Aromatase knockout mice reveal an impact of estrogen on drug-induced alternation of murine electrocardiography parameters

Kurokawa, Junko; Sasano, Tetsuo; Kodama, Motomune; Li, Min; Ebana, Yusuke; Harada, Nobuhiro; Honda, Shin‐ichiro; Nakaya, Haruaki; Furukawa, Tetsushi

doi:10.2131/jts.40.339

Cited by 15 publications

(16 citation statements)

References 42 publications

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“…Our study showed that the heart rate at 21 d in the CDs group was significantly higher than that of the saline group, indicating that CDs had some toxicity in the heart, a result similar to other groups' findings [31,32] . However, the heart rate of the PEG-CDs group was similar to that of the saline group, suggesting the PEGylation could considerably attenuate the heart toxicity of CDs.…”

Section: Discussionsupporting

confidence: 89%

Polyethylene glycol modification decreases the cardiac toxicity of carbonaceous dots in mouse and zebrafish models

et al. 2015

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Aim: Carbonaceous dots (CDs), which have been used for diagnosis, drug delivery and gene delivery, are accumulated in heart at high concentrations. To improve their biocompatibility, polyethylene glycol-modified CDs (PEG-CDs) were prepared. In this study we compared the cardiac toxicity of CDs and PEG-CDs in mouse and zebrafish models. Methods: Mice were intravenously treated with CDs (size: 4.9 nm, 5 mg·kg -1 ·d -1 ) or PEG-CDs (size: 8.3 nm, 5 mg·kg -1 ·d -1 ) for 21 d. Their blood biochemistry indices, ECG, and histological examination were examined for evaluation of cardiac toxicity. CDs or PEG-CDs was added in incubator of cmlc2 transgenic Zebrafish embryos at 6 hpf, and the shape and size of embryos' hearts were observed at 48 hpf using a fluorescent microscope. Furthermore, whole-mount in situ hybridization was used to examine the expression of early cardiac marker gene (clml2) at 48 hpf. Results: Administration of CDs or PEG-CDs in mice caused mild, but statistically insignificant reduction in serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels detected at 7 d, which were returned to the respective control levels at 21 d. Neither CDs nor PEG-CDs caused significant changes in the morphology of heart cells. Administration of CDs, but not PEG-CDs, in mice caused marked increase of heart rate. Both CDs and PEG-CDs did not affect other ECG parameters. In the zebrafish embryos, addition of CDs (20 μg/mL) caused heart development delay, whereas addition of CDs (80 μg/mL) led to heart malformation. In contrast, PEG-CDs caused considerably small changes in heart development, which was consistent with the results from the in situ hybridization experiments. Conclusion: CDs causes greater cardiac toxicity, especially regarding heart development. Polyethylene glycol modification can attenuate the cardiac toxicity of CDs.

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Section: Discussionsupporting

confidence: 89%

Polyethylene glycol modification decreases the cardiac toxicity of carbonaceous dots in mouse and zebrafish models

et al. 2015

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“…Recently, employment of an aromatase knockout mouse as an in vivo estrogen-null model supports the effects of estrogen on cardiac electrophysiology(Kurokawa et al , 2015). The knockout mice were generated by targeted disruption of the CYP19 gene coding aromatase cytochrome P450 (Honda et al , 1998).…”

Section: Estrogenmentioning

confidence: 99%

“…Prolongation of QT c intervals in response to the cumulative administration of E-4031 were compared between late-proestrus female mice (open circles) and aromatase knockout mice (CYP19 KO, closed circles). Modified from(Kurokawa et al , 2015). …”

Section: Figurementioning

confidence: 99%

Sex hormonal regulation of cardiac ion channels in drug-induced QT syndromes

Kurokawa

Kodama

Clancy

et al. 2016

Pharmacology & Therapeutics

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Female sex is an independent risk factor for development of torsade de pointes (TdP) arrhythmias not only in congenital long QT syndromes but also in acquired long QT syndromes. Clinical and experimental evidences suggest that the gender differences may be due to, at least in part, gender differences in regulation of rate-corrected QT (QTC) interval between men and women. In adult women, both QTC interval and arrhythmic risks in TdP alter cyclically during menstrual cycle, suggesting a critical role of female sex hormones in cardiac repolarization process. These gender differences in fundamental cardiac electrophysiology result from variable ion channel expression and diverse sex hormonal regulation via long term genomic and acute non-genomic actions, and sex differences in drug responses and metabolisms. In particular, non-genomic actions of testosterone and progesterone on cardiac ion channels are likely to contribute to the gender differences in cardiac repolarization processes. This review summarizes current knowledge on sex hormonal regulation of cardiac ion channels which contribute to cardiac repolarization processes and its implication for gender differences in drug-induced long QT syndromes.

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“…; Kurokawa et al . ). During the menstrual follicular phase (prior to ovulation), oestrogen level is the highest, QT interval is longer and susceptibility to drug‐induced arrhythmias is increased.…”

Section: Introductionmentioning

confidence: 97%

A multiscale computational modelling approach predicts mechanisms of female sex risk in the setting of arousal‐induced arrhythmias

Yang

Perissinotti

López-Redondo

et al. 2017

The Journal of Physiology

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Key points This study represents a first step toward predicting mechanisms of sex‐based arrhythmias that may lead to important developments in risk stratification and may inform future drug design and screening.We undertook simulations to reveal the conditions (i.e. pacing, drugs, sympathetic stimulation) required for triggering and sustaining reentrant arrhythmias.Using the recently solved cryo‐EM structure for the Eag‐family channel as a template, we revealed potential interactions of oestrogen with the pore loop hERG mutation (G604S).Molecular models suggest that oestrogen and dofetilide blockade can concur simultaneously in the hERG channel pore. AbstractFemale sex is a risk factor for inherited and acquired long‐QT associated torsade de pointes (TdP) arrhythmias, and sympathetic discharge is a major factor in triggering TdP in female long‐QT syndrome patients. We used a combined experimental and computational approach to predict ‘the perfect storm’ of hormone concentration, I Kr block and sympathetic stimulation that induces arrhythmia in females with inherited and acquired long‐QT. More specifically, we developed mathematical models of acquired and inherited long‐QT syndrome in male and female ventricular human myocytes by combining effects of a hormone and a hERG blocker, dofetilide, or hERG mutations. These ‘male’ and ‘female’ model myocytes and tissues then were used to predict how various sex‐based differences underlie arrhythmia risk in the setting of acute sympathetic nervous system discharge. The model predicted increased risk for arrhythmia in females when acute sympathetic nervous system discharge was applied in the settings of both inherited and acquired long‐QT syndrome. Females were predicted to have protection from arrhythmia induction when progesterone is high. Males were protected by the presence of testosterone. Structural modelling points towards two plausible and distinct mechanisms of oestrogen action enhancing torsadogenic effects: oestradiol interaction with hERG mutations in the pore loop containing G604 or with common TdP‐related blockers in the intra‐cavity binding site. Our study presents findings that constitute the first evidence linking structure to function mechanisms underlying female dominance of arousal‐induced arrhythmias.

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Aromatase knockout mice reveal an impact of estrogen on drug-induced alternation of murine electrocardiography parameters

Cited by 15 publications

References 42 publications

Polyethylene glycol modification decreases the cardiac toxicity of carbonaceous dots in mouse and zebrafish models

Polyethylene glycol modification decreases the cardiac toxicity of carbonaceous dots in mouse and zebrafish models

Sex hormonal regulation of cardiac ion channels in drug-induced QT syndromes

A multiscale computational modelling approach predicts mechanisms of female sex risk in the setting of arousal‐induced arrhythmias

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