P4.27 DIABETES-EVOKED PATHOGENIC CHANGES ASSOCIATED WITH ALTERED COPPER UPTAKE/TRANSPORT PATHWAYS IN THE AORTA OF STZ-DIABETIC RATS: EFFECTS OF TREATMENT BY CU(II)-SELECTIVE CHELATION

DOI

10.1016/j.artres.2013.10.145How to use a DOI?

Abstract

Objectives: Cardiovascular disease is the commonest complication of diabetes. Previous studies from our group have identified diabetes-evoked changes in copper homeostasis that cause accumulation of chelatable-Cu(II) in the heart (1). We also showed that treatment by Cu(II)-selective chelation with TETA (triethylenetetramine) ameliorates cardiac left-ventricular/aortic damage in diabetes (2). This study aimed to define the pathogenic role of copper imbalance in diabetic arteriopathy and its response to TETA.

Methods: Pathological changes in the aorta of STZ-diabetic rats with/without TETA treatment were examined by histological and confocal imaging. Expression of genes and proteins involved in regulation of copper uptake/transport in aortic tissues were analysed by RT-qPCR and Western blotting.

Results: Diabetes-induced oxidative aortic damage was associated with increased expression of ET-1, ET-A, ICAM1 and eNOS, and decreased expression of Ctr1 (cell-membrane copper-uptake transporter-1) and Sco1 (copper-chaperone 1 for cytochrome c oxidase). We also identified up-regulation of CCS (copper chaperone for SOD1) and copper-binding metallothioneins (MT1/2) as further compensatory responses apparently aimed at up-regulating copper-related defences in response to altered aortic copper regulation in diabetes. TETA treatment further elevated MT1/2 levels. Moreover, diabetes lowered levels/activity of SOD2, both of which were restored by TETA treatment.

Conclusions: Dysregulation of cellular copper uptake/transport might be an important molecular process contributing to the pathogenesis of diabetic arteriopathy, and TETA treatment could be beneficial by restoring of these acquired defects, at least in part via activation of MT1/2 which are potent antioxidants, and SOD2, the main antioxidant enzyme that scavenges intra-mitochondrial superoxide radical.

Open Access

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TY  - JOUR
AU  - S. Zhang
AU  - H. Xu
AU  - H. Liu
AU  - G. Amarsingh
AU  - G.J.S. Cooper
PY  - 2013
DA  - 2013/11/11
TI  - P4.27 DIABETES-EVOKED PATHOGENIC CHANGES ASSOCIATED WITH ALTERED COPPER UPTAKE/TRANSPORT PATHWAYS IN THE AORTA OF STZ-DIABETIC RATS: EFFECTS OF TREATMENT BY CU(II)-SELECTIVE CHELATION
JO  - Artery Research
SP  - 143
EP  - 143
VL  - 7
IS  - 3-4
SN  - 1876-4401
UR  - https://doi.org/10.1016/j.artres.2013.10.145
DO  - 10.1016/j.artres.2013.10.145
ID  - Zhang2013
ER  -