Restoration of myocellular copper-trafficking proteins and mitochondrial copper enzymes repairs cardiac function in rats with diabetes-evoked heart failure

Zhang, Shaoping; Liu, Hong; Amarsingh, Greeshma Vazhoor; Cheung, Carlos Chun Ho; Wu, Donghai; Narayanan, Umayal; Zhang, Linda; Cooper, Garth J. S.

doi:10.1039/c9mt00223e

Cited by 32 publications

(35 citation statements)

References 56 publications

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“…Furthermore, TNNI3, a gene encoding cardiac sarcomere troponin I protein, was examined as a regulating gene for cardiac proteins necessary for proper assembly of the cardiomyocytes. Changes in TNNI3 are a well-known cause of cardiomyopathy (Mirza et al 2005, Rai et al 2009) and its expression showed down-regulation in cardiac muscles of type2 diabetes (Howarth et al 2011) in which Cu plays an important role in its development due to defective myocellular Cu regulation (Zhang et al 2014, Zhang et al 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Studies revealed that Cu de ciency (CuD) could be a leading cause of adverse cardiac events including ischemic and hypertrophic disorders (DiNicolantonio et al 2018, Li et al 2018, Liu et al 2018. Also, the alteration in the myocardial Cu acquisition mechanism was recently pointed out as the key factor in diabetes-induced heart failure in rats (Zhang et al 2020). Thus, during heart failure, the low level of left ventricular Cu concentration could aggravate the development of cardiac dysfunction due to extensive changes in myo brillar and mitochondrial morphology and distribution (Zhang et al 2014).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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 after copper de ciency (CuD). The current study aimed to investigate the Cu-Ch mRNA expression in goat's heart after experimental CuD and highlight their relationship with the cardiac measurements. Eleven male goats were enrolled and divided into the control group (n = 4) and CuD group (treatment, n = 7), which received copper-reducing dietary regimes (molybdenum and sulfur). Heart function was evaluated by electrocardiography and echocardiography, and at the end of the experiment, all animals were sacri ced, and the cardiac tissues were collected for quantitative mRNA expression by real-time PCR. In the treatment group, cardiac measurements revealed increased preload and the existence of cardiac dilatation and signi cant 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 signi cantly down-regulated in CuD group. Besides, there was a variable signi cant correlation between investigated genes and cardiac measurements; meanwhile, a signi cant 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…Elevated extracellular Cu 2+ in DM cardiomyopathy is likely loosely bound to extracellular matrix components, such as collagens [ 168 , 169 ]. Interestingly, in rodents and humans with DM cardiomyopathy, Cu 2+ -selective chelators, including trientine and triethylenetetramine (TETA) dihydrochloride, prevent excessive cardiac collagen deposition, improve cardiac structure and function, and restore antioxidant defense by promoting copper excretion [ 168 , 174 , 175 , 176 , 177 , 178 ]. Zhang et al reported that the expression of the Ctr1 gene was downregulated in hearts of rats with DM, which is consistent with impaired cardiac copper uptake in DM [ 176 ].…”

Section: Copper Deficiency and Heart Diseasementioning

confidence: 99%

“…These data suggest that TETA normalizes cardiac copper homeostasis and restores cardiac function in DM by restoring expression and localizations of copper transporters and copper-binding proteins. In addition, TETA restores mRNA and protein expression of copper chaperones, including COX11, COX17, CCS, and SOD1 and, thus, restores copper availability and trafficking, and improves cardiac functions in hearts of rats with DM [ 175 ]. Although the highly selective Cu 2+ chelator trientine efficiently treats DM cardiomyopathy, long-term clinical studies are necessary to determine whether the improvement of cardiac function by trientine is associated with long-term benefits for mortality.…”

Section: Copper Deficiency and Heart Diseasementioning

confidence: 99%

An Emerging Role of Defective Copper Metabolism in Heart Disease

Liu

Miao

2022

Nutrients

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Copper is an essential trace metal element that significantly affects human physiology and pathology by regulating various important biological processes, including mitochondrial oxidative phosphorylation, iron mobilization, connective tissue crosslinking, antioxidant defense, melanin synthesis, blood clotting, and neuron peptide maturation. Increasing lines of evidence obtained from studies of cell culture, animals, and human genetics have demonstrated that dysregulation of copper metabolism causes heart disease, which is the leading cause of mortality in the US. Defects of copper homeostasis caused by perturbed regulation of copper chaperones or copper transporters or by copper deficiency resulted in various types of heart disease, including cardiac hypertrophy, heart failure, ischemic heart disease, and diabetes mellitus cardiomyopathy. This review aims to provide a timely summary of the effects of defective copper homeostasis on heart disease and discuss potential underlying molecular mechanisms.

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“…Bioinformatics results have shown that cytochrome c oxidase assembly homologue 11 (COX11) is a target of miR-10a-3p. It participates in metabolism, apoptosis, energy supply, and reactive oxygen production in organisms and plays an important role in cancer and respiratory system diseases (15,16). There is no report on the function of COX11 in MPP.…”

Section: Introductionmentioning

confidence: 99%

The role of targeted regulation of COX11 by miR-10a-3p in the development and progression of paediatric mycoplasma pneumoniae pneumonia

Ding¹,

Zhao²,

Xiong³

et al. 2021

J Thorac Dis

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Background: MiR-10a-3p is associated with the pathogenesis of many immune inflammatory diseases including Mycoplasma pneumoniae pneumonia (MPP), and cytochrome coxidase assembly homologue 11 (COX11) is one of its direct target proteins. This study investigates the function and mechanism of miR-10a-3p targeting with COX11 in the development and progression of paediatric MPP. Methods: Ninty-seven paediatric MPP patients and 100 age-and sex-matched healthy children were enrolled. Clinical and laboratory indicators of paediatric MPP patients were collected. The mRNA levels of the COX11 gene and miR-10a-3p were detected by qRT-PCR. THP-1 mononuclear macrophages were stimulated using MPP lipid-associated membrane proteins (Mp-LAMPs). The relative expression level of miR-10a-3p was detected after 12, 24, and 48 h. THP-1 cells were transfected to overexpress or inhibit the expression of miR-10a-3p, miR-10a-3p, COX11 mRNA, NF-κB signalling pathway-related proteins, and C-reactive protein (CRP) were detected after 48 h by Western blot. Results:The relative expression level of miR-10a-3p in the MPP group was 2.38±0.52, compared with 1.76±0.38 in control group (t=4.584, P<0.001) whileCOX11 in MPP group was 3.70±1.12, compared to 5.78±1.84 in control group (t=4.876, P<0.001). Pearson correlation analysis showed that miR-10a-3p and COX11 in MPP group presented a negative correlation (r=-0.679, P<0.001). By searching in the prediction website of TargetScan database, it was found that miR-10a-3p and Cox11 genes had targeted regulatory binding sites, and the targeting relationship between miR-10a-3p and Cox11 genes was confirmed by dual luciferase reporting assay in 293T cells. Among paediatric MPP patients, miR-10a-3p expression had a positive correlation with the white blood cells count, erythrocyte sedimentation rate (ESR), and CRP expression, while COX11 mRNA expression had a positive correlation with ESR and CRP. After LAMP stimulation, the miR-10a-3p expression level in THP-1 cells significantly increased (P<0.05). After THP-1 cells were transfected with the miR-10a-3p mimic or inhibitor, the relative expression level of miR-10a-3p significantly increased or decreased, respectively. COX11 expression in the mimic group significantly decreased, whereas COX11 in the inhibitor group significantly increased (both P<0.05). In addition, after transfection, IκBα expression significantly decreased and that of p-IKKα/β, p-p65, and CRP significantly increased in the mimic group, and the opposite was true in the inhibitor group. Conclusions:In paediatric MPP, increased miR-10a-3p downregulated COX11, activating NF-κB signalling pathway to promote disease development and progression.Li et al. miR-10a-3p targets COX11 leading paediatric MPP progression

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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.

Cited by 32 publications

References 56 publications

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

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

An Emerging Role of Defective Copper Metabolism in Heart Disease

The role of targeted regulation of COX11 by miR-10a-3p in the development and progression of paediatric mycoplasma pneumoniae pneumonia

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