Expression of cardiac copper chaperone encoding genes and their correlation with cardiac function parameters in goats

Ahmed S Mandour,Katsuhiro Matsuura,Asmaa O Ali,Haney Samir,Ryou Tanaka,Lina Hamabe,Akiko Uemura,Hend A Abdelmageed,Danfu Ma,Tomohiko Yoshida,Ahmed E Mahmoud,Gen Watanabe

doi:10.1007/s11259-021-09811-5

Abstract

Copper deficiency (CuD) is a common cause of oxidative cardiac tissue damage in ruminants. The expression of copper chaperone (Cu-Ch) encoding genes enables an in-depth understanding of copper-associated disorders, but no previous studies have been undertaken to highlight Cu-Ch disturbances in heart tissue in ruminants due to CuD. The current study aimed to investigate the Cu-Ch mRNA expression in the heart of goats after experimental CuD and highlight their relationship with the cardiac measurements. Eleven male goats were enrolledin this study and divided into the control group (n = 4) and CuD group (n = 7), which received copper-reducing dietary regimes for 7months. Heart function was evaluated by electrocardiography and echocardiography, and at the end of the experiment, all animals were sacrificed and the cardiac tissues were collected for histopathology and quantitative mRNA expression by real-time PCR. In the treatment group, cardiac measurements revealed increased preload and the existence of cardiac dilatation, and significant cardiac tissue damage by histopathology. Also, the relative mRNA expression of Cu-Ch encoding genes; ATP7A, CTr1, LOX, COX17, as well as ceruloplasmin (CP), troponin I3 (TNNI3), glutathione peroxidase (GPX1), and matrix metalloprotease inhibitor (MMPI1) genes were significantly down-regulated in CuD group. There was a significant correlation between investigated genes and some cardiac function measurements; meanwhile, a significant inverse correlation was observed between histopathological score and ATP7B, CTr1, LOX, and COX17. In conclusion, this study revealed that CuD induces cardiac dilatation and alters the mRNA expression of Cu-Ch genes, in addition to TNNI3, GPX1, and MMPI1 that are considered key factors in clinically undetectable CuD-induced cardiac damage in goats which necessitate further studies for feasibility as biomarkers.

Highlights

Copper (Cu) is known to have exciting and crucial importance for various physiological processes because of being an essential cofactor for numerous enzymatic activities
The results revealed a significant reduction in P-wave time (P=0.004) as well as T-wave time and T-wave voltage (P=0.021, and 0.042, respectively) in the treatment group compared with the control
The result revealed that the relative expressions of ATP7A, ATP7B,CTr1, lysyl oxidase (LOX), and c oxidase 17 (COX17) were significantly down-regulated in the cardiac tissue of the treatment group compared with the control (P=0.0049, 0.044, 0.023, 0.049, and 0.029, respectively); CCS showed no significant change (P=0.750)

Summary

Introduction

Copper (Cu) is known to have exciting and crucial importance for various physiological processes because of being an essential cofactor for numerous enzymatic activities. Copper homeostasis within the cell is regulated by a distinctive transport and traffic system known as metallochaperones or copper chaperone proteins (Cu-Ch), which helps in delivering Cu to the target site without inflicting harm or becoming impound in unplanned sites These chaperones include Cu transporter protein (CTr1), ATPases 7 alpha and beta (ATP7A, ATP7B), chaperone for superoxide dismutase (CCS), cytochrome c oxidase 17 (COX17), and lysyl oxidase (LOX). These chaperones help to regulate Cu uptake, export, and intracellular compartmentalization, and much of these chaperones have been learned from studies on isolated proteins, knockout or mutant mice, and cell culture systems. The expression of genes encoding these proteins is guarded by certain transcriptional regulators known as metalloregulatory proteins (Fry et al 2013, Prohaska and Gybina 2004, Reyes-Caballero et al 2011)

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