Notch1-mediated histone demethylation of HCN4 contributes to aconitine-induced ventricular myocardial dysrhythmia

Zhou, Wei; Qiu, Li-Zhen; Li, Hong; Deng, Huifang; Yue, Lan-Xin; Gao, Yue

doi:10.1016/j.toxlet.2020.03.017

Cited by 9 publications

(11 citation statements)

References 32 publications

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“…Moreover, 21 studies were deleted because the outcome measurement was not of interest. Ultimately, 32 eligible articles ( Liang et al, 1991 ; Meng, 2006 ; Fu, 2007 ; Liu, 2007 ; Wang, 2007 ; Wang et al, 2007 ; Zhang, 2007 ; Xu, 2008 ; Liu, 2009 ; Deng, 2010 ; Fang et al, 2012 ; Zhang et al, 2012 ; Wang, 2013 ; Zhou et al, 2013 ; Sun et al, 2014 ; Yu, 2015 ; Cui et al, 2018 ; Gao, 2018 ; Gao et al, 2018 ; Hu et al, 2018 ; Li et al, 2018 ; Zhang et al, 2018 ; Liu et al, 2019 ; Wang M. et al, 2020 ; Li et al, 2020 ; Peng et al, 2020 ; Zhang et al, 2020 ; Zhou et al, 2020 ; Xia et al, 2021 ; Yang et al, 2021 ; Ye et al, 2021 ; Wang S. et al, 2022 ) were identified for further evaluation, data extraction, and analysis ( Figure 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…Of them, the animals used in three studies ( Liang et al, 1991 ; Zhang et al, 2012 ; Sun et al, 2014 ) comprised Sprague–Dawley (SD) and Wistar rats, and two studies ( Deng, 2010 ; Wang, 2013 ) guinea pigs. The weight of rats ranged from 150 to 350 g, and the weight of guinea pigs ranged from 300 to 350 g. Among which, zebrafish embryos were employed in seven studies ( Fang et al, 2012 ; Cui et al, 2018 ; Liu et al, 2019 ; Wang S. et al, 2020 ; Li et al, 2020 ; Xia et al, 2021 ; Ye et al, 2021 ), H9c2 cell in nine studies ( Gao, 2018 ; Gao et al, 2018 ; Hu et al, 2018 ; Zhang et al, 2018 ; Li et al, 2020 ; Peng et al, 2020 ; Zhang et al, 2020 ; Yang et al, 2021 ; Wang W. et al, 2022 ), primary cardiomyocytes of SD rats in 10 studies ( Meng, 2006 ; Fu, 2007 ; Wang, 2007 ; Wang et al, 2007 ; Zhang, 2007 ; Xu, 2008 ; Liu, 2009 ; Zhou et al, 2013 ; Yu, 2015 ; Li et al, 2018 ), primary cardiomyocytes of Wistar rats in three studies ( Liu, 2007 ; Sun et al, 2014 ; Zhou et al, 2020 ). Meanwhile, three studies chose primary cardiomyocytes of guinea pigs ( Wang, 2013 ) and AC-16 cells ( Cui et al, 2018 ; Zhou et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

“…The weight of rats ranged from 150 to 350 g, and the weight of guinea pigs ranged from 300 to 350 g. Among which, zebrafish embryos were employed in seven studies ( Fang et al, 2012 ; Cui et al, 2018 ; Liu et al, 2019 ; Wang S. et al, 2020 ; Li et al, 2020 ; Xia et al, 2021 ; Ye et al, 2021 ), H9c2 cell in nine studies ( Gao, 2018 ; Gao et al, 2018 ; Hu et al, 2018 ; Zhang et al, 2018 ; Li et al, 2020 ; Peng et al, 2020 ; Zhang et al, 2020 ; Yang et al, 2021 ; Wang W. et al, 2022 ), primary cardiomyocytes of SD rats in 10 studies ( Meng, 2006 ; Fu, 2007 ; Wang, 2007 ; Wang et al, 2007 ; Zhang, 2007 ; Xu, 2008 ; Liu, 2009 ; Zhou et al, 2013 ; Yu, 2015 ; Li et al, 2018 ), primary cardiomyocytes of Wistar rats in three studies ( Liu, 2007 ; Sun et al, 2014 ; Zhou et al, 2020 ). Meanwhile, three studies chose primary cardiomyocytes of guinea pigs ( Wang, 2013 ) and AC-16 cells ( Cui et al, 2018 ; Zhou et al, 2020 ). For the choice of anesthesia in animal experiments, two studies ( Zhang et al, 2012 ; Yu, 2015 ) used chloral hydrate, one study ( Sun et al, 2014 ) ketamine/xylazine, and one study ( Liu et al, 2019 ) MS-222, three studies ( Wang, 2013 ; Zhou et al, 2013 ; Sun et al, 2014 ) pentobarbital, and the rest of studies was not reported.…”

Section: Resultsmentioning

confidence: 99%

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An Updated Meta-Analysis Based on the Preclinical Evidence of Mechanism of Aconitine-Induced Cardiotoxicity

Jiang

Zhang²,

Zhang³

et al. 2022

Front. Pharmacol.

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Background: Most Aconitum species in traditional Chinese medicine have the effect of dispelling wind, dehumidifying, warming the meridian, and relieving pain. Aconitine is the characteristic chemical component with the function of anti-inflammation, analgesic, and heart-strengthening effects. However, improper use will produce cardiotoxicity and neurotoxicity. Currently, the mechanisms of cardiotoxicity caused by aconitine are wheels within wheels without being fully disclosed. The systematic review and meta-analysis were therefore conducted to summarize the available evidence of myocardial toxicity caused by aconitine.Methods: We searched PubMed, Embase, Web of Science, National Knowledge Infrastructure, WANFANG, and VIP information database for relevant preclinical studies. All the data were analyzed by RevMan version 5.3.Results: Thirty-two studies met the final inclusion criteria, including both in vivo and in vitro study types. After aconitine treatment, the heart rate of animals was obviously abnormal, and the morphology and function of myocardial cells were significantly changed. Aconitine can induce changes in the electrophysiological activity of cardiac myocytes by regulating Na+, Ca2+, and K+ currents. Meanwhile, the mechanisms of cardiotoxicity of aconitine may be related to triggering mitochondrial dysfunction by inducing mitochondrial apoptosis and autophagy. It should not be ignored that the overactivation of NLRP3 inflammasome also exacerbates aconitine’s cardiotoxicity.Conclusion: The altered ion channels and mitochondrial function, as well as the signaling pathways interacting with NLRP3, may deserve further study for aconitine-induced cardiotoxicity.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

An Updated Meta-Analysis Based on the Preclinical Evidence of Mechanism of Aconitine-Induced Cardiotoxicity

Jiang

Zhang²,

Zhang³

et al. 2022

Front. Pharmacol.

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“…However, aconitine, as the main effective component of Aconitum , is a diterpenoid alkaloid with severe cardiovascular toxicity, which often induced tachyarrhythmia and hypotension and led to high mortality [ 27 , 28 ]. Previous studies have shown that aconitine has obvious cytotoxicity on cardiomyocytes, which can induce cardiomyocyte injury through various ways, such as BNIP3-dependent mitophagy and TNF- α /NLRP3 signal transduction [ 11 ], Notch1-mediated histone demethylation of HCN4 [ 29 ], mitochondrial pathway [ 30 ], p38 MAPK signal, and Ca 2+ overload [ 9 ]. In the present study, we demonstrated that aconitine could induce H9c2 cardiomyocyte apoptosis and Ca 2+ influx in a dose-dependent manner ( Figure 1 ), and the mechanism might be related to the activation of TRPV2 and p38 MAPK ( Figure 2 ).…”

Section: Discussionmentioning

confidence: 99%

Aconitine Induces TRPV2-Mediated Ca2+ Influx through the p38 MAPK Signal and Promotes Cardiomyocyte Apoptosis

Yang

Zeng

Cheng

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Aconitine is the main effective component of traditional Chinese medicine Aconitum, which has been proved to have severe cardiovascular toxicity. The toxic effect of aconitine on cardiomyocytes is related to intracellular calcium overload, but the mechanism remains unclear. The aim of this study was to explore the mechanism of aconitine inducing intracellular Ca2+ overload and promoting H9c2 cardiomyocyte apoptosis through transient receptor potential cation channel subfamily V member 2 (TRPV2). After treated with different concentrations of aconitine, the level of cell apoptosis, intracellular Ca2+, and expression of p-p38 MAPK and TRPV2 of H9c2 cardiomyocytes were detected. The results showed that aconitine induced Ca2+ influx and H9c2 cardiomyocyte apoptosis in a dose-dependent manner and promoted p38 MAPK activation as well as TRPV2 expression and plasma membrane (PM) metastasis. siTRPV2, tranilast, and SB202190 reversed intracellular Ca2+ overload and H9c2 cardiomyocyte apoptosis induced by aconitine. These results suggested that aconitine promoted TRPV2 expression and PM metastasis through p38 MAPK signaling, thus inducing intracellular Ca2+ overload and cardiomyocyte apoptosis. Furthermore, TRPV2 is a potential molecular target for the treatment of aconitine poisoning.

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“…However, the way of AC regulating the expression of these genes is still not fully elucidated. Our latest study showed that repeated treatment with AC activated Notch1 signaling and induced the formation of NICD/KDM5A transcriptional complex, which participated in the histone demethylation of HCN4 promoter, eventually contributed to the reappearance of HCN4 channel and the enhancement of I f current in cardiomyocytes, and led to AC‐induced ventricular myocardial dysrhythmia, implying that treatment with AC might regulate specific gene expression via triggering epigenetic modification of genomic DNA, and cause undesired cardiotoxic effects 53 …”

Section: Introductionmentioning

confidence: 99%

Cardiac efficacy and toxicity of aconitine: A new frontier for the ancient poison

Zhou¹,

Liu

Qiu

et al. 2021

Medicinal Research Reviews

Self Cite

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Aconitine (AC) is well‐known as the main toxic ingredient and active compound of Aconitum species, of which several aconites are essential herbal medicines of Traditional Chinese Medicine (TCM) and widely applied to treat diverse diseases for their excellent anti‐inflammatory, analgesic, and cardiotonic effects. However, the cardiotoxicity and neurotoxicity of AC attracted a lot of attention and made it a favorite botanic poison in history. Nowadays, the narrow therapeutic window of AC limits the clinical application of AC‐containing herbal medicines; overdosing on AC always induces ventricular tachyarrhythmia and heart arrest, both of which are potentially lethal. But the underlying cardiotoxic mechanisms remained chaos. Recently, beyond its cardiotoxic effects, emerging evidence shows that low doses of AC or its metabolites could generate cardioprotective effects and are necessary to aconite's clinical efficacy. Consistent with TCM's theory that even toxic substances are powerful medicines, AC thus could not be simply identified as a toxicant or a drug. To prevent cardiotoxicity while digging the unique value of AC in cardiac pharmacology, there exists a huge urge to better know the characteristic of AC being a cardiotoxic agent or a potential heart drug. Here, this article reviews the advances of AC metabolism and focuses on the latest mechanistic findings of cardiac efficacy and toxicity of this aconite alkaloid or its metabolites. We also discuss how to prevent AC‐related cardiotoxicity, as well as the issues before the development of AC‐based medicines that should be solved, to provide new insight into the paradoxical nature of this ancient poison.

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Notch1-mediated histone demethylation of HCN4 contributes to aconitine-induced ventricular myocardial dysrhythmia

Cited by 9 publications

References 32 publications

An Updated Meta-Analysis Based on the Preclinical Evidence of Mechanism of Aconitine-Induced Cardiotoxicity

An Updated Meta-Analysis Based on the Preclinical Evidence of Mechanism of Aconitine-Induced Cardiotoxicity

Aconitine Induces TRPV2-Mediated Ca2+ Influx through the p38 MAPK Signal and Promotes Cardiomyocyte Apoptosis

Cardiac efficacy and toxicity of aconitine: A new frontier for the ancient poison

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