Mutation of the Na+/K+-ATPase Atp1a1a.1 causes QT interval prolongation and bradycardia in zebrafish

Pott, Alexander; Bock, Sarah; Berger, Ina M.; Frese, Karen; Dahme, Tillman; Keßler, Mirjam; Rinné, Susanne; Decher, Niels; Just, Steffen; Rottbauer, Wolfgang

doi:10.1016/j.yjmcc.2018.05.005

Cited by 22 publications

(22 citation statements)

References 76 publications

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“…Remarkably, about 70% of genes identified in the human reference genome have at least one obvious zebrafish orthologue and CVD associated genes in humans are conserved to a great extent compared to orthologous zebrafish genes [34,[43][44][45]. Hence, it comes as no surprise that a broad range of standard cardiovascular drugs for humans used in daily clinical practice has analogous effects on zebrafish heart and vessels underlining the usage of the zebrafish as an important animal model in cardiovascular research (Table 1) [26,[46][47][48][49][50][51][52][53][54].…”

Section: Modeling Human Cardiovascular Disorders Using the Zebrafishmentioning

confidence: 99%

“…Whereas in the beginnings of zebrafish research, developmental biology studies had priority [40,[56][57][58][59][60], more and more, the ability to model essential features of human cardiac disorders moved into the center of attraction [51,[61][62][63][64][65]. Since early development of zebrafish embryos does not require proper blood circulation, this model organism is amenable to a broad range of functional genomic approaches including forward genetics by e.g.…”

Section: Modeling Human Cardiovascular Disorders Using the Zebrafishmentioning

confidence: 99%

“…Based on zebrafish transparency during embryogenesis functional impact on zebrafish cardiovascular system after genome/gene editing can be easily evaluated via simple light microscopy. Using innovative functional genomic approaches several important key molecules regulating cardiac pump function and rhythm were identified leading to a more in-depth understanding of important human cardiac disorders such as cardiomyopathies, arrhythmias or heart failure [38,51,63,64,70] Large forward genetic screens led to the identification of numerous zebrafish mutants with heart defects resembling severe human cardiac pathologies such as cardiomyopathies, valvular defects, arrhythmias and heart failure [57]. Genetic analyses by positional cloning of these mutants identified known and novel genes and molecular pathways of cardiovascular disease and demonstrated the validity of the zebrafish to simulate and model human cardiovascular diseases as well as to dissect the molecular pathomechanisms of human CVD (selected zebrafish mutants see Table 2).…”

Section: Modeling Human Cardiovascular Disorders Using the Zebrafishmentioning

confidence: 99%

“…Very recently, a candidate gene identified from a human genome-wide association study (GWAS) evaluating the genetic background of myocardial repolarization was mechanistically elucidated on genetic and molecular level by using the zebrafish mutant hiphop (hip), containing a missense mutation in the Na + /K + -ATPase gene [51,118]. Despite Na + /K + -ATPase is a well-known transmembrane ion pump crucial for cellular electrophysiology its impact on myocardial repolarization remained largely unclear [119].…”

Section: Modeling Human Cardiovascular Disorders Using the Zebrafishmentioning

confidence: 99%

“…Nevertheless, novel approaches including artificial intelligence (AI) and neural network advancements are promising strategies to fill the current gaps thereby enabling streamlined cardiovascular drug discovery [137]. [14] and [51] with permission of Bentham Science Publishers and Elsevier, respectively).…”

Section: Using Automated Screening Strategies For Streamlining Drug Dmentioning

confidence: 99%

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Streamlining drug discovery assays for cardiovascular disease using zebrafish

Pott

Rottbauer

Just

2019

Expert Opinion on Drug Discovery

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Introduction: In the last decade, our armamentarium of cardiovascular drug therapy has expanded significantly. Using innovative functional genomics strategies such as genome editing by CRISPR/Cas9 as well as high-throughput assays to identify bioactive small chemical compounds has significantly facilitated elaboration of the underlying pathomechanism in various cardiovascular diseases. However, despite scientific progress approvals for cardiovascular drugs has stagnated significantly compared to other fields of drug discovery and therapy during the past years. Areas covered: In this review, the authors discuss the aspects and pitfalls during the early phase of cardiovascular drug discovery and describe the advantages of zebrafish as an in vivo organism to model human cardiovascular diseases (CVD) as well as an in vivo platform for high-throughput chemical compound screening. They also highlight the emerging, promising techniques of automated read-out systems during high-throughput screening (HTS) for the evaluation of important cardiac functional parameters in zebrafish with the potential to streamline CVD drug discovery. Expert opinion: The successful identification of novel drugs to treat CVD is a major challenge in modern biomedical and clinical research. In this context, the definition of the etiologic fundamentals of human cardiovascular diseases is the prerequisite for an efficient and straightforward drug discovery.

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Section: Modeling Human Cardiovascular Disorders Using the Zebrafishmentioning

confidence: 99%

Section: Modeling Human Cardiovascular Disorders Using the Zebrafishmentioning

confidence: 99%

Section: Modeling Human Cardiovascular Disorders Using the Zebrafishmentioning

confidence: 99%

Section: Modeling Human Cardiovascular Disorders Using the Zebrafishmentioning

confidence: 99%

Section: Using Automated Screening Strategies For Streamlining Drug Dmentioning

confidence: 99%

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Streamlining drug discovery assays for cardiovascular disease using zebrafish

Pott

Rottbauer

Just

2019

Expert Opinion on Drug Discovery

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Graphene oxide quantum dot exposure induces abnormalities in locomotor activities and mechanisms in zebrafish (Danio rerio)

Yan

Chen

Zuo

et al. 2020

J of Applied Toxicology

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Graphene oxide quantum dots (GOQDs) have broad applications such as bioimaging and drug delivery, among others, even expanding into the aquatic environment. However, reports on the adverse effects of GOQDs on fish development are limited. In this study, we exposed zebrafish embryos to GOQDs for 7 days after fertilization and found that GOQDs exposure at low concentrations (12.5, 25, 50 or 100 μg/L) decreased the total distance and the mean velocity of larvae movement. Additionally, the GOQDs significantly reduced the enzyme activity related to energy supply and locomotor capacity, including Ca2+‐ATPase in the 12.5, 25, 50 and 100 μg/L GOQDs groups and Na+/K+‐ATPase in the 25 and 50 μg/L GOQDs groups. Moreover, GOQD exposure altered the mRNA expression of genes involved in energy supply and calcium transport. The levels of the atp2a2b, atp2a1, and cacna1sb genes were significantly downregulated in the 25, 50 and 100 μg/L GOQDs groups, and ryr3 expression was significantly reduced in the 25 and 50 μg/L GOQDs groups. The expression level of cacna1c was significantly upregulated in the 50 and 100 μg/L GOQDs groups. In summary, GOQD exposure induced a decrease in locomotor capacity in zebrafish, which may be due to the reduction of Ca2+‐ATPase and Na+/K+‐ATPase activity levels, and dysregulated expression of the genes involved in energy metabolism and calcium transport. Our study provides novel insight into the effects of GOQDs on the embryonic development of fish, which will be useful for the development of environment‐friendly GOQDs that reduce the potential hazard to aquatic species.

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Cardiotoxicity of (−)‐borneol, (+)‐borneol, and isoborneol in zebrafish embryos is associated with Na⁺/K⁺‐ATPase and Ca²⁺‐ATPase inhibition

Yin

et al. 2022

J of Applied Toxicology

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Borneol is an example of traditional Chinese medicine widely used in Asia. There are different isomers of chiral borneol in the market, but its toxicity and effects need further study. In this study, we used zebrafish embryos to examine the effects of exposure to three isomers of borneol [(À)-borneol, (+)-borneol, and isoborneol] on heart development and the association with Na + /K + -ATPase from 4 h postfertilization (4 hpf). The results showed that the three isomers of borneol increased mortality and decreased hatching rate when the zebrafish embryo developed to 72 hpf. All three isomers of borneol (0.01-1.0 mM) significantly reduced heart rate from 48 to 120 hpf and reduced the expression of genes related to Ca 2+ -ATPase (cacna1ab and cacna1da) and Na + /K + -ATPase (atp1b2b, atp1a3b, and atp1a2).At the same time, the three isomers of borneol significantly reduced the activities of Ca 2+ -ATPase and Na + /K + -ATPase at 0.1 to 1.0 mM. (+)-Borneol caused the most significant reduction (p < 0.05), followed by isoborneol and (À)-borneol. Na + /K + -ATPase was mainly expressed in otic vesicles and protonephridium. All three isomers of borneol reduced Na + /K + -ATPase mRNA expression, but isoborneol was the most significant (p < 0.01). Our results indicated that (+)-borneol was the least toxic of the three isomers while the isoborneol showed the most substantial toxic effect, closely related to effects on Na + /K + -ATPase.

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Mutation of the Na+/K+-ATPase Atp1a1a.1 causes QT interval prolongation and bradycardia in zebrafish

Cited by 22 publications

References 76 publications

Streamlining drug discovery assays for cardiovascular disease using zebrafish

Streamlining drug discovery assays for cardiovascular disease using zebrafish

Graphene oxide quantum dot exposure induces abnormalities in locomotor activities and mechanisms in zebrafish (Danio rerio)

Cardiotoxicity of (−)‐borneol, (+)‐borneol, and isoborneol in zebrafish embryos is associated with Na⁺/K⁺‐ATPase and Ca²⁺‐ATPase inhibition

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Mutation of the Na+/K+-ATPase Atp1a1a.1 causes QT interval prolongation and bradycardia in zebrafish

Cited by 22 publications

References 76 publications

Streamlining drug discovery assays for cardiovascular disease using zebrafish

Streamlining drug discovery assays for cardiovascular disease using zebrafish

Graphene oxide quantum dot exposure induces abnormalities in locomotor activities and mechanisms in zebrafish (Danio rerio)

Cardiotoxicity of (−)‐borneol, (+)‐borneol, and isoborneol in zebrafish embryos is associated with Na+/K+‐ATPase and Ca2+‐ATPase inhibition

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Cardiotoxicity of (−)‐borneol, (+)‐borneol, and isoborneol in zebrafish embryos is associated with Na⁺/K⁺‐ATPase and Ca²⁺‐ATPase inhibition