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
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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DOI：
10.1007/s00125-010-1698-8
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发表时间：
2010-06-01
期刊：
影响因子：
8.2
通讯作者：
Cooper, G. J. S.
中科院分区：
文献类型：
--
作者：
Lu, J.;Gong, D.;Cooper, G. J. S.
铜(II)选择性螯合剂三乙烯四胺(Teta)的治疗改善了人类患者的心血管疾病，以及用作糖尿病模型的大鼠的心脏和血管/肾脏疾病。在这里，我们检验了两个假设：第一，Teta在器官功能方面的改善比铜选择性较少的过渡金属靶向治疗更大；第二，Teta的治疗作用与通过抑制氧化应激而调节的作用一致。从发病后8周开始，口服有效剂量的Teta，或三种铜选择性较低的过渡金属靶向治疗之一：D-青霉胺、去铁酮或醋酸锌。治疗效果在体外心脏和主动脉组织、血浆和尿液中进行评估。糖尿病通过削弱心输出量对后负荷增加的生理反应能力以及显著升高尿白蛋白/肌酐比率而损害心脏和肾脏/血管功能。糖尿病还降低了心脏和动脉组织中的总抗氧化潜力和硫酸肝素水平，以及血清铁氧合酶活性，而它却增加了尿硫酸肝素的排泄量。TETA处理可纠正或部分纠正所有这些缺陷，而其他三种实验处理均无效。相比之下，四种药物治疗都没有降低糖尿病引起的血糖或血脂浓度的升高。TETA可能通过加强抗氧化防御机制来限制糖尿病造成的心脏和肾脏/血管损害，可能是通过选择性地螯合“松散结合的”/可螯合的铜(II)。它还可能通过增加血管细胞外超氧化物歧化酶活性来改善硫酸乙酰肝素的动态平衡和增强抗氧化防御。尿白蛋白/肌酐比值可能对监测TETA治疗有帮助。
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.