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
| Autor: | Deming Gong, Soon Y. Choong, S. Fitzpatrick, Jun Lu, Sarah Glyn-Jones, Victor Obolonkin, Shaoping Zhang, Yih-Kai Chan, Xiuyin Chen, Tomoyuki Nakamura, Katya Ruggiero, Hong Xu, Sally D. Poppitt, Garth J. S. Cooper, Anthony R. J. Phillips |
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| Rok vydání: | 2009 |
| Předmět: |
Adult
Male medicine.medical_specialty Pyridones Endocrinology Diabetes and Metabolism Zinc Acetate medicine.disease_cause Ferroxidase activity Kidney Trientine Diabetes Mellitus Experimental Diabetic nephropathy chemistry.chemical_compound Internal medicine Diabetic cardiomyopathy Internal Medicine medicine Animals Humans Deferiprone Rats Wistar Aorta Aged Chelating Agents Creatinine Analysis of Variance business.industry Penicillamine Heart Middle Aged Streptozotocin medicine.disease Rats Oxidative Stress Endocrinology medicine.anatomical_structure chemistry Triethylenetetramine Heparitin Sulfate business Oxidative stress medicine.drug |
| Zdroj: | Diabetologia. 53(6) |
| ISSN: | 1432-0428 |
| Popis: | Treatment 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. Rats 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. Diabetes 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. TETA 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. |
| Databáze: | OpenAIRE |
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