Diabetic cardiomyopathy is associated with defective myocellular copper regulation and both defects are rectified by divalent copper chelation.
Diabetic cardiomyopathy is associated with defective myocellular copper regulation and both defects are rectified by divalent copper chelation.
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DOI：
10.1186/1475-2840-13-100
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发表时间：
2014-06-14
影响因子：
9.3
通讯作者：
Cooper GJ
中科院分区：
文献类型：
--
作者：
Zhang S;Liu H;Amarsingh GV;Cheung CC;Hogl S;Narayanan U;Zhang L;McHarg S;Xu J;Gong D;Kennedy J;Barry B;Choong YS;Phillips AR;Cooper GJ
心脏病是糖尿病患者死亡的主要原因，铜代谢缺陷可能在糖尿病心肌病（DCM）的发病机制中起重要作用。本研究旨在确定心肌铜状态和关键铜蛋白可能会受到糖尿病的损害，以及它们如何对DCM中的Cu（II）选择性螯合剂三亚乙基四胺（TETA）治疗作出反应。实验在链脲佐菌素（STZ）诱导的糖尿病伴或不伴TETA治疗的Wistar大鼠中进行。在离体灌流工作心脏的心功能进行了分析，心肌总铜含量的粒子诱导X射线发射光谱（PIXE）与卢瑟福背散射光谱（RBS）的耦合测量。通过联合RT-qPCR、蛋白质印迹、免疫荧光显微镜和酶活性测定分析介导LV-组织-铜结合和转运的关键蛋白的定量表达（mRNA和蛋白质）和/或活性。使用Student t检验或方差分析进行统计分析，p值< 0.05被认为具有显著性。糖尿病16周后，大鼠左心室（LV）铜水平和功能受到严重抑制，但在TETA治疗8周后，两者意外恢复正常。局部心肌铜缺乏伴随着铜反应性过渡金属结合金属硫蛋白（MT 1/MT 2）的表达减少和聚合增加，与抗氧化防御受损和对促氧化应激的敏感性升高一致。高亲和力铜转运蛋白-1（CTR 1）的水平在糖尿病中被抑制，与受损的膜铜摄取一致，并且没有被TETA改变，相比之下，TETA使心肌铜重新正常化并增加低亲和力铜转运蛋白-2（CTR 2）的水平和细胞膜定位。糖尿病还降低了通过超氧化物歧化酶（CCS）的铜分子伴侣向其靶向铜酶超氧化物歧化酶-1（SOD 1）的细胞内（IC）铜递送指数：TETA治疗纠正了这一途径，使SOD 1活性正常化，从而增强了抗氧化防御。此外，糖尿病抑制了额外的细胞内铜转运蛋白的水平，包括抗氧化蛋白-1（ATOX 1）和铜转运ATP酶-2（ATP 7 B），而TETA升高了铜转运ATP酶-1（ATP 7A）。心肌铜缺乏和缺陷的细胞铜转运/贩运被揭示为糖尿病左心室损害的关键分子缺陷，TETA介导的铜调节恢复为DCM提供了潜在的新一类治疗分子。
Heart 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. Experiments 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. Left-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). Myocardial 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.
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影响因子：
3.9
作者：
Cerrada-Gimenez, Marc;Weisell, Janne;Keinanen, Tuomo A.
通讯作者：
Keinanen, Tuomo A.
影响因子：
5.6
作者：
Bertinato, Jesse;Duval, Sebastien;L'Abbe, Mary R.
通讯作者：
L'Abbe, Mary R.
影响因子：
7.1
作者：
Desai, Vishal;Kaler, Stephen G.
通讯作者：
Kaler, Stephen G.
影响因子：
8.2
作者：
Anzawa, R;Bernard, M;Feuvray, D
通讯作者：
Feuvray, D
DOI：
10.1152/ajpheart.00313.2002
发表时间：
2002-10-01
影响因子：
4.8
作者：
Choi, KM;Zhong, Y;Matlib, MA
通讯作者：
Matlib, MA