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Restoration of Myocellular Copper-Trafficking Proteins and Mitochondrial Copper Enzymes Repairs Cardiac Function in Rats with Diabetes-evoked Heart Failure

Abstract

Diabetes impairs systemic copper regulation, and acts as a major independent risk factor for heart failure (HF) wherein mitochondrial dysfunction is a key pathogenic process. Here we asked whether diabetes might alter mitochondrial structure/function and thus impair cardiac performance by damaging myocellular pathways that mediate cell-copper homeostasis. We measured activity of major mitochondria-resident copper-enzymes cytochrome c oxidase (mt-Cco) and superoxide dismutase 1 (mt-Sod1); expression of three main mitochondrial copper-chaperones [Cco copper chaperone 17 (Cox17), Cox11, and mitochondria-resident copper chaperone for Sod1 (mt-Ccs)]; of copper-dependent Cco-assembly protein Sco1; and regulation of mitochondrial biogenesis in left-ventricular (LV) tissue from groups of non-diabetic-control, untreated-diabetic, and divalent-copper-selective chelator-treated diabetic rats. Diabetes impaired LV pump function; ~halved LV-copper levels; substantively decreased myocellular expression of copper chaperones, and enzymatic activity of mt-Cco and mt-Sod1. Divalent-copper chelation with triethylenetetramine improved cardiac pump function, restored levels of myocardial copper, the copper chaperones, and Sco1; and enzymatic activity of mt-Cco and mt-Sod1. Copper chelation also restored expression of the key mitochondrial biogenesis regulator, peroxisome-proliferator-activated receptor gamma co-activator-1α. This study shows for the first time that altered myocardial copper-trafficking is a key pathogenic process in diabetes-evoked HF. We also describe a novel therapeutic effect of divalent-copper-selective chelation, namely restoration of myocellular copper trafficking, which is thus revealed as a potentially tractable target for novel pharmacological intervention to improve cardiac function.

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Publication details

The article was received on 09 Sep 2019, accepted on 26 Nov 2019 and first published on 02 Dec 2019


Article type: Paper
DOI: 10.1039/C9MT00223E
Metallomics, 2019, Accepted Manuscript

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    Restoration of Myocellular Copper-Trafficking Proteins and Mitochondrial Copper Enzymes Repairs Cardiac Function in Rats with Diabetes-evoked Heart Failure

    S. Zhang, H. Liu, G. V. Amarsingh, C. C. H. Cheung, D. Wu, U. Narayanan, L. Zhang and G. Cooper, Metallomics, 2019, Accepted Manuscript , DOI: 10.1039/C9MT00223E

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