Modelling cadmium‐induced cardiotoxicity using human pluripotent stem cell‐derived cardiomyocytes

Shen, Jiaxi; Wang, Xiaochen; Zhou, Danni; Li, Tongyu; Tang, Ling; Gong, Tingyu; Su, Jun; Liang, Ping

doi:10.1111/jcmm.13702

Cited by 39 publications

(24 citation statements)

References 73 publications

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“…Consistent with previous studies, significantly higher levels of reactive oxygen species (ROS) were observed in CdCl 2 treated cells compared with control [44–46]. In addition, hESC-CMs displayed sarcomeric disorganisation and disruption, increased nucleoplasmic ratio and nuclear membrane shrinkage [47]. These results are in concordance with in vivo studies, in which CdCl 2 disrupts cardiac structure and integrity.…”

Section: Cardiotoxicitysupporting

confidence: 89%

Stem cell models as an in vitro model for predictive toxicology

Lynch

Pridgeon

Duckworth

et al. 2019

Biochemical Journal

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Adverse drug reactions (ADRs) are the unintended side effects of drugs. They are categorised as either predictable or unpredictable drug-induced injury and may be exhibited after a single or prolonged exposure to one or multiple compounds. Historically, toxicology studies rely heavily on animal models to understand and characterise the toxicity of novel compounds. However, animal models are imperfect proxies for human toxicity and there have been several high-profile cases of failure of animal models to predict human toxicity e.g. fialuridine, TGN1412 which highlight the need for improved predictive models of human toxicity. As a result, stem cell-derived models are under investigation as potential models for toxicity during early stages of drug development. Stem cells retain the genotype of the individual from which they were derived, offering the opportunity to model the reproducibility of rare phenotypes in vitro. Differentiated 2D stem cell cultures have been investigated as models of hepato- and cardiotoxicity. However, insufficient maturity, particularly in the case of hepatocyte-like cells, means that their widespread use is not currently a feasible method to tackle the complex issues of off-target and often unpredictable toxicity of novel compounds. This review discusses the current state of the art for modelling clinically relevant toxicities, e.g. cardio- and hepatotoxicity, alongside the emerging need for modelling gastrointestinal toxicity and seeks to address whether stem cell technologies are a potential solution to increase the accuracy of ADR predictivity in humans.

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Section: Cardiotoxicitysupporting

confidence: 89%

Stem cell models as an in vitro model for predictive toxicology

Lynch

Pridgeon

Duckworth

et al. 2019

Biochemical Journal

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“…However, Cd is also toxic to other tissues including the heart, lungs, and adipose tissues [ 2 ]. Epidemiologic and preclinical studies show that low to moderate Cd exposure is associated with cardiovascular (CV) dysfunction and disease including arrhythmias [ 3 , 4 ], hypertension [ 5 , 6 ], myocardial infarction [ 7 , 8 ], and heart failure [ 9 – 11 ]. Urine Cd levels are associated with increased CV disease incidence and mortality [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…Cd toxicity to cardiomyocyte (CM) occurs at 100-fold lower dose than reported for hepatic and renal cell toxicity [ 13 ]. Pathological changes in the heart have been reported following Cd exposure, and the underline mechanisms responsible for Cd toxicity in CV disease [ 3 ] and potential preventive strategies have not been fully characterized.…”

Section: Introductionmentioning

confidence: 99%

Zinc protects against cadmium-induced toxicity in neonatal murine engineered cardiac tissues via metallothionein-dependent and independent mechanisms

Zhen

et al. 2019

Acta Pharmacol Sin

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Cadmium (Cd) is a nonessential heavy metal and a prevalent environmental toxin that has been shown to induce significant cardiomyocyte apoptosis in neonatal murine engineered cardiac tissues (ECTs). In contrast, zinc (Zn) is a potent metallothionein (MT) inducer, which plays an important role in protection against Cd toxicity. In this study, we investigated the protective effects of Zn against Cd toxicity in ECTs and explore the underlying mechanisms. ECTs were constructed from neonatal ventricular cells of wild-type (WT) mice and mice with global MT gene deletion (MT-KO). In WT-ECTs, Cd (5−20 μM) caused a dose-dependent toxicity that was detected within 8 h evidenced by suppressed beating, apoptosis, and LDH release; Zn (50−200 μM) dose-dependently induced MT expression in ECTs without causing ECT toxicity; co-treatment of ECT with Zn (50 µM) prevented Cd-induced toxicity. In MT-KO ECTs, Cd toxicity was enhanced; but unexpectedly, cotreatment with Zn provided partial protection against Cd toxicity. Furthermore, Cd, but not Zn, significantly activated Nrf2 and its downstream targets, including HO-1; inhibition of HO-1 by a specific HO-1 inhibitor, ZnPP (10 µM), significantly increased Cd-induced toxicity, but did not inhibit Zn protection against Cd injury, suggesting that Nrf2-mediated HO-1 activation was not required for Zn protective effect. Finally, the ability of Zn to reduce Cd uptake provided an additional MT-independent mechanism for reducing Cd toxicity. Thus, Zn exerts protective effects against Cd toxicity for murine ECTs that are partially MT-mediated. Further studies are required to translate these findings towards clinical trials.

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“…Among the approximately 2000 proteins investigated in this study, four were suggested to be causal for AF with three (DUSP13, IL-6R and TNFSF12) displaying medium to high drug prioritising scores. Studies suggest that DUSP13 gene expression were upregulated after stress stimulation in cardiomyocytes 23 and that TNFSF12 may be related to angiogenesis. 17 Among these proteins, IL-6R showing the highest drug prioritising score of 0.88.…”

Section: Discussionmentioning

confidence: 99%

A phenome-wide multi-directional Mendelian randomization analysis of atrial fibrillation

Wang

Richardson

Sanderson

et al. 2020

Preprint

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Background: The prevalence of atrial fibrillation (AF) is increasing with an aging worldwide population, yet a comprehensive understanding of its causes and consequences remains limited. Objectives: To assess the causes and consequences of AF via a multi-directional Mendelian randomization (MR) analysis scanning thousands of traits in a hypothesis-free approach. Methods: We used publicly available GWAS data centralised and harmonised by the IEU open GWAS database. We assessed the potential causal role of 5048 exposures on risk of AF and the causal role of genetic liability to AF on 10,308 outcomes via two-sample MR analysis. Multivariable MR analysis was further conducted to explore the comparative role of identified risk factors. Results: MR analysis suggested that 55 out of 5048 exposure traits, including four proteins, play a causal role in AF (P < 1e-5 allowing for multiple comparisons). Multivariable analysis suggested that higher body mass index, height, systolic blood pressure as well as genetic liability to coronary artery diseases independently cause AF. Three out of the four proteins (DUSP13, TNFSF12 and IL6R) had a drug prioritising score for atrial fibrillation of 0.26, 0.38 and 0.88, respectively (values closer to 1 indicating stronger evidence of the protein as a potential drug target). Genetic liability to AF was linked to a higher risk of cardioembolic ischemic stroke. Conclusions: Body mass index, height, systolic blood pressure and genetic liability to coronary artery diseases are independent causal risk factors for AF. Several proteins including DUSP13, IL-6R and TNFSF12 may represent therapeutic potential for preventing AF.

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Modelling cadmium‐induced cardiotoxicity using human pluripotent stem cell‐derived cardiomyocytes

Cited by 39 publications

References 73 publications

Stem cell models as an in vitro model for predictive toxicology

Stem cell models as an in vitro model for predictive toxicology

Zinc protects against cadmium-induced toxicity in neonatal murine engineered cardiac tissues via metallothionein-dependent and independent mechanisms

A phenome-wide multi-directional Mendelian randomization analysis of atrial fibrillation

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