three experimental treatments were ineffectual. By contrast, none of the four drug treatments lowered diabetes-mediated elevations of plasma glucose or lipid concentrations.Conclusions/interpretationTETA may limit the cardiac and renal/vascular damage inflicted by diabetes through its actions to reinforce antioxidant defence mechanisms, probably acting through selective chelation of ‘loosely-bound’/chelatable Cu(II). It may also improve heparan sulphate homeostasis and bolster antioxidant defence by increasing vascular extracellular superoxide dismutase activity. Urinary albumin/creatinine ratio might prove useful for monitoring TETA treatment. |
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